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Effect of B Vitamins from Diet on Hypertension
Archives of Medical Research 48 (2017) 187e194
ORIGINAL ARTICLE
Effect of B Vitamins from Diet on Hypertension Ruru Liu,a,b Baibing Mi,a Yaling Zhao,a Qiang Li,a Hong Yan,a,* and Shaonong Danga,* a
Xi’an JiaoTong University, Health Science Center, bXi’an Center for Disease Control and Prevention, Xi’an, Shaanxi Province, China Received for publication May 15, 2016; accepted February 16, 2017 (ARCMED-D-16-00288).
Background. In western populations, a higher level of dietary B vitamins intake has been associated with a lower risk of hypertension. However, data in Chinese is limited, whose B vitamins consumption is low and rates of hypertension are high. Aim of the Study. To investigate whether the three B vitamins are associated with hypertension in rural Chinese. Methods. Cross-sectional survey among 2241 rural Chinese aged 18e80 years was conducted in northwestern China in 2010. Blood pressure was measured by trained medical staff and dietary nutrients were assessed with a semiquantitative food frequency questionnaire. Results. 592 cases of hypertension were newly diagnosed. The deficiency proportions were 20.5% for vitamin B-6, 43.9% for folate and 98.5% for B-12. For females, participants in the highest quartile of B-6 intake had a significantly lower risk of hypertension (OR 5 0.69; 95% CI: 0.50e0.93; p for trend !0.05). For males, the multivariable OR for the same comparison was 0.75 (95% CI: 0.56e0.99, p for trend O0.05). No significant associations were observed between B-12, folate intake and hypertension. For females, the highest quartile of both folate and B-6 intake was associated with a reduced risk of hypertension (OR 5 0.53; 95% CI: 0.29e0.89), compared with in the middle quartile of both vitamins. Conclusions. Higher intake of vitamin B-6 is independently associated with lower risk of hypertension in Chinese rural adults. Among females with high folate intake, the association between B-6 and hypertension was strongest. Additional studies are warrant to establish the causal inference. Ó 2017 IMSS Published by Elsevier Inc Key Words: Dietary B vitamins, Micro-nutrition status, Hypertension, Rural Chinese adults, Logbinomial regression.
Introduction Hypertension contributes to the burden of stroke, heart disease, kidney failure, disability and mortality. It disproportionately affects populations in low- and middleincome countries where health systems are weak (1). Thus, it was essentially important for promoting public health by *
These authors contributed equally to this work. Address reprint requests to: Hong Yan, Xi’an Jiaotong University, Health Science Center, Xi’an, Shaanxi Province, 710054, China; Tel: 0086-29-82655001; E-mail: [email protected]; Shaonong Dang, Xi’an Jiaotong University, Health Science Center, Xi’an, Shaanxi Province, 710054, China; Tel: 0086-29-82655104 ext 207; Fax:0086-29-82655730; E-mail: [email protected].
identifying risk factors for hypertension and leading to specific preventive interventions. Numerous studies supported the beneficial effect of B vitamins on decreasing blood pressure or incident hypertension (2e4), although the role of B vitamins in the development of cardiovascular disease was controversial, as some large prospective trial did not find the significant association between them (5,6). And what we should bear in mind was that these trial prevention studies focused on the risk reduction of CVD after short-term intervention in highrisk participants, and thus these results cannot be generalized to the overall population (7). Furthermore, it is possible that B-vitamins treatment may prove more effective in individuals without established vascular
0188-4409/$ - see front matter. Copyright Ó 2017 IMSS Published by Elsevier Inc http://dx.doi.org/10.1016/j.arcmed.2017.03.011
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Liu et al./ Archives of Medical Research 48 (2017) 187e194
disease, as a recent meta-analysis of clinical trial data suggested that the incidence of new ischemic stroke was significantly reduced by B-vitamin supplementation while recurrent stroke is not (8). However, uncertainty remains regarding the relationship between these B vitamins from diet with prevalence of hypertension in overall population, especially in rural Chinese. In addition, most previous studies focused on serum B vitamins or supplement with B vitamins but did not examine the interaction of these dietary B vitamins. Therefore, in the current study, we examine dietary intake of vitamin B-6, folate and B-12 in association with risk of hypertension in rural adults of western China, whose diet characterized by low caloric and unbalanced diet pattern.
Methods Study Design and Participants This cross-sectional survey was designed to investigate the prevalence of hypertension and its related risk factors among rural adults aged 18e80 years living in Hanzhong of Shaanxi province in 2010. Using face-to-face interviews, we collected demographic characteristics, history of disease, physical activity and lifestyle. Details of the survey methods were published previously (9). Informed written consent was obtained from each participant prior to participation. The protocol was approved by the Ethics Review Committee, School of Medicine, Xi’an Jiaotong University (Number: 2002001). Totally 3021 participants were investigated. In the current study, some persons were excluded due to stroke (n 5 211) and diabetes (n 5 127) as well as hyperlipidemia (n 5 333), those who reported taking antihypertensive medication (n 5 328), missing data on blood pressure (n 5 20), missing data on food frequency questionnaire (FFQ) (n 5 84), and implausible total energy intake (beyond three standard deviation (SD) from the sexspecific loge-transformed mean caloric intake) (n 5 24) (10). Finally, 2241 participants (774 men and 1467 women) remained for the final analysis. Assessment of B Vitamins Intake Dietary information was assessed through intervieweradministered semiquantitative Food-frequency questionnaire. Validity and reproducibility of the questionnaire have been evaluated and discussed elsewhere (9,11). Respondents were asked to report their frequency and amount of food consumption during the previous 12 months with the assistance of images of a food portion (11,12). General questions about their diet were asked, which elicited specific foods consumed in an open-ended fashion (13). They were also asked to recall the frequency, amount of food consumption for each item named. Nutrient intake was loge-transformed
and caloric-adjusted to 2100 kcal/d for male and 1700 kcal/d for female by the residual method, when the associations between B vitamins and hypertension were examined (14). Vitamin B-6 intake deficiency was defined as lower than 1.0 mg/d of vitamin B-6 for individual aged 18e59 years, 1.2 mg/d for ones over 60 years. Folate and B-12 intake deficiency was defined as lower than 320 mg/ d of folate and 2 mg/d of B-12 for all age. Outcome Assessment Participants were informed of keeping fasted for $8h and avoiding heavy physical activity before medical examination. Blood pressure was measured on the right arm of participants at 1 min intervals after a 5 min rest. Systolic and diastolic blood pressure were recorded as phase I and V Korotkoff sounds. The mean of two measurements was used for analysis. Hypertension was defined according to the Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) cutoff as systolic blood pressure $140 mmHg and/or a diastolic BP $90 mmHg, or the use of antihypertensive medications. Ascertainment of Other Covariates Standardized interview questionnaire was used to assess demographic (age, gender, marital status, education, history of disease) and lifestyle (physical activity and smoking) information. Education was represented as the total years of schooling, which was classified into primary school (school years #6), secondary school (6e9 school years) and senior school and higher education (school years $9) (9). Physical activity was assessed by the lifestyle questionnaire. Participants were asked to report frequency and time spent in leisure, house hold physical activity and farming over the previous 12 months. Intensity score was assessed by metabolic equivalent (MET) multiplied by duration and frequency of the activity converted to per week unit. This MET h/week value was summed for each participant according to the number of physical activities elicited, participants who did not elicit any activity were given a score of zero (15). This continuous score was categorized as ‘‘0e! 5’’, ‘‘5e10’’ and ‘‘O10’’ refer to low, moderate and high intensity. Cigarette smoking was categorized as never, former or current; the current smokers were further classified to 2 categories (!15cigarettes/day, $15cigarettes/day) according to average daily cigarette consumption. Statistical Analysis Principal component analysis (PCA) was used to establish a fortune index to estimate economic status of the subjects. Further, in order to avoid multi-collinearity of nutrients (16), two nutrient principal components were drawn based on all potential nutrients by PCA, which explained 70% of
B Vitamins and Hypertension in Rural Chinese
189
Table 1. Participants characteristic across quartiles of B-vitamins intakea Male Vitamin B-6
Quartile1 Age, years Prevalence of hypertension, % SBP, mm Hg DBP, mm Hg Married, % BMI, kg/m2 Schooling year O9 years, % Family history of hypertension, % Fortune index, % Poor Moderate Rich Current smoker, % Alcohol, g/d Physical activity, high intensity, % Nutrient intakeb Energy, kcal/d Saturated fatty acid, g/d Monounsaturated fatty acid, g/d Polyunsaturated fatty acid, g/d Vitamin B-2, mg/d Vitamin B-6, mg/d Folate, mg/d Vitamin B-12, mg/d Sodium, g/d
Female
Folate
Vitamin B-12
Vitamin B-6
Folate
Vitamin B-12
Quartile Quartile Quartile Quartile Quartile Quartile 4 Quartile1 4 Quartile1 4 Quartile1 4 Quartile1 4 Quartile1 4
51.7 36.8
46.7 25.9
48.9 27.5
51.1 30.1
48.9 27.5
50.1 24.9
50.3 28.1
44.2 18
48.1 29.8
47.1 19.9
47.4 22.1
48.2 27
133.1 81.1 88.1 22.2 18.1
128.1 79.3 94.8 22.6 21.8
129.6 79.6 92.2 22.2 17.6
130 79 93.3 22.8 12.4
129 80.4 89.6 22.5 14
127.7 78 95.3 22.5 18.1
129.7 77.5 89.1 22.4 7.6
123.4 75.9 96.7 22.6 10.4
128.7 77.8 92.9 22.4 7.9
127.7 76.8 91.6 22.5 8.8
126.5 77.4 94.5 22.6 7.7
128.9 77.3 90.7 22.5 8
27.5
34.2
30.1
30.6
30
29
25.9
32.4
32
31.1
24.5
32
45.1 29.3 25.5 39.4 5 25.9
22 35.6 42.4 37.4 8.1 23.8
34.1 29.7 36.3 51.8 8.7 25.4
32.1 35.3 32.6 47.7 7.1 23.3
29.9 32.2 37.9 15.5 7.1 15.5
30.6 32.1 37 19.4 8.7 31.1
43.5 27.3 29.1 1.1 2.1 16.9
18 29.4 52.6 0 1.7 22.1
29.1 34.3 36.6 0.3 2.5 15.8
33.2 26.9 39.9 0.3 1.3 21.5
34.4 32.8 32.8 0.3 0.4 12
28.5 34.4 37.1 1.4 1.9 18.3
2308.8 14.3
2248.9 21.6
2109.2 18.8
2114.6 15.6
2853.2 17.1
2113.2 17.9
1781.9 12.7
1741,5 17.2
1712.1 15.6
1708.7 13.1
2131.5 14.2
1757 14.5
20.9
19.6
22.5
17.8
20.6
19
18.3
17.7
20
16
18.5
16.9
38.7
45.8
47
34.6
41.5
38.9
35.8
40.2
42
32.1
38.1
34.7
428 1.1 0.3 0.8 6665.3
422.2 8.9 0.2 0.9 4718.5
640.1 4 0.6 1.1 4831.2
428.5 4.2 0.9 0.8 5598.1
446.6 4.5 5.7 0.9 5411.9
348.5 0.7 0.2 0.6 6223.2
354.9 5.9 0.1 0.7 4940.4
563.8 2.7 0.2 0.9 5140.5
351.9 2.6 0.1 0.6 4615.7
361.1 2.9 0.5 0.7 5040
248.5 3.9 0.2 0.6 6325.5
194.2 2.4 0.2 0.4 6370.7
a
Values are mean or %. Adjusted for total calorie intake, except energy daily intake.
b
total variance. A detailed description of this methodological issue was already provided (9). Log-binomial regression models were used to evaluate the associations of dietary B vitamins with the occurrence of hypertension. Odd ratios (ORs) for hypertension and their 95% confidence intervals (CIs) were estimated by comparing the prevalence of hypertension in particular dietary intake quartiles with that of the lowest one. A sequential covariateadjusted strategy was used in the analysis. Model 1 adjusted for age, education, family history of hypertension, fortune index, physical activity level, alcohol and smoking. Model 2 adjusted for the variables in model 1 plus BMI, sodium and the two nutrient principal components. The linear trend test across quartiles was evaluated by using the median value of each quartile as a single continuous variable and entering it in the regression model. We also examine the association between B vitamins intake and SBP/DBP by multiple linear
regression models. We further explore the interaction by estimating ORs of hypertension according to categories of combined any two of the three B vitamins. The lowest quartile was defined as ‘low’, the highest quartile as ‘high’. And the other two quartiles as ‘normal’. We combined ‘low’, ‘normal ‘or ‘high’ of any of the three B vitamins. The combination of normal categories was used as the reference group. All analyses were performed separately for gender, given the significant sex B vitamins interaction in regression models. Statistical analysis system 9.1 (SAS Institute, Cary, NC, USA) was used. Two-sided tests were used and p !0.05 was considered statistically significant. Results Baseline characteristics, lifestyle and nutrient intake were described according to highest and lowest quartiles of B
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vitamins intake in Table 1. Men with higher folate intake were likely to be older, higher proportions of hypertension, less educated and noncurrent smoker; on the other hand, men with higher intake of B-6 showed diverse characteristics, respectively. Compared with women in the lowest quartile of folate and B-6, those in the highest quartile were more likely younger, better educated and richer, exercise more and drink less. Also, the three B vitamins were positively associated with saturated fatty acid and B-2 consumption, while inversely associated with polyunsaturated fatty acid and sodium intake. As illustrated in Table 2, median dietary B vitamins intake was 2.3 mg/d of B-6 (1.3e4.2), 344.7 mg/d of folate (258.0e464.5 mg/d) and 0.1 mg/d of B-12 (0.1e1.0) in the overall population. The deficiency rate of folate and low B-6 intake were 50.0% and 25.1% in female, significantly higher than that in male (32.2%, p !0.001; 11.8%, p ! 0.001). 98.5% of participants were insufficient of B-12 intake. Table 3 presented ORs for hypertension according to quartiles of B vitamins consumption by gender from 3 adjusted-models. For males, no significant associations were found between three B vitamins and risk of hypertension. Males in the highest quartile of B-6 intake have a relatively lower risk of hypertension (OR 5 0.75, 95% CI: 0.56e0.99, p for trend 5 0.094), compared with those in the lowest quartile after adjustment for potential confounders (model 2). For females, the prevalence of hypertension was reduced by 36% in participants in the highest quartile compared with those in the lowest quartile of dietary B-6 intake (OR 5 0.64; 95% CI: 0.44e0.83; p for trend !0.001). When further adjusted for demographic, lifestyle and dietary factors, the inverse association was essentially unchanged (OR 5 0.69; 95% CI: 0.50e0.93; p for
Table 2. Daily B vitamins intake of the participants B-6 (mg/d)b RNIsa Overall Median Q2eQ4 Rate of deficiency (%) Male Median Q2eQ4 Rate of deficiency (%) Female Median Q2eQ4 Rate of deficiency (%) a
Folate (mg/d)
B-12 (mg/d)
400.0
2.0
2.3 1.3e4.2 20.5
344.7 258.0e464.5 43.9
0.1 0.1e1.0 98.5
3.1 1.8e5.8 11.8
391.8 311.5e510.6 32.3
1.1 1.0e1.2 97.9
2.0 1.1e3.6 50.0
316.4 239.4e440.9 25.1
0.0 0.0e0.1 98.8
1.2/1.5
Discussion
RNIs refer to recommended dietary nutrient intakes of Chinese. RNIs for vitamin B-6 were provided by age. 1.2 mg/d of vitamin B-6 for individual aged 18e59 years, 1.5 mg/d for individual 64 over 60 years. b
trend 5 0.014). In the age- and energy-adjusted model, folate intake was significantly associated with lower risk of hypertension ( p for trend 5 0.0458). However, the association become weak and insignificant after adjusted for potential confounders ( p for trend 5 0.4982). As shown in Table 4, the interaction between the three B vitamins was estimated by Log-binomial regression models. The OR was 0.53 (95% CI: 0.29e0.89) among women in the highest quartile of both folate and vitamin B6 intake compared with the normal group. Risk of hypertension was reduced among those with higher dietary intake of vitamin B6 and normal intake of folate (OR 5 0.59, 95% CI: 0.39e0.87). No significant interaction of the three B vitamins was observed among males. To explore whether interaction between vitamin B6 and estrogen status existed, a stratified analysis by menopausal status was conducted. The multivariate-adjusted OR were 0.53 (95% CI: 0.30e0.95) among premenopausal women and 0.68 (95% CI: 0.39e1.18) among postmenopausal women compared fourth quartile with the first quartile. Significant interaction was observed between menopausal status and vitamin B6 intake ( pinteraction !0.001, data not shown). For females, the association between blood pressure and the B vitamins was also examined (Table 5). B-6 was inversely associated with systolic blood pressure in females. After controlling potential confounders (model 2), One standard deviation increment of B-6 resulted in a decrease of 1.234 mmHg ( 1.234, 95% CI: 2.291 to 0.181; p value 5 0.022). No significant association was observed between B vitamins and diastolic blood pressure. The main food sources of vitamin B6 were cereals (21.1%), potatoes (29.6%), leafy green vegetables (21.5%) and red meat (11.2%) in this study. And the associations between these food and blood pressure were future explored. Dietary cereal intake was positively related to SBP and DBP, independent of demographic and behavior characteristics (b 5 0.007, p 5 0.037; b 5 0.005, p 5 0.010, respectively). The other three foods were not associated with blood pressure ( p valueO0.05) (Data not shown).
The present study demonstrated the inverse association between vitamin B-6 and risk of hypertension in females with worse B vitamin status, and the inverse association was stronger in a higher consumption of both B-6 and folate than any other category. The inverse association was supported by significant reduction of SBP with increasing B-6 in females. The results persisted after controlling for many potential confounders in our study, also we found that the beneficial effect of vitamin B-6 was stronger in premenopausal women. However, they still need be confirmed in large prospective or randomized control trial studies.
B Vitamins and Hypertension in Rural Chinese
191
Table 3. Multivariable ORs of hypertension by quartile of B-vitamins intake Male
Q1 Vitamin B-6 Median intake, mg/d No. of cases PR (95% CI) Age/energy-adjusted
Q2
Q3
Q4
1.6 71
2.4 51
4.3 56
7.9 50
1.0
0.69 (0.51e0.94) 0.74 (0.54e1.00) 0.75 (0.55e0.99)
0.77 (0.57e1.03) 0.85 (0.62e1.15) 0.84 (0.62e1.12)
0.70 (0.51e0.94) 0.75 (0.55e1.02) 0.75 (0.56e0.99)
351.4 53
439.5 64
598.3 58
0.99 (0.72e1.38) 0.98 (0.71e1.34) 1.02 (0.73e1.44)
1.20 (0.89e1.64) 1.17 (0.87e1.57) 1.23 (0.90e1.68)
1.09 (0.80e1.50) 1.00 (0.74e1.37) 1.14 (0.83e1.58)
1.0e1.06 62
1.06e1.19 65
O1.19 48
1.21 (0.74e1.97) 1.31 (0.79e2.19) 1.37 (0.79e2.37)
1.29 (0.78e2.12) 1.45 (0.86e2.44) 1.40 (0.80e2.45)
0.85 (0.52e1.39) 0.90 (0.54e1.51) 0.81 (0.46e1.42)
Model 1a
1.0
Model 2b
1.0
Folate Median intake, mg/d No. of cases PR (95% CI) Age/energy-adjusted
249.6 53 1.0
Model 1a
1.0
Model 2b
1.0
Vitamin B-12c Median intake, mg/d No. of cases PR (95% CI) Age/energy-adjusted
Female
!1.0 53 1.0
Model 1a
1.0
Model 2b
1.0
p for trend
Q1
Q2
Q3
Q4
0.8 103
1.6 97
2.6 98
5.1 66
0.93 (0.74e1.18) 0.97 (0.76e1.24) 0.97 (0.76e1.24)
0.94 (0.74e1.19) 1.00 (0.78e1.27) 1.01 (0.79e1.30)
0.64 (0.44e0.83) 0.66 (0.49e0.89) 0.69 (0.50e0.93)
278.5 95
367.0 80
530.4 87
0.86 (0.60e1.23) 0.88 (0.61e1.28) 0.87 (0.58e1.30)
0.69 (0.47e1.01) 0.67 (0.45e0.99) 0.65 (0.39e1.11)
0.76 (0.53e1.08) 0.77 (0.53e1.12) 0.73 (0.35e1.53)
0e0.03 90
0.03e0.10 94
O0.10 99
0.98 (0.67e1.43) 0.93 (0.61e1.44) 0.94 (0.60e1.47)
1.08 (0.75e1.55) 1.10 (0.72e1.66) 1.11 (0.72e1.71)
1.20 (0.85e1.71) 1.09 (0.72e1.64) 1.14 (0.74e1.74)
0.082
1.0
0.205
1.0
0.094
1.0
201.1 102 0.426
1.0
0.832
1.0
0.317
1.0
0 81 0.285
1.0
0.172
1.0
0.122
1.0
p for trend
!0.001 0.006 0.014
0.0458 0.0605 0.4982
0.613 0.801 0.749
BMI, body mass index; CI, confidence interval; PR, prevalence ratio. a Model 1: adjusted for age, energy, education, family history of hypertension, fortune index, physical activity level, alcohol and smoking. b Model 2: Model 1 further adjusted for BMI, sodium and the two nutrient principal components. Additionally adjusted for vitamin B-6 for effect of folate and additionally adjusted for folate for effect of vitamin B-6. c The average intake of vitamin B-12 was too low to express with number in quartile 1 and quartile 2, so range of vitamin B-12 in each quartile was used instead of median intake.
Previous studies demonstrated that large proportion of Chinese were in low folate and vitamin B-12 status with large geographic variations, the prevalence of B vitamin deficiency in north was much higher than that in south (17). And clearly in northwestern China, women had a very higher prevalence of deficiency in vitamin B-12; especially it was worse in the rural area (17). The results were supported by plasma B vitamins concentration (18). The participants in our study shared the same trend of low B vitamins intake with adults in other rural area in China. Notably, in our sample, the nutritional status of females was much poorer than males (9). Our finding is in agreement with those from previous studies. A randomized placebo-controlled trial has shown that long-term homocysteine-lowering treatment with folic acid plus B-6 is associated with reduced BP over 2 year trial period (4). The results of Nurses’ Health Study indicated
that intake of B-6 above the recommended dietary allowance was important in the primary prevention of coronary heart disease among women (19). Yet, there is also some contradictory evidence. Study conducted among Japanese suggested that dietary B-6 was not significantly associated with blood pressure (20). However, the subjects included only children, and the results were not applicable to adults. Higher dietary B-12 and folate intake reduced neither risk of hypertension nor BP, and no beneficial interaction was observed, inconsistent with conclusion of study in Japanese preschool children (20). Also, the plasma B12 levels were influenced more by absorption than intake (19), thus the lack of association between extreme quartiles of dietary B12 and risk of hypertension (OR 5 0.81 [95% CI: 0.46e1.42] in male 1.14 [95% CI: 0.74e1.74] in female) was expected. Some observational researches indicated that B-12 and folate may have synergic effects on BP by promoting endothelial function
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Table 4. Odd Ratios (ORs) of hypertension according to the interaction between the three B vitamins by log-binomial regressionabcd Normal Vitamin B-6 Male Folate Normal Low High Vitamin B-12 Normal Low High Female Folate Normal Low High Vitamin B-12 Normal Low High Vitamin B-12 Male Folate Normal Low High Female Folate Normal Low High
Low
High
1.0 1.66 (0.93e3.21) 1.19 (0.71e2.24) 1.06 (0.54e2.17) 1.57 (0.85e3.08) 0.71 (0.29e1.64) 1.22 (0.74e2.27) 1.52 (0.81e3.01) 1.19 (0.61e2.42)
1.0 1.20 (0.84e1.68) 1.25 (0.86e1.77) 0.96 (0.59e1.49) 1.12 (0.69e1.77) 0.57 (0.23e1.13) 0.83 (0.54e1.24) 1.24 (0.68e2.02) 0.58 (0.27e1.05)
1.0 1.05 (0.78e1.40) 0.59 (0.39e0.87)e 0.97 (0.71e1.30) 1.16 (0.83e1.57) 1.04 (0.65e1.53) 1.06 (0.77e1.42) 0.64 (0.35e1.04) 0.53 (0.29e0.89)f
1.0 0.95 (0.66e1.34) 1.08 (0.80e1.42) 0.91 (0.66e1.22) 1.07 (0.70e1.56) 0.55 (0.28e1.05) 0.73 (0.50e1.03) 1.18 (0.80e1.65) 0.69 (0.40e1.09)
1.0 0.66 (0.40e1.04) 0.93 (0.62e1.34) 0.99 (0.69e1.39) 1.07 (0.58e1.77) 0.53 (0.24e1.09) 1.24 (0.87e1.73) 1.03 (0.64e1.60) 0.71 (0.35e1.22)
1.0 0.89 (0.61e1.27) 0.97 (0.70e1.31) 0.91 (0.67e1.24) 1.24 (0.81e1.81) 1.37 (0.96e1.88) 0.91 (0.65e1.25) 0.71 (0.39e1.16) 0.91 (0.56e1.39)
a
Adjusted for age, energy, education, family history of hypertension, fortune index, physical activity level, alcohol and smoking, education BMI, sodium and the two nutrient principal components. b The categories ‘low’, ‘normal’ and ‘high’ of dietary folate were based on quartiles(Q) and defined as follows: !311.54 mg/d (Q1), 311.54e510.58 mg/d (Q2 and Q3), O510.58 mg/d (Q4) in male. !239.35 mg/d (Q1), 239.35e440.86 mg/ d (Q2 and Q3), O440.86 mg/d (Q4) in female, respectively. c The categories ‘low’, ‘normal’ and ‘high’ dietary vitamin B-6 were based on quartiles (Q) and defined as follows: !1.78 mg/d (Q1), 1.78e5.82 mg/ d (Q2 and Q3), O5.82 mg/d (Q4) in male. !1.14 mg/d (Q1), 1.14e3.55 mg/d (Q2 and Q3), O3.55 mg/d (Q4) in female. d The categories ‘low’, ‘normal’ and ‘high’ of dietary vitamin B-12 were based on quartiles(Q) and defined as follows: !1.0 mg/d (Q1), 1.0e1.19 mg/d (Q2 and Q3), O1.19 mg/d (Q4) in male. !0.0009 mg/ d (Q1), 0.0009e0.11 mg/d (Q2 and Q3), O0.11 mg/d (Q4) in female. e p value50.011. f p value50.037.
or converting homocysteine (21). There is also some contradictory evidence. Evidence from a meta-analysis which indicated dietary folate supplement had no significant association with cardiovascular events within 5 years (22). Moreover, recent randomized controlled trials verified the conclusion that lowering homocysteine by vitamin intervention, even combination of B-6, folate and B-12 reduced neither cardiovascular events nor mortality (6,23). A harmful effect of
excessive B vitamin (folate and B-12) was pronounced in patients who had had an acute myocardial infarction (5). However, the outcome of these RCTs was cardiovascular disease but not referred to specifically hypertension. A fact cannot be ignored was that high prevalence of deficiency of the two vitamins might affect their associations with hypertension in our study. Thus, further studies are warrant to test our findings. The high carbohydrate diet pattern may account for the elevated effect of cereals on blood pressure (24), given that cereals were the main food source carbohydrate in this study and excessive intake of cereals (the average intake were 570.0 g/d in male and 445.0 g/d in female) were very common. The unbalanced diet and poor nutrition of participants was very common in our study, which may be partly responsible for the negative results (25). For example, the average daily intake of red meat was 26.7 g in male and 16.8 g in female, and neither of them reached the recommended nutrient intake (50e70 g). And the small diversity may weaken association between these foods and hypertension prevalence. On the other hand, the interaction among various nutrients contained by the same kinds of food may result in the no significant association, in some extent. It was worth noting that gender significantly modified the inverse association between vitamin B-6 intake and hypertension, with a greater benefit in females. Gender was also indicated to modify the homocysteine-CHD in a previous study (6). In our study, this modification effect may be partially explained, by the higher intake of vitamin B-6 in males [median (25the75th percentiles): 3.1 (1.8e5.8) mg/d] than in females (2.0 [1.1e3.6]) given the nutrition status may play a more positive effect in less nourished subjects (9,26). Another possibility is that the significant inverse trend of association between vitamin B6 consumption and the risk of hypertension in female might be influenced by an interaction with a sex hormone, the abundant ovarian hormones produced by premenopausal women might protect them from cardiovascular disease (27,28). Finally, an interaction might exist between smoking status and vitamin B6 with hypertension and cigarette smoking may weaken the association. A stronger inverse association was observed between fruit and vegetable intake and cardiovascular disease mortality in subjects who had never smoked (29), consistent with the conclusion of the study in Japanese (28). Because the proportion of smoker in male was much larger than in female in present analysis, the difference might be responsible for the no significant association. The mechanism for the beneficial effect B vitamins on blood pressure was still unclear. It was hypothesized that vitamin B-6 and folate might be independently associated with blood homocysteine concentrations in Chinese (17). It was also conceivable that folate could improve the FMD value to enhance endothelial function independently of homocysteine lowering (7,30), as after adjustment for baseline homocysteine level, the significantly inverse association between the combination use of enalapril and folic acid and risk of the first
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Table 5. Estimated Blood Pressure changes (mmHg) with one SD increment of B vitamins based on different multiple linear regression models in female SBP Modela Vitamin B-6
Folate
Vitamin B-12
Age/energy-adjusted Model 1 Model 2 Age/energy-adjusted Model 1 Model 2 Age/energy-adjusted Model 1 Model 2
Change 1.435 1.260 1.234 0.321 0.314 0.114 0.364 0.425 0.276
DBP p
95% CI 2.449, 2.306, 2.291, 1.259, 1.264, 1.436, 1.551, 1.505, 1.585,
0.421 0.214 0.181 0.616 0.637 1.664 2.278 2.355 2.137
0.006 0.018 0.022 0.502 0.517 0.885 0.710 0.666 0.949
Change 0.390 0.472 0.446 0.223 0.148 0.055 0.152 0.198 0.116
95% CI 0.914, 1.014, 0.993, 0.742, 0.679, 0.809, 0.908, 0.866, 0.912,
0.134 0.071 0.100 0.296 0.383 0.919 1.212 1.293 1.144
p 0.144 0.088 0.110 0.399 0.584 0.901 0.779 0.715 0.825
a Model for adjustments, Model 1: adjusted for age, energy, education, family history of hypertension, fortune index, physical activity level, alcohol and smoking; Model 2: Model 1 further adjusted for BMI, sodium and the two principal components. Additionally, adjusted for vitamin B-6 and B-12 for effect of folate and additionally adjusted for folate and vitamin B-12 for effect of vitamin B-6.
stroke persisted among adults with hypertension, compared with enalapril alone (31). This possibility was supported by modification of cellular oxidative metabolism to increase the availability of tetrahydrobiopterin, a co-factor for NO synthase through acting as an antioxidant, regenerating the cofactor for NOS or directly stimulating eNOS (30), through acting as an antioxidant (32), regenerating the cofactor for NOS (33) or directly stimulating eNOS (34). Unfortunately, we do not collect data from our present study to test these hypotheses. Further studies are necessary to examine the mechanisms. Our study has some limitations. First, the study’s crosssectional design represents a limitation as causality cannot be established. Additionally, it was not possible to adjust the analysis for other factors potentially associated with BP such as genetic factors and intrauterine development. Third, plasma homocysteine and other related variables were not collected in present study, the potential mechanisms for the beneficial effect of B vitamins on blood pressure were not evaluated. Forth, the generalizability of our findings was limited because the study was not national. However, the same trend of diet pattern and nutrition status was shared by the other rural adults and our subjects in China (25). Fifth, information on the supplements containing B vitamins was not collected, as almost no micronutrient supplements would be used by the local rural subjects (25). The main strengths enhanced the validity of our study. First, blood pressure was directly measured by trained personnel according to standardized procedures, not being self-reported, which completely reduced measurement error. Second, the FFQ that we used in the dietary assessment has been evaluated and reasonably reflects long-term diet intake (9). In addition, to reduce the bias of selection bias, because participants might change their diet after they developed some intermediate disease and these changes would possibly attenuate the association between intake of B vitamins and risk of hypertension, we excluded participants with history of cardiovascular diseases and diabetes (35). And our
findings were unlikely to be explained by recall or selection bias because of high quality of study management. Third, our study directly relating dietary B vitamins intake to risk of hypertension among rural Chinese, which is valuable for making individual and policy decisions. Forth, both significantly inverse associations with systolic blood pressure and with hypertension were observed in our study. And, this interpretation is also supported by results of interaction analysis between the three B vitamins in females, which reflect the robustness of our findings. Finally, Sodium was also a key concern in our previous study (9). We also found the participants with higher intake of B vitamins tended to take in less sodium; hence we adjusted sodium in final models. However, effect of sodium in Chinese population seemed limited because excessive intake of sodium was very common among our participants but no significant risk of hypertension related to dietary sodium was observed (9), which is in agreement with other Chinese study (36).
Conclusion In summary, our findings support a beneficial effect of dietary vitamin B-6 intake on risk of hypertension in females with low B vitamins status. The inverse association was more pronounced in higher consumption of both B-6 and folate. Further studies are warranted to validate the conclusion and establish the casual inference.
Acknowledgments The authors appreciate all participants for their participation, the investigators of Xi’an Jiaotong University, and doctors of the People’s Hospital of Hanzhong and the village doctors for their organization. This work was supported by the China Medical Board (Grant Number: 08e925) and National Natural Science Foundation of China (Grant Number: 81230016). Conflicts of interest: There are no conflicts of interest.
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References 1. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet 2005;365:217e223. 2. Forman JP, Rimm EB, Stampfer MJ, et al. Folate intake and the risk of incident hypertension among US women. JAMA 2005;293: 320e329. 3. de Moraes AC, Gracia-Marco L, Iglesia I, et al. Vitamins and iron blood biomarkers are associated with blood pressure levels in European adolescents. The HELENA study. Nutrition 2014;30: 1294e1300. 4. van Dijk RA, Rauwerda JA, Steyn M, et al. Long-term homocysteinelowering treatment with folic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery endothelium-dependent vasodilation or carotid artery stiffness: a 2year, randomized, placebo-controlled trial. Arterioscler Thromb Vasc Biol 2001;21:2072e2079. 5. Bonaa KH, Njolstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006;354:1578e1588. 6. Albert CM, Cook NR, Gaziano JM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA 2008;299:2027e2036. 7. de Bree A, van Mierlo LA, Draijer R. Folic acid improves vascular reactivity in humans: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2007;86:610e617. 8. Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 2007;369: 1876e1882. 9. Liu R, Dang S, Yan H, et al. Association between dietary protein intake and the risk of hypertension: a cross-sectional study from rural western China. Hypertens Res 2013;36:972e979. 10. Park Y, Spiegelman D, Hunter DJ, et al. Intakes of vitamins A, C, and E and use of multiple vitamin supplements and risk of colon cancer: a pooled analysis of prospective cohort studies. Cancer Causes Control 2010;21:1745e1757. 11. Dang SN, Wang ZJ, Kang YJ, et al. Study on the dietary pattern assessed with semi-quantitative food frequency questionnaire among rural Tibetan women with children younger than 2 years in Lhasa city. Zhonghua Liu Xing Bing Xue Za Zhi 2010;31:394e399. 12. Cheng Y, Dibley MJ, Zhang X, et al. Assessment of dietary intake among pregnant women in a rural area of western China. BMC Public Health 2009;9:222. 13. Xun P, Liu K, Loria CM, et al. Folate intake and incidence of hypertension among American young adults: a 20-y follow-up study. Am J Clin Nutr 2012;95:1023e1030. 14. Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol 1986;124:17e27. 15. Lagerros YT, Lagiou P. Assessment of physical activity and energy expenditure in epidemiological research of chronic diseases. Eur J Epidemiol 2007;22:353e362. 16. Filmer D, Pritchett LH. Estimating wealth effects without expenditure dataeor tears: an application to educational enrollments in states of India. Demography 2001;38:115e132. 17. Hao L, Ma J, Zhu J, et al. High prevalence of hyperhomocysteinemia in Chinese adults is associated with low folate, vitamin B-12, and vitamin B-6 status. J Nutr 2007;137:407e413. 18. Dang S, Yan H, Zeng L, et al. The status of vitamin B12 and folate among Chinese women: a population-based cross-sectional study in northwest China. PLoS One 2014;9:e112586.
19. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998;279:359e364. 20. Tamai Y, Wada K, Tsuji M, et al. Dietary intake of vitamin B12 and folic acid is associated with lower blood pressure in Japanese preschool children. Am J Hypertens 2011;24:1215e1221. 21. Verhoef P, Stampfer MJ, Buring JE, et al. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol 1996;143:845e859. 22. Clarke R, Halsey J, Lewington S, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med 2010;170:1622e1631. 23. Heinz J, Kropf S, Domrose U, et al. B vitamins and the risk of total mortality and cardiovascular disease in end-stage renal disease: results of a randomized controlled trial. Circulation 2010;121:1432e1438. 24. Hodgson JM, Burke V, Beilin LJ, et al. Partial substitution of carbohydrate intake with protein intake from lean red meat lowers blood pressure in hypertensive persons. Am J Clin Nutr 2006;83:780e787. 25. Liu R, Dang S, Yan H, et al. Dietary patterns and nutrients intakes in rural residents in Hanzhong of Shaanxi Province. Wei Sheng Yan Jiu 2012;41:997e1003. 26. Appel LJ, Sacks FM, Carey VJ, et al. Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial. JAMA 2005;294: 2455e2464. 27. McCarthy JJ. Gene by sex interaction in the etiology of coronary heart disease and the preceding metabolic syndrome. Nutr Metab Cardiovasc Dis 2007;17:153e161. 28. Nakamura K, Nagata C, Oba S, et al. Fruit and vegetable intake and mortality from cardiovascular disease are inversely associated in Japanese women but not in men. J Nutr 2008;138:1129e1134. 29. Genkinger JM, Platz EA, Hoffman SC, et al. Fruit, vegetable, and antioxidant intake and all-cause, cancer, and cardiovascular disease mortality in a community-dwelling population in Washington County, Maryland. Am J Epidemiol 2004;160:1223e1233. 30. Pullin CH, Ashfield-Watt PA, Burr ML, et al. Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype. J Am Coll Cardiol 2001;38:1799e1805. 31. Huo Y, Li J, Qin X, et al. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA 2015;313:1325e1335. 32. Verhaar MC, Wever RM, Kastelein JJ, et al. 5-methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation 1998;97:237e241. 33. Antoniades C, Shirodaria C, Warrick N, et al. 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation 2006;114:1193e1201. 34. Stroes ES, van Faassen EE, Yo M, et al. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res 2000;86:1129e1134. 35. He K, Merchant A, Rimm EB, et al. Folate, vitamin B6, and B12 intakes in relation to risk of stroke among men. Stroke 2004;35: 169e174. 36. ZQ l. The trend of salt intake and its association with prevalence of hypertension in Chinese. Zhonghua Gao Xue Ya Za Zhi 2009;17: 482e485.
ORIGINAL ARTICLE
Effect of B Vitamins from Diet on Hypertension Ruru Liu,a,b Baibing Mi,a Yaling Zhao,a Qiang Li,a Hong Yan,a,* and Shaonong Danga,* a
Xi’an JiaoTong University, Health Science Center, bXi’an Center for Disease Control and Prevention, Xi’an, Shaanxi Province, China Received for publication May 15, 2016; accepted February 16, 2017 (ARCMED-D-16-00288).
Background. In western populations, a higher level of dietary B vitamins intake has been associated with a lower risk of hypertension. However, data in Chinese is limited, whose B vitamins consumption is low and rates of hypertension are high. Aim of the Study. To investigate whether the three B vitamins are associated with hypertension in rural Chinese. Methods. Cross-sectional survey among 2241 rural Chinese aged 18e80 years was conducted in northwestern China in 2010. Blood pressure was measured by trained medical staff and dietary nutrients were assessed with a semiquantitative food frequency questionnaire. Results. 592 cases of hypertension were newly diagnosed. The deficiency proportions were 20.5% for vitamin B-6, 43.9% for folate and 98.5% for B-12. For females, participants in the highest quartile of B-6 intake had a significantly lower risk of hypertension (OR 5 0.69; 95% CI: 0.50e0.93; p for trend !0.05). For males, the multivariable OR for the same comparison was 0.75 (95% CI: 0.56e0.99, p for trend O0.05). No significant associations were observed between B-12, folate intake and hypertension. For females, the highest quartile of both folate and B-6 intake was associated with a reduced risk of hypertension (OR 5 0.53; 95% CI: 0.29e0.89), compared with in the middle quartile of both vitamins. Conclusions. Higher intake of vitamin B-6 is independently associated with lower risk of hypertension in Chinese rural adults. Among females with high folate intake, the association between B-6 and hypertension was strongest. Additional studies are warrant to establish the causal inference. Ó 2017 IMSS Published by Elsevier Inc Key Words: Dietary B vitamins, Micro-nutrition status, Hypertension, Rural Chinese adults, Logbinomial regression.
Introduction Hypertension contributes to the burden of stroke, heart disease, kidney failure, disability and mortality. It disproportionately affects populations in low- and middleincome countries where health systems are weak (1). Thus, it was essentially important for promoting public health by *
These authors contributed equally to this work. Address reprint requests to: Hong Yan, Xi’an Jiaotong University, Health Science Center, Xi’an, Shaanxi Province, 710054, China; Tel: 0086-29-82655001; E-mail: [email protected]; Shaonong Dang, Xi’an Jiaotong University, Health Science Center, Xi’an, Shaanxi Province, 710054, China; Tel: 0086-29-82655104 ext 207; Fax:0086-29-82655730; E-mail: [email protected].
identifying risk factors for hypertension and leading to specific preventive interventions. Numerous studies supported the beneficial effect of B vitamins on decreasing blood pressure or incident hypertension (2e4), although the role of B vitamins in the development of cardiovascular disease was controversial, as some large prospective trial did not find the significant association between them (5,6). And what we should bear in mind was that these trial prevention studies focused on the risk reduction of CVD after short-term intervention in highrisk participants, and thus these results cannot be generalized to the overall population (7). Furthermore, it is possible that B-vitamins treatment may prove more effective in individuals without established vascular
0188-4409/$ - see front matter. Copyright Ó 2017 IMSS Published by Elsevier Inc http://dx.doi.org/10.1016/j.arcmed.2017.03.011
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disease, as a recent meta-analysis of clinical trial data suggested that the incidence of new ischemic stroke was significantly reduced by B-vitamin supplementation while recurrent stroke is not (8). However, uncertainty remains regarding the relationship between these B vitamins from diet with prevalence of hypertension in overall population, especially in rural Chinese. In addition, most previous studies focused on serum B vitamins or supplement with B vitamins but did not examine the interaction of these dietary B vitamins. Therefore, in the current study, we examine dietary intake of vitamin B-6, folate and B-12 in association with risk of hypertension in rural adults of western China, whose diet characterized by low caloric and unbalanced diet pattern.
Methods Study Design and Participants This cross-sectional survey was designed to investigate the prevalence of hypertension and its related risk factors among rural adults aged 18e80 years living in Hanzhong of Shaanxi province in 2010. Using face-to-face interviews, we collected demographic characteristics, history of disease, physical activity and lifestyle. Details of the survey methods were published previously (9). Informed written consent was obtained from each participant prior to participation. The protocol was approved by the Ethics Review Committee, School of Medicine, Xi’an Jiaotong University (Number: 2002001). Totally 3021 participants were investigated. In the current study, some persons were excluded due to stroke (n 5 211) and diabetes (n 5 127) as well as hyperlipidemia (n 5 333), those who reported taking antihypertensive medication (n 5 328), missing data on blood pressure (n 5 20), missing data on food frequency questionnaire (FFQ) (n 5 84), and implausible total energy intake (beyond three standard deviation (SD) from the sexspecific loge-transformed mean caloric intake) (n 5 24) (10). Finally, 2241 participants (774 men and 1467 women) remained for the final analysis. Assessment of B Vitamins Intake Dietary information was assessed through intervieweradministered semiquantitative Food-frequency questionnaire. Validity and reproducibility of the questionnaire have been evaluated and discussed elsewhere (9,11). Respondents were asked to report their frequency and amount of food consumption during the previous 12 months with the assistance of images of a food portion (11,12). General questions about their diet were asked, which elicited specific foods consumed in an open-ended fashion (13). They were also asked to recall the frequency, amount of food consumption for each item named. Nutrient intake was loge-transformed
and caloric-adjusted to 2100 kcal/d for male and 1700 kcal/d for female by the residual method, when the associations between B vitamins and hypertension were examined (14). Vitamin B-6 intake deficiency was defined as lower than 1.0 mg/d of vitamin B-6 for individual aged 18e59 years, 1.2 mg/d for ones over 60 years. Folate and B-12 intake deficiency was defined as lower than 320 mg/ d of folate and 2 mg/d of B-12 for all age. Outcome Assessment Participants were informed of keeping fasted for $8h and avoiding heavy physical activity before medical examination. Blood pressure was measured on the right arm of participants at 1 min intervals after a 5 min rest. Systolic and diastolic blood pressure were recorded as phase I and V Korotkoff sounds. The mean of two measurements was used for analysis. Hypertension was defined according to the Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) cutoff as systolic blood pressure $140 mmHg and/or a diastolic BP $90 mmHg, or the use of antihypertensive medications. Ascertainment of Other Covariates Standardized interview questionnaire was used to assess demographic (age, gender, marital status, education, history of disease) and lifestyle (physical activity and smoking) information. Education was represented as the total years of schooling, which was classified into primary school (school years #6), secondary school (6e9 school years) and senior school and higher education (school years $9) (9). Physical activity was assessed by the lifestyle questionnaire. Participants were asked to report frequency and time spent in leisure, house hold physical activity and farming over the previous 12 months. Intensity score was assessed by metabolic equivalent (MET) multiplied by duration and frequency of the activity converted to per week unit. This MET h/week value was summed for each participant according to the number of physical activities elicited, participants who did not elicit any activity were given a score of zero (15). This continuous score was categorized as ‘‘0e! 5’’, ‘‘5e10’’ and ‘‘O10’’ refer to low, moderate and high intensity. Cigarette smoking was categorized as never, former or current; the current smokers were further classified to 2 categories (!15cigarettes/day, $15cigarettes/day) according to average daily cigarette consumption. Statistical Analysis Principal component analysis (PCA) was used to establish a fortune index to estimate economic status of the subjects. Further, in order to avoid multi-collinearity of nutrients (16), two nutrient principal components were drawn based on all potential nutrients by PCA, which explained 70% of
B Vitamins and Hypertension in Rural Chinese
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Table 1. Participants characteristic across quartiles of B-vitamins intakea Male Vitamin B-6
Quartile1 Age, years Prevalence of hypertension, % SBP, mm Hg DBP, mm Hg Married, % BMI, kg/m2 Schooling year O9 years, % Family history of hypertension, % Fortune index, % Poor Moderate Rich Current smoker, % Alcohol, g/d Physical activity, high intensity, % Nutrient intakeb Energy, kcal/d Saturated fatty acid, g/d Monounsaturated fatty acid, g/d Polyunsaturated fatty acid, g/d Vitamin B-2, mg/d Vitamin B-6, mg/d Folate, mg/d Vitamin B-12, mg/d Sodium, g/d
Female
Folate
Vitamin B-12
Vitamin B-6
Folate
Vitamin B-12
Quartile Quartile Quartile Quartile Quartile Quartile 4 Quartile1 4 Quartile1 4 Quartile1 4 Quartile1 4 Quartile1 4
51.7 36.8
46.7 25.9
48.9 27.5
51.1 30.1
48.9 27.5
50.1 24.9
50.3 28.1
44.2 18
48.1 29.8
47.1 19.9
47.4 22.1
48.2 27
133.1 81.1 88.1 22.2 18.1
128.1 79.3 94.8 22.6 21.8
129.6 79.6 92.2 22.2 17.6
130 79 93.3 22.8 12.4
129 80.4 89.6 22.5 14
127.7 78 95.3 22.5 18.1
129.7 77.5 89.1 22.4 7.6
123.4 75.9 96.7 22.6 10.4
128.7 77.8 92.9 22.4 7.9
127.7 76.8 91.6 22.5 8.8
126.5 77.4 94.5 22.6 7.7
128.9 77.3 90.7 22.5 8
27.5
34.2
30.1
30.6
30
29
25.9
32.4
32
31.1
24.5
32
45.1 29.3 25.5 39.4 5 25.9
22 35.6 42.4 37.4 8.1 23.8
34.1 29.7 36.3 51.8 8.7 25.4
32.1 35.3 32.6 47.7 7.1 23.3
29.9 32.2 37.9 15.5 7.1 15.5
30.6 32.1 37 19.4 8.7 31.1
43.5 27.3 29.1 1.1 2.1 16.9
18 29.4 52.6 0 1.7 22.1
29.1 34.3 36.6 0.3 2.5 15.8
33.2 26.9 39.9 0.3 1.3 21.5
34.4 32.8 32.8 0.3 0.4 12
28.5 34.4 37.1 1.4 1.9 18.3
2308.8 14.3
2248.9 21.6
2109.2 18.8
2114.6 15.6
2853.2 17.1
2113.2 17.9
1781.9 12.7
1741,5 17.2
1712.1 15.6
1708.7 13.1
2131.5 14.2
1757 14.5
20.9
19.6
22.5
17.8
20.6
19
18.3
17.7
20
16
18.5
16.9
38.7
45.8
47
34.6
41.5
38.9
35.8
40.2
42
32.1
38.1
34.7
428 1.1 0.3 0.8 6665.3
422.2 8.9 0.2 0.9 4718.5
640.1 4 0.6 1.1 4831.2
428.5 4.2 0.9 0.8 5598.1
446.6 4.5 5.7 0.9 5411.9
348.5 0.7 0.2 0.6 6223.2
354.9 5.9 0.1 0.7 4940.4
563.8 2.7 0.2 0.9 5140.5
351.9 2.6 0.1 0.6 4615.7
361.1 2.9 0.5 0.7 5040
248.5 3.9 0.2 0.6 6325.5
194.2 2.4 0.2 0.4 6370.7
a
Values are mean or %. Adjusted for total calorie intake, except energy daily intake.
b
total variance. A detailed description of this methodological issue was already provided (9). Log-binomial regression models were used to evaluate the associations of dietary B vitamins with the occurrence of hypertension. Odd ratios (ORs) for hypertension and their 95% confidence intervals (CIs) were estimated by comparing the prevalence of hypertension in particular dietary intake quartiles with that of the lowest one. A sequential covariateadjusted strategy was used in the analysis. Model 1 adjusted for age, education, family history of hypertension, fortune index, physical activity level, alcohol and smoking. Model 2 adjusted for the variables in model 1 plus BMI, sodium and the two nutrient principal components. The linear trend test across quartiles was evaluated by using the median value of each quartile as a single continuous variable and entering it in the regression model. We also examine the association between B vitamins intake and SBP/DBP by multiple linear
regression models. We further explore the interaction by estimating ORs of hypertension according to categories of combined any two of the three B vitamins. The lowest quartile was defined as ‘low’, the highest quartile as ‘high’. And the other two quartiles as ‘normal’. We combined ‘low’, ‘normal ‘or ‘high’ of any of the three B vitamins. The combination of normal categories was used as the reference group. All analyses were performed separately for gender, given the significant sex B vitamins interaction in regression models. Statistical analysis system 9.1 (SAS Institute, Cary, NC, USA) was used. Two-sided tests were used and p !0.05 was considered statistically significant. Results Baseline characteristics, lifestyle and nutrient intake were described according to highest and lowest quartiles of B
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vitamins intake in Table 1. Men with higher folate intake were likely to be older, higher proportions of hypertension, less educated and noncurrent smoker; on the other hand, men with higher intake of B-6 showed diverse characteristics, respectively. Compared with women in the lowest quartile of folate and B-6, those in the highest quartile were more likely younger, better educated and richer, exercise more and drink less. Also, the three B vitamins were positively associated with saturated fatty acid and B-2 consumption, while inversely associated with polyunsaturated fatty acid and sodium intake. As illustrated in Table 2, median dietary B vitamins intake was 2.3 mg/d of B-6 (1.3e4.2), 344.7 mg/d of folate (258.0e464.5 mg/d) and 0.1 mg/d of B-12 (0.1e1.0) in the overall population. The deficiency rate of folate and low B-6 intake were 50.0% and 25.1% in female, significantly higher than that in male (32.2%, p !0.001; 11.8%, p ! 0.001). 98.5% of participants were insufficient of B-12 intake. Table 3 presented ORs for hypertension according to quartiles of B vitamins consumption by gender from 3 adjusted-models. For males, no significant associations were found between three B vitamins and risk of hypertension. Males in the highest quartile of B-6 intake have a relatively lower risk of hypertension (OR 5 0.75, 95% CI: 0.56e0.99, p for trend 5 0.094), compared with those in the lowest quartile after adjustment for potential confounders (model 2). For females, the prevalence of hypertension was reduced by 36% in participants in the highest quartile compared with those in the lowest quartile of dietary B-6 intake (OR 5 0.64; 95% CI: 0.44e0.83; p for trend !0.001). When further adjusted for demographic, lifestyle and dietary factors, the inverse association was essentially unchanged (OR 5 0.69; 95% CI: 0.50e0.93; p for
Table 2. Daily B vitamins intake of the participants B-6 (mg/d)b RNIsa Overall Median Q2eQ4 Rate of deficiency (%) Male Median Q2eQ4 Rate of deficiency (%) Female Median Q2eQ4 Rate of deficiency (%) a
Folate (mg/d)
B-12 (mg/d)
400.0
2.0
2.3 1.3e4.2 20.5
344.7 258.0e464.5 43.9
0.1 0.1e1.0 98.5
3.1 1.8e5.8 11.8
391.8 311.5e510.6 32.3
1.1 1.0e1.2 97.9
2.0 1.1e3.6 50.0
316.4 239.4e440.9 25.1
0.0 0.0e0.1 98.8
1.2/1.5
Discussion
RNIs refer to recommended dietary nutrient intakes of Chinese. RNIs for vitamin B-6 were provided by age. 1.2 mg/d of vitamin B-6 for individual aged 18e59 years, 1.5 mg/d for individual 64 over 60 years. b
trend 5 0.014). In the age- and energy-adjusted model, folate intake was significantly associated with lower risk of hypertension ( p for trend 5 0.0458). However, the association become weak and insignificant after adjusted for potential confounders ( p for trend 5 0.4982). As shown in Table 4, the interaction between the three B vitamins was estimated by Log-binomial regression models. The OR was 0.53 (95% CI: 0.29e0.89) among women in the highest quartile of both folate and vitamin B6 intake compared with the normal group. Risk of hypertension was reduced among those with higher dietary intake of vitamin B6 and normal intake of folate (OR 5 0.59, 95% CI: 0.39e0.87). No significant interaction of the three B vitamins was observed among males. To explore whether interaction between vitamin B6 and estrogen status existed, a stratified analysis by menopausal status was conducted. The multivariate-adjusted OR were 0.53 (95% CI: 0.30e0.95) among premenopausal women and 0.68 (95% CI: 0.39e1.18) among postmenopausal women compared fourth quartile with the first quartile. Significant interaction was observed between menopausal status and vitamin B6 intake ( pinteraction !0.001, data not shown). For females, the association between blood pressure and the B vitamins was also examined (Table 5). B-6 was inversely associated with systolic blood pressure in females. After controlling potential confounders (model 2), One standard deviation increment of B-6 resulted in a decrease of 1.234 mmHg ( 1.234, 95% CI: 2.291 to 0.181; p value 5 0.022). No significant association was observed between B vitamins and diastolic blood pressure. The main food sources of vitamin B6 were cereals (21.1%), potatoes (29.6%), leafy green vegetables (21.5%) and red meat (11.2%) in this study. And the associations between these food and blood pressure were future explored. Dietary cereal intake was positively related to SBP and DBP, independent of demographic and behavior characteristics (b 5 0.007, p 5 0.037; b 5 0.005, p 5 0.010, respectively). The other three foods were not associated with blood pressure ( p valueO0.05) (Data not shown).
The present study demonstrated the inverse association between vitamin B-6 and risk of hypertension in females with worse B vitamin status, and the inverse association was stronger in a higher consumption of both B-6 and folate than any other category. The inverse association was supported by significant reduction of SBP with increasing B-6 in females. The results persisted after controlling for many potential confounders in our study, also we found that the beneficial effect of vitamin B-6 was stronger in premenopausal women. However, they still need be confirmed in large prospective or randomized control trial studies.
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191
Table 3. Multivariable ORs of hypertension by quartile of B-vitamins intake Male
Q1 Vitamin B-6 Median intake, mg/d No. of cases PR (95% CI) Age/energy-adjusted
Q2
Q3
Q4
1.6 71
2.4 51
4.3 56
7.9 50
1.0
0.69 (0.51e0.94) 0.74 (0.54e1.00) 0.75 (0.55e0.99)
0.77 (0.57e1.03) 0.85 (0.62e1.15) 0.84 (0.62e1.12)
0.70 (0.51e0.94) 0.75 (0.55e1.02) 0.75 (0.56e0.99)
351.4 53
439.5 64
598.3 58
0.99 (0.72e1.38) 0.98 (0.71e1.34) 1.02 (0.73e1.44)
1.20 (0.89e1.64) 1.17 (0.87e1.57) 1.23 (0.90e1.68)
1.09 (0.80e1.50) 1.00 (0.74e1.37) 1.14 (0.83e1.58)
1.0e1.06 62
1.06e1.19 65
O1.19 48
1.21 (0.74e1.97) 1.31 (0.79e2.19) 1.37 (0.79e2.37)
1.29 (0.78e2.12) 1.45 (0.86e2.44) 1.40 (0.80e2.45)
0.85 (0.52e1.39) 0.90 (0.54e1.51) 0.81 (0.46e1.42)
Model 1a
1.0
Model 2b
1.0
Folate Median intake, mg/d No. of cases PR (95% CI) Age/energy-adjusted
249.6 53 1.0
Model 1a
1.0
Model 2b
1.0
Vitamin B-12c Median intake, mg/d No. of cases PR (95% CI) Age/energy-adjusted
Female
!1.0 53 1.0
Model 1a
1.0
Model 2b
1.0
p for trend
Q1
Q2
Q3
Q4
0.8 103
1.6 97
2.6 98
5.1 66
0.93 (0.74e1.18) 0.97 (0.76e1.24) 0.97 (0.76e1.24)
0.94 (0.74e1.19) 1.00 (0.78e1.27) 1.01 (0.79e1.30)
0.64 (0.44e0.83) 0.66 (0.49e0.89) 0.69 (0.50e0.93)
278.5 95
367.0 80
530.4 87
0.86 (0.60e1.23) 0.88 (0.61e1.28) 0.87 (0.58e1.30)
0.69 (0.47e1.01) 0.67 (0.45e0.99) 0.65 (0.39e1.11)
0.76 (0.53e1.08) 0.77 (0.53e1.12) 0.73 (0.35e1.53)
0e0.03 90
0.03e0.10 94
O0.10 99
0.98 (0.67e1.43) 0.93 (0.61e1.44) 0.94 (0.60e1.47)
1.08 (0.75e1.55) 1.10 (0.72e1.66) 1.11 (0.72e1.71)
1.20 (0.85e1.71) 1.09 (0.72e1.64) 1.14 (0.74e1.74)
0.082
1.0
0.205
1.0
0.094
1.0
201.1 102 0.426
1.0
0.832
1.0
0.317
1.0
0 81 0.285
1.0
0.172
1.0
0.122
1.0
p for trend
!0.001 0.006 0.014
0.0458 0.0605 0.4982
0.613 0.801 0.749
BMI, body mass index; CI, confidence interval; PR, prevalence ratio. a Model 1: adjusted for age, energy, education, family history of hypertension, fortune index, physical activity level, alcohol and smoking. b Model 2: Model 1 further adjusted for BMI, sodium and the two nutrient principal components. Additionally adjusted for vitamin B-6 for effect of folate and additionally adjusted for folate for effect of vitamin B-6. c The average intake of vitamin B-12 was too low to express with number in quartile 1 and quartile 2, so range of vitamin B-12 in each quartile was used instead of median intake.
Previous studies demonstrated that large proportion of Chinese were in low folate and vitamin B-12 status with large geographic variations, the prevalence of B vitamin deficiency in north was much higher than that in south (17). And clearly in northwestern China, women had a very higher prevalence of deficiency in vitamin B-12; especially it was worse in the rural area (17). The results were supported by plasma B vitamins concentration (18). The participants in our study shared the same trend of low B vitamins intake with adults in other rural area in China. Notably, in our sample, the nutritional status of females was much poorer than males (9). Our finding is in agreement with those from previous studies. A randomized placebo-controlled trial has shown that long-term homocysteine-lowering treatment with folic acid plus B-6 is associated with reduced BP over 2 year trial period (4). The results of Nurses’ Health Study indicated
that intake of B-6 above the recommended dietary allowance was important in the primary prevention of coronary heart disease among women (19). Yet, there is also some contradictory evidence. Study conducted among Japanese suggested that dietary B-6 was not significantly associated with blood pressure (20). However, the subjects included only children, and the results were not applicable to adults. Higher dietary B-12 and folate intake reduced neither risk of hypertension nor BP, and no beneficial interaction was observed, inconsistent with conclusion of study in Japanese preschool children (20). Also, the plasma B12 levels were influenced more by absorption than intake (19), thus the lack of association between extreme quartiles of dietary B12 and risk of hypertension (OR 5 0.81 [95% CI: 0.46e1.42] in male 1.14 [95% CI: 0.74e1.74] in female) was expected. Some observational researches indicated that B-12 and folate may have synergic effects on BP by promoting endothelial function
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Table 4. Odd Ratios (ORs) of hypertension according to the interaction between the three B vitamins by log-binomial regressionabcd Normal Vitamin B-6 Male Folate Normal Low High Vitamin B-12 Normal Low High Female Folate Normal Low High Vitamin B-12 Normal Low High Vitamin B-12 Male Folate Normal Low High Female Folate Normal Low High
Low
High
1.0 1.66 (0.93e3.21) 1.19 (0.71e2.24) 1.06 (0.54e2.17) 1.57 (0.85e3.08) 0.71 (0.29e1.64) 1.22 (0.74e2.27) 1.52 (0.81e3.01) 1.19 (0.61e2.42)
1.0 1.20 (0.84e1.68) 1.25 (0.86e1.77) 0.96 (0.59e1.49) 1.12 (0.69e1.77) 0.57 (0.23e1.13) 0.83 (0.54e1.24) 1.24 (0.68e2.02) 0.58 (0.27e1.05)
1.0 1.05 (0.78e1.40) 0.59 (0.39e0.87)e 0.97 (0.71e1.30) 1.16 (0.83e1.57) 1.04 (0.65e1.53) 1.06 (0.77e1.42) 0.64 (0.35e1.04) 0.53 (0.29e0.89)f
1.0 0.95 (0.66e1.34) 1.08 (0.80e1.42) 0.91 (0.66e1.22) 1.07 (0.70e1.56) 0.55 (0.28e1.05) 0.73 (0.50e1.03) 1.18 (0.80e1.65) 0.69 (0.40e1.09)
1.0 0.66 (0.40e1.04) 0.93 (0.62e1.34) 0.99 (0.69e1.39) 1.07 (0.58e1.77) 0.53 (0.24e1.09) 1.24 (0.87e1.73) 1.03 (0.64e1.60) 0.71 (0.35e1.22)
1.0 0.89 (0.61e1.27) 0.97 (0.70e1.31) 0.91 (0.67e1.24) 1.24 (0.81e1.81) 1.37 (0.96e1.88) 0.91 (0.65e1.25) 0.71 (0.39e1.16) 0.91 (0.56e1.39)
a
Adjusted for age, energy, education, family history of hypertension, fortune index, physical activity level, alcohol and smoking, education BMI, sodium and the two nutrient principal components. b The categories ‘low’, ‘normal’ and ‘high’ of dietary folate were based on quartiles(Q) and defined as follows: !311.54 mg/d (Q1), 311.54e510.58 mg/d (Q2 and Q3), O510.58 mg/d (Q4) in male. !239.35 mg/d (Q1), 239.35e440.86 mg/ d (Q2 and Q3), O440.86 mg/d (Q4) in female, respectively. c The categories ‘low’, ‘normal’ and ‘high’ dietary vitamin B-6 were based on quartiles (Q) and defined as follows: !1.78 mg/d (Q1), 1.78e5.82 mg/ d (Q2 and Q3), O5.82 mg/d (Q4) in male. !1.14 mg/d (Q1), 1.14e3.55 mg/d (Q2 and Q3), O3.55 mg/d (Q4) in female. d The categories ‘low’, ‘normal’ and ‘high’ of dietary vitamin B-12 were based on quartiles(Q) and defined as follows: !1.0 mg/d (Q1), 1.0e1.19 mg/d (Q2 and Q3), O1.19 mg/d (Q4) in male. !0.0009 mg/ d (Q1), 0.0009e0.11 mg/d (Q2 and Q3), O0.11 mg/d (Q4) in female. e p value50.011. f p value50.037.
or converting homocysteine (21). There is also some contradictory evidence. Evidence from a meta-analysis which indicated dietary folate supplement had no significant association with cardiovascular events within 5 years (22). Moreover, recent randomized controlled trials verified the conclusion that lowering homocysteine by vitamin intervention, even combination of B-6, folate and B-12 reduced neither cardiovascular events nor mortality (6,23). A harmful effect of
excessive B vitamin (folate and B-12) was pronounced in patients who had had an acute myocardial infarction (5). However, the outcome of these RCTs was cardiovascular disease but not referred to specifically hypertension. A fact cannot be ignored was that high prevalence of deficiency of the two vitamins might affect their associations with hypertension in our study. Thus, further studies are warrant to test our findings. The high carbohydrate diet pattern may account for the elevated effect of cereals on blood pressure (24), given that cereals were the main food source carbohydrate in this study and excessive intake of cereals (the average intake were 570.0 g/d in male and 445.0 g/d in female) were very common. The unbalanced diet and poor nutrition of participants was very common in our study, which may be partly responsible for the negative results (25). For example, the average daily intake of red meat was 26.7 g in male and 16.8 g in female, and neither of them reached the recommended nutrient intake (50e70 g). And the small diversity may weaken association between these foods and hypertension prevalence. On the other hand, the interaction among various nutrients contained by the same kinds of food may result in the no significant association, in some extent. It was worth noting that gender significantly modified the inverse association between vitamin B-6 intake and hypertension, with a greater benefit in females. Gender was also indicated to modify the homocysteine-CHD in a previous study (6). In our study, this modification effect may be partially explained, by the higher intake of vitamin B-6 in males [median (25the75th percentiles): 3.1 (1.8e5.8) mg/d] than in females (2.0 [1.1e3.6]) given the nutrition status may play a more positive effect in less nourished subjects (9,26). Another possibility is that the significant inverse trend of association between vitamin B6 consumption and the risk of hypertension in female might be influenced by an interaction with a sex hormone, the abundant ovarian hormones produced by premenopausal women might protect them from cardiovascular disease (27,28). Finally, an interaction might exist between smoking status and vitamin B6 with hypertension and cigarette smoking may weaken the association. A stronger inverse association was observed between fruit and vegetable intake and cardiovascular disease mortality in subjects who had never smoked (29), consistent with the conclusion of the study in Japanese (28). Because the proportion of smoker in male was much larger than in female in present analysis, the difference might be responsible for the no significant association. The mechanism for the beneficial effect B vitamins on blood pressure was still unclear. It was hypothesized that vitamin B-6 and folate might be independently associated with blood homocysteine concentrations in Chinese (17). It was also conceivable that folate could improve the FMD value to enhance endothelial function independently of homocysteine lowering (7,30), as after adjustment for baseline homocysteine level, the significantly inverse association between the combination use of enalapril and folic acid and risk of the first
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Table 5. Estimated Blood Pressure changes (mmHg) with one SD increment of B vitamins based on different multiple linear regression models in female SBP Modela Vitamin B-6
Folate
Vitamin B-12
Age/energy-adjusted Model 1 Model 2 Age/energy-adjusted Model 1 Model 2 Age/energy-adjusted Model 1 Model 2
Change 1.435 1.260 1.234 0.321 0.314 0.114 0.364 0.425 0.276
DBP p
95% CI 2.449, 2.306, 2.291, 1.259, 1.264, 1.436, 1.551, 1.505, 1.585,
0.421 0.214 0.181 0.616 0.637 1.664 2.278 2.355 2.137
0.006 0.018 0.022 0.502 0.517 0.885 0.710 0.666 0.949
Change 0.390 0.472 0.446 0.223 0.148 0.055 0.152 0.198 0.116
95% CI 0.914, 1.014, 0.993, 0.742, 0.679, 0.809, 0.908, 0.866, 0.912,
0.134 0.071 0.100 0.296 0.383 0.919 1.212 1.293 1.144
p 0.144 0.088 0.110 0.399 0.584 0.901 0.779 0.715 0.825
a Model for adjustments, Model 1: adjusted for age, energy, education, family history of hypertension, fortune index, physical activity level, alcohol and smoking; Model 2: Model 1 further adjusted for BMI, sodium and the two principal components. Additionally, adjusted for vitamin B-6 and B-12 for effect of folate and additionally adjusted for folate and vitamin B-12 for effect of vitamin B-6.
stroke persisted among adults with hypertension, compared with enalapril alone (31). This possibility was supported by modification of cellular oxidative metabolism to increase the availability of tetrahydrobiopterin, a co-factor for NO synthase through acting as an antioxidant, regenerating the cofactor for NOS or directly stimulating eNOS (30), through acting as an antioxidant (32), regenerating the cofactor for NOS (33) or directly stimulating eNOS (34). Unfortunately, we do not collect data from our present study to test these hypotheses. Further studies are necessary to examine the mechanisms. Our study has some limitations. First, the study’s crosssectional design represents a limitation as causality cannot be established. Additionally, it was not possible to adjust the analysis for other factors potentially associated with BP such as genetic factors and intrauterine development. Third, plasma homocysteine and other related variables were not collected in present study, the potential mechanisms for the beneficial effect of B vitamins on blood pressure were not evaluated. Forth, the generalizability of our findings was limited because the study was not national. However, the same trend of diet pattern and nutrition status was shared by the other rural adults and our subjects in China (25). Fifth, information on the supplements containing B vitamins was not collected, as almost no micronutrient supplements would be used by the local rural subjects (25). The main strengths enhanced the validity of our study. First, blood pressure was directly measured by trained personnel according to standardized procedures, not being self-reported, which completely reduced measurement error. Second, the FFQ that we used in the dietary assessment has been evaluated and reasonably reflects long-term diet intake (9). In addition, to reduce the bias of selection bias, because participants might change their diet after they developed some intermediate disease and these changes would possibly attenuate the association between intake of B vitamins and risk of hypertension, we excluded participants with history of cardiovascular diseases and diabetes (35). And our
findings were unlikely to be explained by recall or selection bias because of high quality of study management. Third, our study directly relating dietary B vitamins intake to risk of hypertension among rural Chinese, which is valuable for making individual and policy decisions. Forth, both significantly inverse associations with systolic blood pressure and with hypertension were observed in our study. And, this interpretation is also supported by results of interaction analysis between the three B vitamins in females, which reflect the robustness of our findings. Finally, Sodium was also a key concern in our previous study (9). We also found the participants with higher intake of B vitamins tended to take in less sodium; hence we adjusted sodium in final models. However, effect of sodium in Chinese population seemed limited because excessive intake of sodium was very common among our participants but no significant risk of hypertension related to dietary sodium was observed (9), which is in agreement with other Chinese study (36).
Conclusion In summary, our findings support a beneficial effect of dietary vitamin B-6 intake on risk of hypertension in females with low B vitamins status. The inverse association was more pronounced in higher consumption of both B-6 and folate. Further studies are warranted to validate the conclusion and establish the casual inference.
Acknowledgments The authors appreciate all participants for their participation, the investigators of Xi’an Jiaotong University, and doctors of the People’s Hospital of Hanzhong and the village doctors for their organization. This work was supported by the China Medical Board (Grant Number: 08e925) and National Natural Science Foundation of China (Grant Number: 81230016). Conflicts of interest: There are no conflicts of interest.
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