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Relationship between higher serum selenium level and adverse blood lipid profile
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Clinical Nutrition xxx (2017) 1e6
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Original article
Q3 Q2
Relationship between higher serum selenium level and adverse blood lipid profile Wen Ju a, Mei Ji b, Xia Li a, Zhe Li a, Guanrui Wu a, Xiaofeng Fu a, Xiaomei Yang a, Xibao Gao a, * a b
Department of Public Health, Shandong University, Jinan 250012, Shandong, China Laboratory of Physical and Chemical Inspection, Jinan Municipal Railway Center for Disease Control and Prevention, Jinan 250119, Shandong, China
a r t i c l e i n f o
s u m m a r y
Article history: Received 16 March 2017 Accepted 28 August 2017
Background: As the key component of glutathione peroxidase with unique antioxidant properties, selenium has been considered to play an important part on lipid metabolism. However, the associations of serum selenium concentrations with lipid concentrations and dyslipidemia are still controversial. Methods: We analyzed cross-sectional data including serum selenium levels, lipid concentrations and other related indexes of 8198 rural Chinese. Serum selenium was measured by inductively coupled plasma mass spectrometry, and total cholesterol (TC), triglyceride (TG), high density lipoproteincholesterol (HDL-c) and low density lipoprotein-cholesterol (LDL-c) of serum were measured with kits. Results: Overall, mean serum selenium was 120 mg/l. Multivariate liner regression revealed that selenium concentrations were positively correlated with TC (P < 0.001), HDL-c (P < 0.001), TG (P < 0.001) and LDL-c (P < 0.001). Compared with the lowest quintile of serum selenium, participants in quintile 3, 4 and 5 had higher risks of High-TC dyslipidemia (P 0.02) and High-LDLC dyslipidemia (P < 0.02) after adjusting for covariates. In the stratified analyses, we found that the seleniumedyslipidemia associations were significantly stronger in post-menopausal women (OR: 2.72; 95% CI: 1.97, 4.17) and diabetics (OR: 9.40; 95% CI: 3.02, 29.26). Conclusion: Elevated serum selenium levels were correlated with the increased concentrations of TC, LDL-c, HDL-c and TG, and increased the risk of High-TC and High-LDLC dyslipidemia among rural Chinese. However, the real associations between serum selenium and lipid profile should be verified in specifically designed randomized trials in future. © 2017 Published by Elsevier Ltd.
Keywords: Selenium Rural Chinese Lipid profile Dyslipidemia
1. Introduction Selenium (Se), as an essential microelement, is considered to have beneficial effect on human health, mainly based on the antioxidant capacity of glutathione peroxidases (GPx) and other selenoproteins involved in essential enzymatic functions, such as redox homeostasis, thyroid hormone metabolism, and reproduction [1,2]. A wide range of dietary selenium sources comprises meat, guts, seafood, and cereals. Recommended Dietary Allowance for selenium (55 mg/d) is crucial for maintaining the function and homeostasis of the human body. Selenium levels in people vary widely. Published studies showed that the mean serum selenium
* Corresponding author. Department of Public Health, Shandong University, 44 Wenhua Road, Lixia District, Jinan 250012, Shandong, China. Fax: þ86 531 88382149. E-mail address: [email protected] (X. Gao).
levels were ranging from 51.8 to 142.9 mg/l among people in Britain, Canada, Finland, Germany, South Africa and USA [3e8]. Previous epidemiological researches revealed that the correlation between serum selenium levels and cardiovascular diseases was inconsistent. Studies from Germany [6] and Denmark [9] showed that reduced selenium levels could be one of the risk factors for cardiovascular diseases (CVD). A follow-up study among Italian [10] corroborated high selenium levels with dyslipidemia and diabetes. However, some studies have been unable to demonstrate a correlation of serum selenium with the risk of CVD [11e13]. As a modifiable risk factor of CVD, dyslipidemia, which is characterized by abnormal levels of circulating lipids and lipoproteins, can be divided into four common types, high total cholesterol (TC) dyslipidemia (TC > 5.17 mmol/l), high low density lipoprotein (LDL) cholesterol dyslipidemia (LDL-c > 3.36 mmol/l), high triglycerides (TG) dyslipidemia (TG > 1.69 mmol/l), and low high density lipoprotein (HDL) cholesterol dyslipidemia (HDL-c < 1.04 mmol/l)
http://dx.doi.org/10.1016/j.clnu.2017.08.025 0261-5614/© 2017 Published by Elsevier Ltd.
Please cite this article in press as: Ju W, et al., Relationship between higher serum selenium level and adverse blood lipid profile, Clinical Nutrition (2017), http://dx.doi.org/10.1016/j.clnu.2017.08.025
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according to Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults [14]. As the crucial component of GPx with unique antioxidant properties, selenium has been regarded as one of the important factors for lipid metabolism [15]. However, an increased risk of dyslipidemia in people with high selenium exposure has been observed in recent researches. Observational studies have revealed that serum selenium was positively correlated with LDL-c [8,16e18], TC [3,8,16e18], or TG [8]. However, randomized controlled trials (RCTs) on the effect of selenium supplementation on lipid concentrations are limited to studies in which selenium supplements were given combined with other minerals or to small short-term studies, and results of RCTs didn't find significant association between serum selenium and lipid profile [19e21]. China has a large proportion of agriculture and rural people. Rural Chinese usually eat locally produced food, and seldom eat any dietary supplements. In addition, most of them are local inhabitants at the same place during their lifetime [22]. So it is of great significance to probe into the correlations between serum selenium concentrations and lipid or dyslipidemia in rural Chinese. To our knowledge, there were few large-scale studies conducted in China to evaluate the correlations between serum selenium levels and lipid concentrations. Su et al. found that high selenium level in nail could increase the risk of dyslipidemia [23]. A study [24] from Zhoukoudian area, Beijing in 2007 revealed that selenium concentrations were positively correlated with TC, and negatively correlated with TG and HDL-c. However, the final result may be limited to the small sample size. Our objective in the cross-sectional study, therefore, was to explore the associations between serum selenium levels and lipid concentrations, and further investigated the effect of selenium status on the risk of dyslipidemia among participants over eighteen from rural areas in China.
reported. We used traditional methods to measure height, weight, and blood pressure (BP). The average values of the two measurements were obtained, and the results were accurate to 0.1 cm, 0.1 kg, 1 mmHg. Hypertension was defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg. The dietary pattern and nutritional status of participants were investigated by 24 h dietary investigation inquiring for three days.
2. Methods
3. Result
2.1. Study population
3.1. Baseline clinical characteristics
The study population of our study was from Shandong University health research base, a cohort study on participants from rural areas in three counties (Junan, Liangshan and Pingyin) of Shandong Province in China. We excluded population under 18 years old and people with missing data on selenium, and the final sample size was 8198. All people involved in this study obtained written informed consent before collecting blood samples.
A total of 8198 participants aged from 18 to 95 were included in our cross-sectional analysis at baseline. Table 1 describes the general characteristics of the people involved in our study across quintile categories of plasma selenium. Mean concentration of selenium in the general population was 120 mg/l. Mean serum selenium concentration of each quintile group was 80.87 mg/l, 101.78 mg/l, 116.36 mg/l, 132.60 mg/l, 168.51 mg/l. Higher selenium was correlated with higher age, higher BMI, higher BP, higher blood glucose, smoking status, drinking status, lower static activities time and higher fat intakes from dietary.
2.2. Examination of blood biochemical indicators Fasting serum TC, TG, LDL-c, HDL-c, plasma glucose, serum selenium were determined with the morning fasting venous blood. Serum samples were centrifuged with 1000 rpm for 5e10 min after placing at room temperature for 30 min, then draw the upper layer of serum into the centrifuge tube. All blood samples were kept in 80 C refrigerator until analysis. Blood glucose was determined by Glucose Oxidase method, and used the blood glucose Kit in fully automatic chemistry analyzer. Serum selenium was determined by inductively coupled plasma mass spectrometry. TC, TG, HDL-c and LDL-c of serum were measured with TC kit, TG kit, HDL-c kit, and LDL-c kit. 2.3. Other variables Age, gender, current cigarette smoking (yes, no), current alcohol use (yes, no), cardiovascular diseases (yes, no), family history of cardiovascular diseases (yes, no) and static activities (h) were self-
2.4. Statistical analysis Participants were divided into quintiles by serum selenium concentration, and participants in the lowest quintiles were chosen as the reference group. Measurement data are expressed as the mean ± standard deviation (SD), and dichotomous variables were expressed as percentages. We estimated the differences in the levels of TC, TG, LDL-c, and HDL-c by multivariate linear regression, and calculated the odds ratios (OR) and 95% confidence intervals (CI) for 4 kinds of dyslipidemia by logistic regression, comparing the 4 higher quintiles to the lowest quintile. We used three models with progressive degrees of adjustment. Model 1 was adjusted for sex (male, female), age. Model 2 was further adjusted for BMI, hypertension (yes, no), diabetes (yes, no), family history of CVD (yes, no), current cigarette smoking (yes, no), current alcohol use (yes, no) and static activities time. Model 3 was further adjusted for the dietary intakes of energy, fat, vitamins E, calcium, and magnesium. Moreover, we estimated the correlation between serum selenium level and dyslipidemia (including four types) by performing analyses in which people were stratified according to covariates, including age (<40, 40e60, >60), gender (male, pre-menopausal women, post-menopausal women), current smoking status (yes, no), current alcohol use (yes, no), diabetes (yes, no), hypertension (yes, no) with Model 3 adjustment. All analyses were performed with using the SPSS statistical software version 23.0.
3.2. Relationships between serum selenium and lipid profile In multivariate liner regression analysis, high serum selenium levels were associated with higher level of TC, TG, LDL-c, and HDL-c. The multivariable-adjusted differences in TG, TC, LDL-c, and HDL-c were 0.24 mmol/l (95% CI: 0.17, 0.31), 0.57 mmol/l (95% CI: 0.49, 0.65), 0.37 mmol/l (95% CI: 0.32, 0.42), and 0.12 mmol/l (95% CI: 0.08, 0.16), respectively (Table 2). 3.3. Relationships between serum selenium and dyslipidemia Table 3 revealed positive associations of serum selenium concentrations with High-TC and High-LDLC dyslipidemia after adjusting the age and sex, and adjustment for lifestyle and dietary factors only slightly attenuated these associations. Multivariableadjusted OR in High-TC dyslipidemia comparing quintiles 3e5 to
Please cite this article in press as: Ju W, et al., Relationship between higher serum selenium level and adverse blood lipid profile, Clinical Nutrition (2017), http://dx.doi.org/10.1016/j.clnu.2017.08.025
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Table 1 Baseline characteristics of the study population by quintile (Q) of serum selenium concentration. Characteristics
Q1
Q2
Q3
Q4
Q5
Overall
P value
n Serum selenium, Mean ± SD, mg/l Age, Mean ± SD, y Male (%) BMI, Mean ± SD, kg/m2 SBP, Mean ± SD, mmHg DBP, Mean ± SD, mmHg Glucose, Mean ± SD, mmol/l TG, Mean ± SD, mmol/l TC, Mean ± SD, mmol/l LDL-c, Mean ± SD, mmol/l HDL-c, Mean ± SD, mmol/l Prevalence of CVD (%) Family history of CVD (%) Smokers (%) Drinkers (%) Static activities time, Mean ± SD, h Se intake from food, Mean ± SD, mg/d Energy, Mean ± SD, kcal/d Fat, Mean ± SD, g/d Vitamins E, Mean ± SD, mg/d Calcium, Mean ± SD, mg/d Magnesium, Mean ± SD, mg/d
1640 80.87 ± 11.01 48.41 ± 15.00 41.20 21.94 ± 4.70 125.43 ± 24.16 78.58 ± 12.70 5.18 ± 0.82 1.24 ± 0.82 4.43 ± 1.04 2.33 ± 0.62 1.65 ± 0.41 5.90 10.70 22.50 13.10 7.35 ± 3.04 38.56 ± 17.36 2286.00 ± 851.90 63.47 ± 31.55 30.32 ± 13.00 1131.82 ± 554.97 264.80 ± 150.41
1647 101.78 ± 4.48 50.22 ± 14.80 39.40 22.64 ± 4.36 127.80 ± 22.33 79.68 ± 12.05 5.21 ± 0.89 1.32 ± 0.99 4.54 ± 1.10 2.44 ± 0.82 1.70 ± 0.47 7.30 9.40 22.60 12.00 7.48 ± 2.93 38.77 ± 18.32 2315.55 ± 881.98 65.44 ± 30.32 30.92 ± 12.38 1084.86 ± 556.90 250.48 ± 104.55
1633 116.36 ± 4.06 50.1 ± 14.91 39.30 22.91 ± 4.27 131.47 ± 23.92 81.09 ± 11.85 5.41 ± 1.32 1.38 ± 1.02 4.73 ± 1.78 2.52 ± 0.64 1.71 ± 0.45 8.20 10.00 25.70 14.60 7.48 ± 3.06 39 ± 17.99 2301.75 ± 845.44 64.88 ± 30.19 31.0 ± 12.86 1068.27 ± 609.38 253.60 ± 131.91
1639 132.6 ± 5.61 50.18 ± 14.56 39.20 23.31 ± 4.02 133.99 ± 23.82 81.78 ± 11.75 5.5 ± 1.44 1.38 ± 0.99 4.82 ± 1.13 2.63 ± 0.72 1.72 ± 0.50 9.10 9.50 25.20 18.20 7.4 ± 2.97 39.83 ± 20.02 2295.98 ± 922.56 67.50 ± 33.44 31.60 ± 13.40 1076.46 ± 641.84 261.30 ± 134.57
1639 168.51 ± 27.80 51.06 ± 13.96 41.00 23.61 ± 3.87 135.87 ± 22.46 83.29 ± 11.37 5.68 ± 1.61 1.5 ± 1.27 5.06 ± 1.10 2.73 ± 0.69 1.77 ± 0.54 9.90 10.70 26.70 19.00 7.15 ± 3.13 40.24 ± 18.82 2290.72 ± 902.57 66.36 ± 32.52 31.48 ± 13.35 1051.47 ± 621.80 261.80 ± 117.20
8198 120 ± 32.72 49.99 ± 14.67 40 22.88 ± 4.29 130.91 ± 23.66 80.88 ± 12.06 5.41 ± 1.29 1.37 ± 1.04 4.73 ± 1.28 2.54 ± 0.72 1.71 ± 0.48 8.20 10.00 24.60 15.50 7.37 ± 3.03 39.33 ± 18.59 2298.13 ± 882.93 65.64 ± 31.69 31.10 ± 13.02 1082.60 ± 598.42 258.41 ± 128.74
<0.001 0.872 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.245 0.967 0.005 <0.001 0.036 0.147 0.949 0.042 0.168 0.002 0.006
P value refers to comparisons of the means or proportions among the groups by the 1-way ANOVA and ManneWhitney tests. BMI indicates body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglyceride; TC, total cholesterol; LDL-c, low-density lipoprotein-cholesterol; HDL-c, high-density lipoprotein-cholesterol; CVD, cardiovascular disease.
Table 2 Adjusted differences (95% confidence interval) in lipid concentrations comparing the 4 highest quartiles to the lowest quartile of plasma selenium.
TG Model Model Model TC Model Model Model LDL-c Model Model Model HDL-c Model Model Model
Q1
Q2
Q3
Q4
Q5
P-value
1a 2b 3c
0 0 0
0.07 (0.00, 0.14) 0.05 (0.02, 0.12) 0.05 (0.02, 0.12)
0.14 (0.07, 0.21) 0.13 (0.06, 0.20) 0.14 (0.07, 0.21)
0.14 (0.07, 0.21) 0.12 (0.05, 0.19) 0.11 (0.04, 0.18)
0.26 (0.18, 0.34) 0.24 (0.17, 0.31) 0.24 (0.17, 0.31)
<0.001 <0.001 <0.001
1a 2b 3c
0 0 0
0.11 (0.03, 0.19) 0.12 (0.04, 0.20) 0.1 (0.02, 0.18)
0.3 (0.19, 0.41) 0.28 (0.17, 0.39) 0.27 (0.15, 0.39)
0.39 (0.31, 0.47) 0.33 (0.25, 0.41) 0.33 (0.25, 0.41)
0.63 (0.55, 0.71) 0.61 (0.53, 0.69) 0.57 (0.49, 0.65)
<0.001 <0.001 <0.001
1a 2b 3c
0 0 0
0.11 (0.06, 0.16) 0.12 (0.06, 0.18) 0.1 (0.04, 0.16)
0.19 (0.14, 0.24) 0.17 (0.12, 0.22) 0.15 (0.1, 0.2)
0.3 (0.25, 0.35) 0.27 (0.22, 0.32) 0.27 (0.22, 0.32)
0.4 (0.35, 0.45) 0.37 (0.32, 0.42) 0.37 (0.32, 0.42)
<0.001 <0.001 <0.001
1a 2b 3c
0 0 0
0.05 (0.02, 0.08) 0.04 (0.01, 0.07) 0.03 (0, 0.06)
0.06 (0.03, 0.09) 0.05 (0.02, 0.08) 0.05 (0.02, 0.08)
0.07 (0.04, 0.1) 0.04 (0.01, 0.07) 0.06 (0.03, 0.09)
0.12 (0.08, 0.16) 0.12 (0.08, 0.16) 0.12 (0.08, 0.16)
<0.001 <0.001 <0.001
P value refers to the comparisons of the 4 higher quintiles to the lowest quintile by multivariate linear regression. a Adjusted for age (continuous), gender (male, female). b Further adjusted for BMI (continuous), hypertension (yes, no), diabetes (yes, no), family history of coronary heart disease (yes, no), current cigarette smoking (yes, no), current alcohol use (yes, no) and static activities time (continuous). c Further adjusted for dietary intakes of energy (continuous), fat (continuous), vitamins E (continuous), calcium (continuous), and magnesium (continuous).
quintile 1 of selenium level were 1.32 (95% CI: 1.05, 1.66), 1.49 (95% CI: 1.19, 1.87) and 2.19 (95% CI: 1.75, 2.73), respectively (p 0.02). OR in High-LDLC dyslipidemia was separately 1.77 (95% CI: 1.15, 2.72), 1.67 (95% CI: 1.09, 2.57), 2.36 (95% CI: 1.57, 3.55) and 3.54 (95% CI: 2.38, 5.26), respectively (p < 0.02). However, serum selenium concentrations were not associated with Low-HDLC dyslipidemia and High-TG dyslipidemia after adjusting the for lifestyle and dietary factors. 3.4. Stratified analyses of association between serum selenium and dyslipidemia In the stratified analyses, we found that the seleniumedyslipidemia associations were significantly stronger in the post-menopausal women (OR: 2.72; 95% CI: 1.97, 4.17) and diabetic
(OR: 9.40; 95% CI: 3.02, 29.26), However, no interaction was detected with other variables (Table 4). 4. Discussion In this study, we found that higher serum selenium level was correlated with higher level of TC, TG, LDL-c, and HDL-c after adjusting for age, gender, lifestyle and dietary factors. Compared to lowest quintile of selenium, participants in higher quintiles of serum selenium had higher risk of High-TC and High-LDLC dyslipidemia. Elevated blood lipid has been found to be an independent risk factor for cardiovascular diseases such as ischemic stroke, myocardial infarction, and sudden cardiac death due to atherosclerosis and lacunar infarctions [25]. TC and LDL-c were thought to initiate atherosclerotic plaques when it penetrates through the
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
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Table 3 Multivariable-adjusted odds ratios for four types of dyslipidemia comparing the 4 highest quartiles to the lowest quartile of plasma selenium. Q1
Q2
Q3
n (%) Reference n (%) OR (95% CI) High-TC Model 1 Model 2 Model 3 High-TG Model 1 Model 2 Model 3 High-LDL Model 1 Model 2 Model 3 Low-HDL Model 1 Model 2 Model 3
Q4
P-value n (%) OR (95% CI)
Q5
P-value n (%) OR (95% CI)
P value
P-value n (%) OR (95% CI)
P-value
21.80 1 1 1
25.50 1.18 (0.99,1.42) 0.070 1.14 (0.92,1.41) 0.222 1.10 (0.87,1.40) 0.426
30.80 1.55 (1.30,1.84) <0.001 34.00 1.80 (1.52,2.14) <0.001 44.00 2.72 (2.30,3.21) <0.001 <0.001 1.37 (1.12,1.69) 0.002 1.52 (1.24,1.86) <0.001 2.31 (1.90,2.82) <0.001 <0.001 1.32 (1.05,1.66) 0.020 1.49 (1.19,1.87) 0.001 2.19 (1.75,2.73) <0.001 <0.001
18.60 1 1 1
19.80 1.05 (0.86,1.27) 0.631 1.0 (0.80,1.26) 0.99 1.02 (0.79,1.31) 0.91
22.10 1.24 (1.02,1.49) 0.027 1.17 (0.94,1.94) 0.168 1.13 (0.88,1.45) 0.346
4.90
1 1 1
9.10
1.89 (1.38,2.60) <0.001 8.90 1.88 (1.30,2.72) 0.001 1.77 (1.15,2.72) 0.010
1.88 (1.37,2.58) <0.001 12.30 2.61 (1.93,3.53) <0.001 17.20 3.89 (2.91,5.20) <0.001 <0.001 1.83 (1.27,2.64) 0.001 2.35 (1.65,3.34) <0.001 3.66 (2.60,5.14) <0.001 <0.001 1.67 (1.09,2.57) 0.019 2.36 (1.57,3.55) <0.001 3.54 (2.38,5.26) <0.001 <0.001
4.60
1 1 1
4.00
0.92 (0.63,1.33) 0.641 0.89 (0.58,1.36) 0.577 0.97 (0.61,1.54) 0.893
0.71 (0.48,1.05) 0.086 0.69 (0.44,1.09) 0.112 0.71 (0.43,1.17) 0.176
3.20
23.30 1.33 (1.11,1.60) 0.003 1.17 (0.94,1.46) 0.158 1.16 (0.91,1.49) 0.230
3.80
0.88 (0.61,1.28) 0.513 0.88 (0.58,1.34) 0.553 0.94 (0.60,1.50) 0.805
24.70 1.40 (1.17,1.68) <0.001 <0.001 1.18 (0.95,1.48) 0.134 0.008 1.20 (0.94,1.53) 0.151 0.008
2.90
0.66 (0.44,0.97) 0.031 0.65 (0.41,1.02) 0.061 0.70 (0.42,1.14) 0.153
0.112 0.235 0.333
P value refers to the comparisons of the 4 higher quintiles to the lowest quintile by multivariate linear regression. CI, confidence interval; OR, odds ratios.
endothelium of a coronary artery into its wall [26]. Furthermore, High-TC and High-LDLC dyslipidemia are associated with the development of atherosclerotic heart diseases (ASCVD) including coronary heart disease (CHD), stroke, and peripheral arterial disease [27]. Our results demonstrated that high serum selenium may be prospectively associated with a trend for an increased risk of CVD. Previous results from different participants involved in studies investigating the associations between serum selenium levels and lipid concentrations can be seen in Supplemental Table. In Table 4 Stratified analyses of the associations [multivariable-adjusted odds ratio (95% confidence interval)] between serum selenium concentrations and dyslipidemia.
Age, y <40 40e59 >60 Gender Male Pre-menopausal womena Post-menopausal womena BMI, kg/m2 <24 24e26.99 >27 Current cigarette smoking No Yes Current alcohol use No Yes Static activities time, h <6 6e8 >9 Diabetes Noa Yesa Hypertension No Yes a
ORb
95% CI
1.63 1.73 2.53
1.06, 2.46 1.30, 2.30 1.59, 4.04
1.91 1.42 2.72
1.37, 2.66 0.89, 1.90 1.97, 4.17
1.91 1.61 1.40
1.44, 2.54 1.14, 2.28 0.74, 2.63
1.59 2.07
1.26, 2.01 1.35, 3.16
1.63 2.35
1.30, 2.03 1.39, 4.00
1.53 1.77 1.73
1.02, 2.29 1.27, 2.47 1.23, 2.43
1.72 9.40
1.66, 2.40 3.02, 29.26
1.57 1.92
1.21, 2.05 1.39, 2.66
Significant difference in subgroups. Adjusted for age (continuous), gender (male, female), BMI (continuous), hypertension (yes, no), diabetes (yes, no), family history of coronary heart disease (yes, no), current cigarette smoking (yes, no), current alcohol use (yes, no), static activities time (continuous), dietary intakes of energy (continuous), fat (continuous), vitamins E (continuous), calcium (continuous), and magnesium (continuous). b
agreement with our results, a cross-sectional study [16] among US adults in National Health and Nutrition Examination Survey (NHANES) showed that elevated serum selenium levels were positively correlated with increased serum levels of TC and LDL-c, and this correlation was also observed between selenium level and HDL-c at low selenium levels. Similar results were also found in European countries. In addition, serum selenium concentrations were positively associated with TC and non-HDL cholesterol in UK adults [3], with TC and LDL-c in Spanish [17], and with TC in Danish [9] and Italian men [28]. A cross-sectional study in China [23] found that participants with high nail selenium concentration had higher risks of four types of dyslipidemia. However, evidence from some randomized controlled trials [19,20] was limited because selenium supplementations were always combined with other minerals, and the effect of selenium cannot be isolated. An RCT [21] from Iran showed that selenium supplementations alone were not associated with lipid concentrations. In the UK PRECISE Pilot Study [29], crosssectional analyses at baseline revealed a positive association between selenium concentration and TC. Interestingly, total and nonHDL cholesterol levels were significantly decreased after the selenium intakes of 100 or 200 mg per day for 6 months, while daily selenium intake of 300 mg did not affect total and non-HDL cholesterol levels, but it significantly increased HDL-c levels. According to WHO, China has been defined as low-Se area or Se deficiency area. The Se deficiency diseases (Keshan disease and Kashin-Beck disease) were first identified in the low-selenium geological belt with selenium contents in soil stretching from northeast to southwest of China [30]. The mean selenium concentration of our study population is higher to those concentrations obtained in other countries such as the UK [3], Germany [6], and Spain [17], while is lower to that obtained in the US in the NHANES [16], where it was 136.7 mg/l. Compared with other studies in China, our result of the serum selenium level is higher than that obtained in Zhoukoudian area of Beijing [31], but is lower than that in Shanghai [32]. The underlying mechanisms for the associations between high selenium levels and lipid profile were still in discussion. Previous studies have investigated the function of selenoprotein in cardiovascular disease by analysis of oxidative stress under conditions of selenium supplementation or deficiency. Animal experiments showed significant increases in the activity of LDL-receptor and the expression of mRNA after selenium supplementation, which may be mediated by the iodothyronine deiodinases (DIOs) [33,34]. DIOs are selenoproteins involved in the activity of thyroxine to
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triiodothyronine, which increases the expression of LDL-receptor gene [35]. Moreover, the correlation between selenium and lipid level was associated with insulin sensitivity in humans. Reactive oxygen species (ROS), as the second messenger in insulin signal transduction, could be scavenged by selenoprotein. Constitutive expression of selenoprotein impaired insulin signaling and reduced the systemic insulin sensitivity. Evidence from a review showed that insulin sensitivity was associated with lipid accumulation, and insulin sensitivity was inversely correlated with plasma level of triglyceride [36,37]. Furthermore, protein tyrosine phosphatase 1B (PTP1B), which is considered to be a key enzyme and play an important role in stimulating the fatty acid synthesis (FAS) and in reverse regulation of insulin signaling, has been widely studied for the correlation between selenium concentration and lipid profile. Firstly, expression and activity of PTP1B were elevated in rats with fructose-rich diets, resulting in the induction of FAS and in an increase of the level of liver triglyceride [38,39]. In addition, evidence from animal experiments revealed that selenium could also elevate PTP1b activity in liver of rats, which might cause the decrease of insulin sensitivity further [40]. According to the results of stratified analysis, post-menopausal women with high serum selenium status may be at particularly high risk of dyslipidemia. Postmenopausal women experienced a drop in the level of estrogens, which play a significant biological role in modulating the antioxidant/pro-oxidant balance, and an increase in lipid peroxidation and formation of reactive oxygen species has been observed after the decline of estrogens [41]. Moreover, more significant seleniumedyslipidemia associations were observed in diabetics, which were often accompanied with insulin resistance. As above mentioned, high selenium level may be associated with the reduced insulin sensitivity, and promote the lipid accumulation in diabetics. A positive association was observed between serum selenium concentration and blood glucose in our study, and a similar phenomenon has also been observed in other studies [42,43]. In addition, the seleniumedyslipidemia correlation was slightly higher in smokers, drinkers and hypertensive patients as compared with their counterparts, while the differences were not statistically significant. Future analyses of serum selenium levels and dyslipidemia should carefully evaluate the effect of the above mentioned influence factors to confirm interactions that we observed in this study. Because of our cross-sectional design, we could not determine whether dyslipidemia as a consequence of selenium supplementation, or whether a common metabolic pathway might explain the correlation between serum selenium level and lipid profile. So rigorous randomized controlled trials should be conducted to verify our conclusion. Moreover, our study didn't consider that genetic factors might affect the correlation between serum selenium level and lipid concentration. A finding showed that selenium concentration was associated with genetic variation in certain genes related to lipid metabolic pathways [44]. Targeted removal of the tRNA[Ser]Sec gene (Trsp) in mouse leads to the selenium deficiency, and then resulted in elevating Apolipoprotein E (APOE) level which was accompanied by increasing cholesterol levels [45]. Epidemiological study revealed that Apolipoprotein E genotyping may influence the risk of dyslipidemia [23]. Though causality was not established in our cross-sectional study, several strengths of this study should be emphasized. Our included participants aged from 18 to 95 with a wide range of coverage, and have stable dietary structures, which reduced the confounding bias to some degree. To our knowledge, our study is the first large-scale study conducted in China to investigate the effect of serum selenium level on lipid concentration and dyslipidemia. Furthermore, stratified analyses were conducted in subgroups and contributed to find the high-risk population.
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5. Conclusion High serum selenium level was associated with high serum concentrations of TC, TG, LDL-c, HDL-c, and increased the risk of dyslipidemia of (High-TC and High-LDLC) among rural Chinese. Moreover, post-menopausal women and diabetics who are in high serum selenium status had higher risk of dyslipidemia. However, whether dyslipidemia as a consequence of increased selenium intake can't be tested in our study, and the real associations should be verified in specifically designed clinical studies in future. Financial support This work was supported by the National Natural Science Foundation of China (81373048) and Natural Science Foundation of Shandong Province (Y2006C117). Statement of authorship Xibao Gao was responsible for the design of the current study, and has the primary responsibility for the final content. Wen Ju participated at the design, in data analysis and wrote the manuscript. Mei Ji reviewed the final version of manuscript. Xia Li, Zhe Li, Guanrui Wu, Xiaofeng Fu and Xiaomei Yang were responsible for the conducted the research (data collection). Conflict of interest None. Acknowledgments We sincerely appreciate all participants for their kind cooperation in our study. We also wish to acknowledge all of the investigators in our study. Appendix A. Supplementary material Supplementary material associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.clnu. 2017.08.025. References [1] Burk RF. Selenium, an antioxidant nutrient. Nutr Clin Care 2002;5:75e9. [2] Papp LV, Lu J, Holmgren A, Khanna KK. From selenium to selenoproteins: synthesis, identity, and their role in human health. Antioxid Redox Signal 2007;9:775e806. [3] Stranges S, Laclaustra M, Ji C, Cappuccio FP, Navas-Acien A, Ordovas JM, et al. Higher selenium status is associated with adverse blood lipid profile in British adults. J Nutr 2010;140:81e7. [4] Lalonde L, Jean Y, Roberts KD, Chapdelaine A, Bleau G. Fluorometry of selenium in serum or urine. Clin Chem 1982;28:172e4. [5] Salonen JT, Alfthan G, Huttunen JK, Pikkarainen J, Puska P. Association between cardiovascular death and myocardial infarction and serum selenium in a matched-pair longitudinal study. Lancet 1982;2:175e9. [6] Lubos E, Sinning CR, Schnabel RB, Wild PS, Zeller T, Rupprecht HJ, et al. Serum selenium and prognosis in cardiovascular disease: results from the AtheroGene study. Atherosclerosis 2010;209:271e7. [7] Heese HD, Lawrence MA, Dempster WS, Pocock F. Reference concentrations of serum selenium and manganese in healthy nulliparas. South Afr Med J 1988;73:163e5. [8] Bleys J, Navas-Acien A, Stranges S, Menke A, Miller 3rd ER, Guallar E. Serum selenium and serum lipids in US adults. Am J Clin Nutr 2008;88:416e23. [9] Suadicani P, Hein HO, Gyntelberg F. Serum selenium concentration and risk of ischaemic heart disease in a prospective cohort study of 3000 males. Atherosclerosis 1992;96:33e42. [10] Stranges S, Galletti F, Farinaro E, D'Elia L, Russo O, Iacone R, et al. Associations of selenium status with cardiometabolic risk factors: an 8-year follow-up analysis of the Olivetti Heart study. Atherosclerosis 2011;217:274e8.
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Original article
Q3 Q2
Relationship between higher serum selenium level and adverse blood lipid profile Wen Ju a, Mei Ji b, Xia Li a, Zhe Li a, Guanrui Wu a, Xiaofeng Fu a, Xiaomei Yang a, Xibao Gao a, * a b
Department of Public Health, Shandong University, Jinan 250012, Shandong, China Laboratory of Physical and Chemical Inspection, Jinan Municipal Railway Center for Disease Control and Prevention, Jinan 250119, Shandong, China
a r t i c l e i n f o
s u m m a r y
Article history: Received 16 March 2017 Accepted 28 August 2017
Background: As the key component of glutathione peroxidase with unique antioxidant properties, selenium has been considered to play an important part on lipid metabolism. However, the associations of serum selenium concentrations with lipid concentrations and dyslipidemia are still controversial. Methods: We analyzed cross-sectional data including serum selenium levels, lipid concentrations and other related indexes of 8198 rural Chinese. Serum selenium was measured by inductively coupled plasma mass spectrometry, and total cholesterol (TC), triglyceride (TG), high density lipoproteincholesterol (HDL-c) and low density lipoprotein-cholesterol (LDL-c) of serum were measured with kits. Results: Overall, mean serum selenium was 120 mg/l. Multivariate liner regression revealed that selenium concentrations were positively correlated with TC (P < 0.001), HDL-c (P < 0.001), TG (P < 0.001) and LDL-c (P < 0.001). Compared with the lowest quintile of serum selenium, participants in quintile 3, 4 and 5 had higher risks of High-TC dyslipidemia (P 0.02) and High-LDLC dyslipidemia (P < 0.02) after adjusting for covariates. In the stratified analyses, we found that the seleniumedyslipidemia associations were significantly stronger in post-menopausal women (OR: 2.72; 95% CI: 1.97, 4.17) and diabetics (OR: 9.40; 95% CI: 3.02, 29.26). Conclusion: Elevated serum selenium levels were correlated with the increased concentrations of TC, LDL-c, HDL-c and TG, and increased the risk of High-TC and High-LDLC dyslipidemia among rural Chinese. However, the real associations between serum selenium and lipid profile should be verified in specifically designed randomized trials in future. © 2017 Published by Elsevier Ltd.
Keywords: Selenium Rural Chinese Lipid profile Dyslipidemia
1. Introduction Selenium (Se), as an essential microelement, is considered to have beneficial effect on human health, mainly based on the antioxidant capacity of glutathione peroxidases (GPx) and other selenoproteins involved in essential enzymatic functions, such as redox homeostasis, thyroid hormone metabolism, and reproduction [1,2]. A wide range of dietary selenium sources comprises meat, guts, seafood, and cereals. Recommended Dietary Allowance for selenium (55 mg/d) is crucial for maintaining the function and homeostasis of the human body. Selenium levels in people vary widely. Published studies showed that the mean serum selenium
* Corresponding author. Department of Public Health, Shandong University, 44 Wenhua Road, Lixia District, Jinan 250012, Shandong, China. Fax: þ86 531 88382149. E-mail address: [email protected] (X. Gao).
levels were ranging from 51.8 to 142.9 mg/l among people in Britain, Canada, Finland, Germany, South Africa and USA [3e8]. Previous epidemiological researches revealed that the correlation between serum selenium levels and cardiovascular diseases was inconsistent. Studies from Germany [6] and Denmark [9] showed that reduced selenium levels could be one of the risk factors for cardiovascular diseases (CVD). A follow-up study among Italian [10] corroborated high selenium levels with dyslipidemia and diabetes. However, some studies have been unable to demonstrate a correlation of serum selenium with the risk of CVD [11e13]. As a modifiable risk factor of CVD, dyslipidemia, which is characterized by abnormal levels of circulating lipids and lipoproteins, can be divided into four common types, high total cholesterol (TC) dyslipidemia (TC > 5.17 mmol/l), high low density lipoprotein (LDL) cholesterol dyslipidemia (LDL-c > 3.36 mmol/l), high triglycerides (TG) dyslipidemia (TG > 1.69 mmol/l), and low high density lipoprotein (HDL) cholesterol dyslipidemia (HDL-c < 1.04 mmol/l)
http://dx.doi.org/10.1016/j.clnu.2017.08.025 0261-5614/© 2017 Published by Elsevier Ltd.
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according to Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults [14]. As the crucial component of GPx with unique antioxidant properties, selenium has been regarded as one of the important factors for lipid metabolism [15]. However, an increased risk of dyslipidemia in people with high selenium exposure has been observed in recent researches. Observational studies have revealed that serum selenium was positively correlated with LDL-c [8,16e18], TC [3,8,16e18], or TG [8]. However, randomized controlled trials (RCTs) on the effect of selenium supplementation on lipid concentrations are limited to studies in which selenium supplements were given combined with other minerals or to small short-term studies, and results of RCTs didn't find significant association between serum selenium and lipid profile [19e21]. China has a large proportion of agriculture and rural people. Rural Chinese usually eat locally produced food, and seldom eat any dietary supplements. In addition, most of them are local inhabitants at the same place during their lifetime [22]. So it is of great significance to probe into the correlations between serum selenium concentrations and lipid or dyslipidemia in rural Chinese. To our knowledge, there were few large-scale studies conducted in China to evaluate the correlations between serum selenium levels and lipid concentrations. Su et al. found that high selenium level in nail could increase the risk of dyslipidemia [23]. A study [24] from Zhoukoudian area, Beijing in 2007 revealed that selenium concentrations were positively correlated with TC, and negatively correlated with TG and HDL-c. However, the final result may be limited to the small sample size. Our objective in the cross-sectional study, therefore, was to explore the associations between serum selenium levels and lipid concentrations, and further investigated the effect of selenium status on the risk of dyslipidemia among participants over eighteen from rural areas in China.
reported. We used traditional methods to measure height, weight, and blood pressure (BP). The average values of the two measurements were obtained, and the results were accurate to 0.1 cm, 0.1 kg, 1 mmHg. Hypertension was defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg. The dietary pattern and nutritional status of participants were investigated by 24 h dietary investigation inquiring for three days.
2. Methods
3. Result
2.1. Study population
3.1. Baseline clinical characteristics
The study population of our study was from Shandong University health research base, a cohort study on participants from rural areas in three counties (Junan, Liangshan and Pingyin) of Shandong Province in China. We excluded population under 18 years old and people with missing data on selenium, and the final sample size was 8198. All people involved in this study obtained written informed consent before collecting blood samples.
A total of 8198 participants aged from 18 to 95 were included in our cross-sectional analysis at baseline. Table 1 describes the general characteristics of the people involved in our study across quintile categories of plasma selenium. Mean concentration of selenium in the general population was 120 mg/l. Mean serum selenium concentration of each quintile group was 80.87 mg/l, 101.78 mg/l, 116.36 mg/l, 132.60 mg/l, 168.51 mg/l. Higher selenium was correlated with higher age, higher BMI, higher BP, higher blood glucose, smoking status, drinking status, lower static activities time and higher fat intakes from dietary.
2.2. Examination of blood biochemical indicators Fasting serum TC, TG, LDL-c, HDL-c, plasma glucose, serum selenium were determined with the morning fasting venous blood. Serum samples were centrifuged with 1000 rpm for 5e10 min after placing at room temperature for 30 min, then draw the upper layer of serum into the centrifuge tube. All blood samples were kept in 80 C refrigerator until analysis. Blood glucose was determined by Glucose Oxidase method, and used the blood glucose Kit in fully automatic chemistry analyzer. Serum selenium was determined by inductively coupled plasma mass spectrometry. TC, TG, HDL-c and LDL-c of serum were measured with TC kit, TG kit, HDL-c kit, and LDL-c kit. 2.3. Other variables Age, gender, current cigarette smoking (yes, no), current alcohol use (yes, no), cardiovascular diseases (yes, no), family history of cardiovascular diseases (yes, no) and static activities (h) were self-
2.4. Statistical analysis Participants were divided into quintiles by serum selenium concentration, and participants in the lowest quintiles were chosen as the reference group. Measurement data are expressed as the mean ± standard deviation (SD), and dichotomous variables were expressed as percentages. We estimated the differences in the levels of TC, TG, LDL-c, and HDL-c by multivariate linear regression, and calculated the odds ratios (OR) and 95% confidence intervals (CI) for 4 kinds of dyslipidemia by logistic regression, comparing the 4 higher quintiles to the lowest quintile. We used three models with progressive degrees of adjustment. Model 1 was adjusted for sex (male, female), age. Model 2 was further adjusted for BMI, hypertension (yes, no), diabetes (yes, no), family history of CVD (yes, no), current cigarette smoking (yes, no), current alcohol use (yes, no) and static activities time. Model 3 was further adjusted for the dietary intakes of energy, fat, vitamins E, calcium, and magnesium. Moreover, we estimated the correlation between serum selenium level and dyslipidemia (including four types) by performing analyses in which people were stratified according to covariates, including age (<40, 40e60, >60), gender (male, pre-menopausal women, post-menopausal women), current smoking status (yes, no), current alcohol use (yes, no), diabetes (yes, no), hypertension (yes, no) with Model 3 adjustment. All analyses were performed with using the SPSS statistical software version 23.0.
3.2. Relationships between serum selenium and lipid profile In multivariate liner regression analysis, high serum selenium levels were associated with higher level of TC, TG, LDL-c, and HDL-c. The multivariable-adjusted differences in TG, TC, LDL-c, and HDL-c were 0.24 mmol/l (95% CI: 0.17, 0.31), 0.57 mmol/l (95% CI: 0.49, 0.65), 0.37 mmol/l (95% CI: 0.32, 0.42), and 0.12 mmol/l (95% CI: 0.08, 0.16), respectively (Table 2). 3.3. Relationships between serum selenium and dyslipidemia Table 3 revealed positive associations of serum selenium concentrations with High-TC and High-LDLC dyslipidemia after adjusting the age and sex, and adjustment for lifestyle and dietary factors only slightly attenuated these associations. Multivariableadjusted OR in High-TC dyslipidemia comparing quintiles 3e5 to
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Table 1 Baseline characteristics of the study population by quintile (Q) of serum selenium concentration. Characteristics
Q1
Q2
Q3
Q4
Q5
Overall
P value
n Serum selenium, Mean ± SD, mg/l Age, Mean ± SD, y Male (%) BMI, Mean ± SD, kg/m2 SBP, Mean ± SD, mmHg DBP, Mean ± SD, mmHg Glucose, Mean ± SD, mmol/l TG, Mean ± SD, mmol/l TC, Mean ± SD, mmol/l LDL-c, Mean ± SD, mmol/l HDL-c, Mean ± SD, mmol/l Prevalence of CVD (%) Family history of CVD (%) Smokers (%) Drinkers (%) Static activities time, Mean ± SD, h Se intake from food, Mean ± SD, mg/d Energy, Mean ± SD, kcal/d Fat, Mean ± SD, g/d Vitamins E, Mean ± SD, mg/d Calcium, Mean ± SD, mg/d Magnesium, Mean ± SD, mg/d
1640 80.87 ± 11.01 48.41 ± 15.00 41.20 21.94 ± 4.70 125.43 ± 24.16 78.58 ± 12.70 5.18 ± 0.82 1.24 ± 0.82 4.43 ± 1.04 2.33 ± 0.62 1.65 ± 0.41 5.90 10.70 22.50 13.10 7.35 ± 3.04 38.56 ± 17.36 2286.00 ± 851.90 63.47 ± 31.55 30.32 ± 13.00 1131.82 ± 554.97 264.80 ± 150.41
1647 101.78 ± 4.48 50.22 ± 14.80 39.40 22.64 ± 4.36 127.80 ± 22.33 79.68 ± 12.05 5.21 ± 0.89 1.32 ± 0.99 4.54 ± 1.10 2.44 ± 0.82 1.70 ± 0.47 7.30 9.40 22.60 12.00 7.48 ± 2.93 38.77 ± 18.32 2315.55 ± 881.98 65.44 ± 30.32 30.92 ± 12.38 1084.86 ± 556.90 250.48 ± 104.55
1633 116.36 ± 4.06 50.1 ± 14.91 39.30 22.91 ± 4.27 131.47 ± 23.92 81.09 ± 11.85 5.41 ± 1.32 1.38 ± 1.02 4.73 ± 1.78 2.52 ± 0.64 1.71 ± 0.45 8.20 10.00 25.70 14.60 7.48 ± 3.06 39 ± 17.99 2301.75 ± 845.44 64.88 ± 30.19 31.0 ± 12.86 1068.27 ± 609.38 253.60 ± 131.91
1639 132.6 ± 5.61 50.18 ± 14.56 39.20 23.31 ± 4.02 133.99 ± 23.82 81.78 ± 11.75 5.5 ± 1.44 1.38 ± 0.99 4.82 ± 1.13 2.63 ± 0.72 1.72 ± 0.50 9.10 9.50 25.20 18.20 7.4 ± 2.97 39.83 ± 20.02 2295.98 ± 922.56 67.50 ± 33.44 31.60 ± 13.40 1076.46 ± 641.84 261.30 ± 134.57
1639 168.51 ± 27.80 51.06 ± 13.96 41.00 23.61 ± 3.87 135.87 ± 22.46 83.29 ± 11.37 5.68 ± 1.61 1.5 ± 1.27 5.06 ± 1.10 2.73 ± 0.69 1.77 ± 0.54 9.90 10.70 26.70 19.00 7.15 ± 3.13 40.24 ± 18.82 2290.72 ± 902.57 66.36 ± 32.52 31.48 ± 13.35 1051.47 ± 621.80 261.80 ± 117.20
8198 120 ± 32.72 49.99 ± 14.67 40 22.88 ± 4.29 130.91 ± 23.66 80.88 ± 12.06 5.41 ± 1.29 1.37 ± 1.04 4.73 ± 1.28 2.54 ± 0.72 1.71 ± 0.48 8.20 10.00 24.60 15.50 7.37 ± 3.03 39.33 ± 18.59 2298.13 ± 882.93 65.64 ± 31.69 31.10 ± 13.02 1082.60 ± 598.42 258.41 ± 128.74
<0.001 0.872 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.245 0.967 0.005 <0.001 0.036 0.147 0.949 0.042 0.168 0.002 0.006
P value refers to comparisons of the means or proportions among the groups by the 1-way ANOVA and ManneWhitney tests. BMI indicates body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglyceride; TC, total cholesterol; LDL-c, low-density lipoprotein-cholesterol; HDL-c, high-density lipoprotein-cholesterol; CVD, cardiovascular disease.
Table 2 Adjusted differences (95% confidence interval) in lipid concentrations comparing the 4 highest quartiles to the lowest quartile of plasma selenium.
TG Model Model Model TC Model Model Model LDL-c Model Model Model HDL-c Model Model Model
Q1
Q2
Q3
Q4
Q5
P-value
1a 2b 3c
0 0 0
0.07 (0.00, 0.14) 0.05 (0.02, 0.12) 0.05 (0.02, 0.12)
0.14 (0.07, 0.21) 0.13 (0.06, 0.20) 0.14 (0.07, 0.21)
0.14 (0.07, 0.21) 0.12 (0.05, 0.19) 0.11 (0.04, 0.18)
0.26 (0.18, 0.34) 0.24 (0.17, 0.31) 0.24 (0.17, 0.31)
<0.001 <0.001 <0.001
1a 2b 3c
0 0 0
0.11 (0.03, 0.19) 0.12 (0.04, 0.20) 0.1 (0.02, 0.18)
0.3 (0.19, 0.41) 0.28 (0.17, 0.39) 0.27 (0.15, 0.39)
0.39 (0.31, 0.47) 0.33 (0.25, 0.41) 0.33 (0.25, 0.41)
0.63 (0.55, 0.71) 0.61 (0.53, 0.69) 0.57 (0.49, 0.65)
<0.001 <0.001 <0.001
1a 2b 3c
0 0 0
0.11 (0.06, 0.16) 0.12 (0.06, 0.18) 0.1 (0.04, 0.16)
0.19 (0.14, 0.24) 0.17 (0.12, 0.22) 0.15 (0.1, 0.2)
0.3 (0.25, 0.35) 0.27 (0.22, 0.32) 0.27 (0.22, 0.32)
0.4 (0.35, 0.45) 0.37 (0.32, 0.42) 0.37 (0.32, 0.42)
<0.001 <0.001 <0.001
1a 2b 3c
0 0 0
0.05 (0.02, 0.08) 0.04 (0.01, 0.07) 0.03 (0, 0.06)
0.06 (0.03, 0.09) 0.05 (0.02, 0.08) 0.05 (0.02, 0.08)
0.07 (0.04, 0.1) 0.04 (0.01, 0.07) 0.06 (0.03, 0.09)
0.12 (0.08, 0.16) 0.12 (0.08, 0.16) 0.12 (0.08, 0.16)
<0.001 <0.001 <0.001
P value refers to the comparisons of the 4 higher quintiles to the lowest quintile by multivariate linear regression. a Adjusted for age (continuous), gender (male, female). b Further adjusted for BMI (continuous), hypertension (yes, no), diabetes (yes, no), family history of coronary heart disease (yes, no), current cigarette smoking (yes, no), current alcohol use (yes, no) and static activities time (continuous). c Further adjusted for dietary intakes of energy (continuous), fat (continuous), vitamins E (continuous), calcium (continuous), and magnesium (continuous).
quintile 1 of selenium level were 1.32 (95% CI: 1.05, 1.66), 1.49 (95% CI: 1.19, 1.87) and 2.19 (95% CI: 1.75, 2.73), respectively (p 0.02). OR in High-LDLC dyslipidemia was separately 1.77 (95% CI: 1.15, 2.72), 1.67 (95% CI: 1.09, 2.57), 2.36 (95% CI: 1.57, 3.55) and 3.54 (95% CI: 2.38, 5.26), respectively (p < 0.02). However, serum selenium concentrations were not associated with Low-HDLC dyslipidemia and High-TG dyslipidemia after adjusting the for lifestyle and dietary factors. 3.4. Stratified analyses of association between serum selenium and dyslipidemia In the stratified analyses, we found that the seleniumedyslipidemia associations were significantly stronger in the post-menopausal women (OR: 2.72; 95% CI: 1.97, 4.17) and diabetic
(OR: 9.40; 95% CI: 3.02, 29.26), However, no interaction was detected with other variables (Table 4). 4. Discussion In this study, we found that higher serum selenium level was correlated with higher level of TC, TG, LDL-c, and HDL-c after adjusting for age, gender, lifestyle and dietary factors. Compared to lowest quintile of selenium, participants in higher quintiles of serum selenium had higher risk of High-TC and High-LDLC dyslipidemia. Elevated blood lipid has been found to be an independent risk factor for cardiovascular diseases such as ischemic stroke, myocardial infarction, and sudden cardiac death due to atherosclerosis and lacunar infarctions [25]. TC and LDL-c were thought to initiate atherosclerotic plaques when it penetrates through the
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Table 3 Multivariable-adjusted odds ratios for four types of dyslipidemia comparing the 4 highest quartiles to the lowest quartile of plasma selenium. Q1
Q2
Q3
n (%) Reference n (%) OR (95% CI) High-TC Model 1 Model 2 Model 3 High-TG Model 1 Model 2 Model 3 High-LDL Model 1 Model 2 Model 3 Low-HDL Model 1 Model 2 Model 3
Q4
P-value n (%) OR (95% CI)
Q5
P-value n (%) OR (95% CI)
P value
P-value n (%) OR (95% CI)
P-value
21.80 1 1 1
25.50 1.18 (0.99,1.42) 0.070 1.14 (0.92,1.41) 0.222 1.10 (0.87,1.40) 0.426
30.80 1.55 (1.30,1.84) <0.001 34.00 1.80 (1.52,2.14) <0.001 44.00 2.72 (2.30,3.21) <0.001 <0.001 1.37 (1.12,1.69) 0.002 1.52 (1.24,1.86) <0.001 2.31 (1.90,2.82) <0.001 <0.001 1.32 (1.05,1.66) 0.020 1.49 (1.19,1.87) 0.001 2.19 (1.75,2.73) <0.001 <0.001
18.60 1 1 1
19.80 1.05 (0.86,1.27) 0.631 1.0 (0.80,1.26) 0.99 1.02 (0.79,1.31) 0.91
22.10 1.24 (1.02,1.49) 0.027 1.17 (0.94,1.94) 0.168 1.13 (0.88,1.45) 0.346
4.90
1 1 1
9.10
1.89 (1.38,2.60) <0.001 8.90 1.88 (1.30,2.72) 0.001 1.77 (1.15,2.72) 0.010
1.88 (1.37,2.58) <0.001 12.30 2.61 (1.93,3.53) <0.001 17.20 3.89 (2.91,5.20) <0.001 <0.001 1.83 (1.27,2.64) 0.001 2.35 (1.65,3.34) <0.001 3.66 (2.60,5.14) <0.001 <0.001 1.67 (1.09,2.57) 0.019 2.36 (1.57,3.55) <0.001 3.54 (2.38,5.26) <0.001 <0.001
4.60
1 1 1
4.00
0.92 (0.63,1.33) 0.641 0.89 (0.58,1.36) 0.577 0.97 (0.61,1.54) 0.893
0.71 (0.48,1.05) 0.086 0.69 (0.44,1.09) 0.112 0.71 (0.43,1.17) 0.176
3.20
23.30 1.33 (1.11,1.60) 0.003 1.17 (0.94,1.46) 0.158 1.16 (0.91,1.49) 0.230
3.80
0.88 (0.61,1.28) 0.513 0.88 (0.58,1.34) 0.553 0.94 (0.60,1.50) 0.805
24.70 1.40 (1.17,1.68) <0.001 <0.001 1.18 (0.95,1.48) 0.134 0.008 1.20 (0.94,1.53) 0.151 0.008
2.90
0.66 (0.44,0.97) 0.031 0.65 (0.41,1.02) 0.061 0.70 (0.42,1.14) 0.153
0.112 0.235 0.333
P value refers to the comparisons of the 4 higher quintiles to the lowest quintile by multivariate linear regression. CI, confidence interval; OR, odds ratios.
endothelium of a coronary artery into its wall [26]. Furthermore, High-TC and High-LDLC dyslipidemia are associated with the development of atherosclerotic heart diseases (ASCVD) including coronary heart disease (CHD), stroke, and peripheral arterial disease [27]. Our results demonstrated that high serum selenium may be prospectively associated with a trend for an increased risk of CVD. Previous results from different participants involved in studies investigating the associations between serum selenium levels and lipid concentrations can be seen in Supplemental Table. In Table 4 Stratified analyses of the associations [multivariable-adjusted odds ratio (95% confidence interval)] between serum selenium concentrations and dyslipidemia.
Age, y <40 40e59 >60 Gender Male Pre-menopausal womena Post-menopausal womena BMI, kg/m2 <24 24e26.99 >27 Current cigarette smoking No Yes Current alcohol use No Yes Static activities time, h <6 6e8 >9 Diabetes Noa Yesa Hypertension No Yes a
ORb
95% CI
1.63 1.73 2.53
1.06, 2.46 1.30, 2.30 1.59, 4.04
1.91 1.42 2.72
1.37, 2.66 0.89, 1.90 1.97, 4.17
1.91 1.61 1.40
1.44, 2.54 1.14, 2.28 0.74, 2.63
1.59 2.07
1.26, 2.01 1.35, 3.16
1.63 2.35
1.30, 2.03 1.39, 4.00
1.53 1.77 1.73
1.02, 2.29 1.27, 2.47 1.23, 2.43
1.72 9.40
1.66, 2.40 3.02, 29.26
1.57 1.92
1.21, 2.05 1.39, 2.66
Significant difference in subgroups. Adjusted for age (continuous), gender (male, female), BMI (continuous), hypertension (yes, no), diabetes (yes, no), family history of coronary heart disease (yes, no), current cigarette smoking (yes, no), current alcohol use (yes, no), static activities time (continuous), dietary intakes of energy (continuous), fat (continuous), vitamins E (continuous), calcium (continuous), and magnesium (continuous). b
agreement with our results, a cross-sectional study [16] among US adults in National Health and Nutrition Examination Survey (NHANES) showed that elevated serum selenium levels were positively correlated with increased serum levels of TC and LDL-c, and this correlation was also observed between selenium level and HDL-c at low selenium levels. Similar results were also found in European countries. In addition, serum selenium concentrations were positively associated with TC and non-HDL cholesterol in UK adults [3], with TC and LDL-c in Spanish [17], and with TC in Danish [9] and Italian men [28]. A cross-sectional study in China [23] found that participants with high nail selenium concentration had higher risks of four types of dyslipidemia. However, evidence from some randomized controlled trials [19,20] was limited because selenium supplementations were always combined with other minerals, and the effect of selenium cannot be isolated. An RCT [21] from Iran showed that selenium supplementations alone were not associated with lipid concentrations. In the UK PRECISE Pilot Study [29], crosssectional analyses at baseline revealed a positive association between selenium concentration and TC. Interestingly, total and nonHDL cholesterol levels were significantly decreased after the selenium intakes of 100 or 200 mg per day for 6 months, while daily selenium intake of 300 mg did not affect total and non-HDL cholesterol levels, but it significantly increased HDL-c levels. According to WHO, China has been defined as low-Se area or Se deficiency area. The Se deficiency diseases (Keshan disease and Kashin-Beck disease) were first identified in the low-selenium geological belt with selenium contents in soil stretching from northeast to southwest of China [30]. The mean selenium concentration of our study population is higher to those concentrations obtained in other countries such as the UK [3], Germany [6], and Spain [17], while is lower to that obtained in the US in the NHANES [16], where it was 136.7 mg/l. Compared with other studies in China, our result of the serum selenium level is higher than that obtained in Zhoukoudian area of Beijing [31], but is lower than that in Shanghai [32]. The underlying mechanisms for the associations between high selenium levels and lipid profile were still in discussion. Previous studies have investigated the function of selenoprotein in cardiovascular disease by analysis of oxidative stress under conditions of selenium supplementation or deficiency. Animal experiments showed significant increases in the activity of LDL-receptor and the expression of mRNA after selenium supplementation, which may be mediated by the iodothyronine deiodinases (DIOs) [33,34]. DIOs are selenoproteins involved in the activity of thyroxine to
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triiodothyronine, which increases the expression of LDL-receptor gene [35]. Moreover, the correlation between selenium and lipid level was associated with insulin sensitivity in humans. Reactive oxygen species (ROS), as the second messenger in insulin signal transduction, could be scavenged by selenoprotein. Constitutive expression of selenoprotein impaired insulin signaling and reduced the systemic insulin sensitivity. Evidence from a review showed that insulin sensitivity was associated with lipid accumulation, and insulin sensitivity was inversely correlated with plasma level of triglyceride [36,37]. Furthermore, protein tyrosine phosphatase 1B (PTP1B), which is considered to be a key enzyme and play an important role in stimulating the fatty acid synthesis (FAS) and in reverse regulation of insulin signaling, has been widely studied for the correlation between selenium concentration and lipid profile. Firstly, expression and activity of PTP1B were elevated in rats with fructose-rich diets, resulting in the induction of FAS and in an increase of the level of liver triglyceride [38,39]. In addition, evidence from animal experiments revealed that selenium could also elevate PTP1b activity in liver of rats, which might cause the decrease of insulin sensitivity further [40]. According to the results of stratified analysis, post-menopausal women with high serum selenium status may be at particularly high risk of dyslipidemia. Postmenopausal women experienced a drop in the level of estrogens, which play a significant biological role in modulating the antioxidant/pro-oxidant balance, and an increase in lipid peroxidation and formation of reactive oxygen species has been observed after the decline of estrogens [41]. Moreover, more significant seleniumedyslipidemia associations were observed in diabetics, which were often accompanied with insulin resistance. As above mentioned, high selenium level may be associated with the reduced insulin sensitivity, and promote the lipid accumulation in diabetics. A positive association was observed between serum selenium concentration and blood glucose in our study, and a similar phenomenon has also been observed in other studies [42,43]. In addition, the seleniumedyslipidemia correlation was slightly higher in smokers, drinkers and hypertensive patients as compared with their counterparts, while the differences were not statistically significant. Future analyses of serum selenium levels and dyslipidemia should carefully evaluate the effect of the above mentioned influence factors to confirm interactions that we observed in this study. Because of our cross-sectional design, we could not determine whether dyslipidemia as a consequence of selenium supplementation, or whether a common metabolic pathway might explain the correlation between serum selenium level and lipid profile. So rigorous randomized controlled trials should be conducted to verify our conclusion. Moreover, our study didn't consider that genetic factors might affect the correlation between serum selenium level and lipid concentration. A finding showed that selenium concentration was associated with genetic variation in certain genes related to lipid metabolic pathways [44]. Targeted removal of the tRNA[Ser]Sec gene (Trsp) in mouse leads to the selenium deficiency, and then resulted in elevating Apolipoprotein E (APOE) level which was accompanied by increasing cholesterol levels [45]. Epidemiological study revealed that Apolipoprotein E genotyping may influence the risk of dyslipidemia [23]. Though causality was not established in our cross-sectional study, several strengths of this study should be emphasized. Our included participants aged from 18 to 95 with a wide range of coverage, and have stable dietary structures, which reduced the confounding bias to some degree. To our knowledge, our study is the first large-scale study conducted in China to investigate the effect of serum selenium level on lipid concentration and dyslipidemia. Furthermore, stratified analyses were conducted in subgroups and contributed to find the high-risk population.
5
5. Conclusion High serum selenium level was associated with high serum concentrations of TC, TG, LDL-c, HDL-c, and increased the risk of dyslipidemia of (High-TC and High-LDLC) among rural Chinese. Moreover, post-menopausal women and diabetics who are in high serum selenium status had higher risk of dyslipidemia. However, whether dyslipidemia as a consequence of increased selenium intake can't be tested in our study, and the real associations should be verified in specifically designed clinical studies in future. Financial support This work was supported by the National Natural Science Foundation of China (81373048) and Natural Science Foundation of Shandong Province (Y2006C117). Statement of authorship Xibao Gao was responsible for the design of the current study, and has the primary responsibility for the final content. Wen Ju participated at the design, in data analysis and wrote the manuscript. Mei Ji reviewed the final version of manuscript. Xia Li, Zhe Li, Guanrui Wu, Xiaofeng Fu and Xiaomei Yang were responsible for the conducted the research (data collection). Conflict of interest None. Acknowledgments We sincerely appreciate all participants for their kind cooperation in our study. We also wish to acknowledge all of the investigators in our study. Appendix A. Supplementary material Supplementary material associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.clnu. 2017.08.025. References [1] Burk RF. Selenium, an antioxidant nutrient. Nutr Clin Care 2002;5:75e9. [2] Papp LV, Lu J, Holmgren A, Khanna KK. From selenium to selenoproteins: synthesis, identity, and their role in human health. Antioxid Redox Signal 2007;9:775e806. [3] Stranges S, Laclaustra M, Ji C, Cappuccio FP, Navas-Acien A, Ordovas JM, et al. Higher selenium status is associated with adverse blood lipid profile in British adults. J Nutr 2010;140:81e7. [4] Lalonde L, Jean Y, Roberts KD, Chapdelaine A, Bleau G. Fluorometry of selenium in serum or urine. Clin Chem 1982;28:172e4. [5] Salonen JT, Alfthan G, Huttunen JK, Pikkarainen J, Puska P. Association between cardiovascular death and myocardial infarction and serum selenium in a matched-pair longitudinal study. Lancet 1982;2:175e9. [6] Lubos E, Sinning CR, Schnabel RB, Wild PS, Zeller T, Rupprecht HJ, et al. Serum selenium and prognosis in cardiovascular disease: results from the AtheroGene study. Atherosclerosis 2010;209:271e7. [7] Heese HD, Lawrence MA, Dempster WS, Pocock F. Reference concentrations of serum selenium and manganese in healthy nulliparas. South Afr Med J 1988;73:163e5. [8] Bleys J, Navas-Acien A, Stranges S, Menke A, Miller 3rd ER, Guallar E. Serum selenium and serum lipids in US adults. Am J Clin Nutr 2008;88:416e23. [9] Suadicani P, Hein HO, Gyntelberg F. Serum selenium concentration and risk of ischaemic heart disease in a prospective cohort study of 3000 males. Atherosclerosis 1992;96:33e42. [10] Stranges S, Galletti F, Farinaro E, D'Elia L, Russo O, Iacone R, et al. Associations of selenium status with cardiometabolic risk factors: an 8-year follow-up analysis of the Olivetti Heart study. Atherosclerosis 2011;217:274e8.
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Please cite this article in press as: Ju W, et al., Relationship between higher serum selenium level and adverse blood lipid profile, Clinical Nutrition (2017), http://dx.doi.org/10.1016/j.clnu.2017.08.025
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