Low High Density Lipoprotein Cholesterol: Prevalence and Associated Risk-Factors in a Large French Population

Low High Density Lipoprotein Cholesterol: Prevalence and Associated Risk-Factors in a Large French Population MARION ROUVRE, MD, SYLVIANE VOL, MSC, GAE¨LLE GUSTO, PHD, CATHERINE BORN, MD, OLIVIER LANTIERI, MD, MPH, JEAN TICHET, MD, AND PIERRE LECOMTE, MD

PURPOSE: High density lipoprotein-cholesterol (HDL-C) is a strong predictor of cardiovascular risk. We investigated the distribution of HDL-C in a French general population according to age, sex, and the risk factors associated with low HDL-C values. METHODS: A group of 18,483 men and 22,047 women 16–79 years of age were investigated during a medical check-up. Relevant parameters were studied in three groups according to age and genderspecific percentile classes (<5th [HDL5] median and O95th). Gender-specific logistic regression models selected variables associated with HDL5. RESULTS: Using the National Cholesterol Education Program Adult Treatment Panel III criteria (threshold: 40 mg/dL in men, 50 mg/dL in women) the prevalence of low HDL-C was 11.1% and 26.4% in men and women and it decreased with age. Mean HDL-C levels increased with age. HDL5 was positively associated with a sedentary lifestyle and deprivation (p ! 0.00001) even after adjustment on alcohol consumption and smoking. Abdominal obesity, smoking, hypertriglyceridemia, hyperleucocytosis, and low alcohol consumption were associated with HDL5 for both genders. CONCLUSIONS: The prevalence of low HDL-C was similar to that observed in other Europeans but lower than in the United States. HDL5 was associated with cardiovascular risk factors, metabolic syndrome, and social deprivation. A prevention policy to increase HDL-C levels should focus on reducing smoking and abdominal obesity, particularly in deprived subjects. Ann Epidemiol 2011;21:118–127. Ó 2011 Elsevier Inc. All rights reserved. KEY WORDS:

HDL Cholesterol, Reference Values, Psychosocial Deprivation, Risk Factors, Epidemiologic Study, Risk Reduction Behavior.

INTRODUCTION Low density lipoprotein-cholesterol (LDL-C) is the main target of treatments aiming to prevent coronary heart disease (CHD). Despite lower LDL-C levels, the prevalence of CHD remains high in developed countries. High density lipoproteincholesterol (HDL-C) is a well-recognized (1, 2), although recently disputed (3), independent risk factor for CHD. The Framingham Study identified HDL-C as the main lipid risk factor in men and women 49–82 years of age, showing an inverse relationship with the incidence of CHD (4). This lipid fraction was associated with each major manifestation of CHD, even when other lipid fractions and standard risk factors for CHD were taken into consideration. Barter et al. (5) recently showed that HDL-C levels are predictive of major cardiovascular events in patients treated with statins, even when LDL-C levels are less than 70 mg/ dL, underlining the anti-atherogenic effects of HDL-C. From the Centre Hospitalier Re´gional et Universitaire (CHRU) Bretonneau, Tours Cedex 09, France (M.R., P.L.); and Institut inter Re´gional pour la Sante´, La Riche, France (S.V., G.G., C.B., O.L., J.T.). Address correspondence to: Pierre Lecomte, MD, CHRU Bretonneau, Unite´ d’Endocrinologie et Me´tabolisme, 1 Boulevard Tonnelle´, 37044 Tours cedex 09, France. Tel.: þ33-2-47-47-99-45; Fax: þ33-2-47-47-3804. E-mail: [email protected]. Received April 23, 2010; accepted July 22, 2010. Ó 2011 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010

Most people with low HDL-C levels have additional cardiovascular risk factors, such as hypertension, obesity, diabetes, sedentary lifestyle, and smoking (6). Both lifestyle and genetic factors can influence HDL-C levels (sedentary lifestyle, obesity, smoking, alcohol consumption, and polymorphism of the cholesteryl ester transfer protein (CETP) gene (7)). Exercise raises HDL-C and lowers CETP levels (8–10). HDL-C less than 40 mg/dL in men and 50 mg/dL in women is one component of metabolic syndrome defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP-III) (11). Only a few studies have measured the prevalence of low HDL-C levels in general populations, with results varying from 7% in men in France to 60% in men in the Philippines (12–17). The aims of this epidemiological study were to investigate the distribution of HDL-C levels in both men and women in a large French population and to analyze relationships between HDL-C levels and other cardiovascular risk factors, biochemical profile, lifestyle, nutritional habits, and social variables.

POPULATION AND METHODS The study, undertaken from November 2005 to July 2006, involved a population comprising men and women 16–79 1047-2797/$ - see front matter doi:10.1016/j.annepidem.2010.07.097

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Selected Abbreviations and Acronyms BMI Z body mass index CETP Z cholesteryl ester transfer protein CHD Z coronary heart disease FPG Z fasting plasma glucose GGT Z gamma glutamyl transferase HDL-C Z high density lipoprotein-cholesterol LDL-C Z low density lipoprotein-cholesterol NCEP-ATP-III Z National Cholesterol Education Program Adult Treatment Panel III PA Z physical activity WBC Z white blood cell

years of age voluntarily attending a free routine medical and biochemical check-up provided by their medical insurance organization to which 85% of the entire French population is affiliated. They were examined at 11 medical centers of the ‘‘Institut inter-Re´gional pour la Sante´’’ in Western and Central France. The population included 47,853 subjects, of whom 28.0% were socially deprived according to the Evaluation de la Pre´carite´ et des Ine´galite´s de Sante´ dans les Centres d’Examens de Sante´ (EPICES) score (18). Because of this overrepresentation, the sample was calibrated by random selection to the percentage of deprived subjects in the general French population, i.e., 13.2% in 2006 according to the ‘‘Institut National de la Statistique et des Etudes Economiques’’ indicator (19). The study finally included 40,530 subjects (18,483 men and 22,047 women). All participants completed a self-administered questionnaire on their socioeconomic and family status, personal and familial medical history, and lifestyle behaviors. Subjects who had smoked within the previous year were considered to be smokers. Physical activity (PA), focusing on sport practice, was assessed by a question according to four levels of frequency (i.e., never, less than once a week, one or twice a week, and more than twice a week). Subjects who took part in PA less than once a week were considered to have a sedentary lifestyle. Social deprivation was assessed using the EPICES score (18) that is an individual index developed by the French Health examination centers taking into account the multidimensional aspect of deprivation (education, income, occupation, family structure, housing conditions, employment, social benefits, financial difficulties, leisure activities, social support, self-perceived health). The continuous score is the sum of coefficients corresponding to responses to 11 binary questions and varied from 0 (least deprived) to 100 (most deprived). Deprivation was defined as a value greater than or equal to 30, the French official threshold. A 18-item nutrition questionnaire provided quantitative estimation of nutrients, using 15 questions for energy intake, 8 for lipids, 8 for sucrose, 8 for proteins, 3 for alcohol, 6 for cholesterol and 4 for calcium (20). Alcohol consumption was divided into three groups

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(men/women): none, less than or equal to 30/20 g/day, or greater than 30/20 g/day. Body mass index [BMI Z weight (kg)/height2 (m2)] was determined by a nurse who measured weight and height using a standardized procedure on participants wearing only underwear. Obesity was defined as BMI greater than or equal to 30 kg/m2. A physician measured the waist circumference (smallest circumference between lowest rib and the iliac crest) and measured systolic and diastolic blood pressures in a sitting position after 5 minutes rest. Information about current treatments was also gathered. Blood samples were collected after overnight fasting for about 12 hours. Several biochemical parameters were assessed on the C8000 Architect Abbott analyzer (Rungis, France), (total cholesterol, triglycerides, and gammaglutamyltransferase [GGT]) by an enzymatic method, HDL-C by an elimination method (intraassay CV of 1.0% and interassay CV of 3.6%) with 3K2802 reagent, fasting plasma glucose (FPG) concentration by the Hexokinase method and serum creatinine by the direct kinetics Jaffe method. White blood cell (WBC) counts were evaluated on the Advia 1220 automated hematology analyzer (Bayer-Siemens Diagnostics, Puteaux, France). LDL-C was calculated by the Friedewald formula. Diabetes was defined by FPG level greater than or equal to 126 mg/dL or treatment for hyperglycemia (insulin or oral agents). Hepatic steatosis was suspected if the fatty liver index (calculated according to BMI, waist circumference, triglycerides, and GGT) was greater than or equal to 60 (21). Low HDL-C was defined as HDL-C less than 40/50 mg/ dL (men/women). Metabolic syndrome was defined according to the NCEPATP-III-R definition (11) as the presence of three or more of the following criteria: waist circumference greater than 102/ 88 cm (men/women); low HDL-C; triglycerides greater than or equal to 150 mg/dL or lipid lowering medication; systolic/ diastolic blood pressure greater than or equal to 130/85 mm Hg or antihypertensive medication; and FPG concentration greater than or equal to 110 mg/dL or treatment for hyperglycemia. Statistical Analyses Data were analyzed using NCSS (Number Cruncher Statistical Systems 2000). Values are expressed as means (standard deviations) or percentages. Triglyceride and GGT levels, and WBC count were log-transformed, as their distributions were skewed, and are expressed as medians (interquartile ranges). We aimed to describe what defined subjects with very low HDL-C values (!5th percentile). To neutralize the ageeffect, a nonmodifiable variable, three groups were constituted on the basis of percentiles of HDL-C values per age

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class and per gender: HDL5 was defined as HDL-C less than or equal to 5th percentile, HDLm as HDL-C at the 7% median, and HDL95 as HDL-C greater than 95th percentile. The measure step (1 mg/dL) and the proximity of the HDL-C distribution mode led to select 7% of the population for the median group. Mean age was thus similar in the three groups for each gender. A univariate logistic model was used to test for interactions with gender for each variable. Significant interactions explained separate analyses between the three groups according to gender. General linear model analysis of variance (GLM ANOVA) was used for continuous variables, c2 test for categorical variables, and linear regression analysis to demonstrate linear trends. We adjusted all variables on alcohol consumption and smoking habits as they are modifiable factors known to be linked to HDL-C values. Adjustments were carried out by logistic regression or GLM ANOVA. Linearity of each continuous variable according to the logit of HDL5, standardized according to gender, was tested by adding the squared term of the continuous variable in a univariate regression model and comparing nested models by likelihood ratio tests. All variables were linearly related with the logit of HDL5. To select variables associated with HDL5, a logistic regression model was constructed using forward and backward selection criteria including all significant variables even if significant for only one gender. All statistical tests were considered significant at p ! 5%.

RESULTS Several percentiles of HDL-C concentrations according to age and gender are shown in Figures 1A and 1B. Higher HDL-C concentrations were observed with ageing for both genders. Prevalence of low HDL-C gradually decreased in men from 21.2% in their 20s to 7.6% in their 60s, whereas for women the prevalence decreased from 42.4% to 16.3% (Figure 1C) with the same slope.

FIGURE 1. (A,B) Percentiles of HDL-C concentrations according to age and gender. (C) Prevalence of low HDL-C decreased from 21.2% to 7.6% for men and from 42.4% to 16.3% for women.

63.4%, respectively. In perimenopausal period (40–52 years), 16.5% of women were taking estrogens.

Population Characteristics The prevalence of low HDL-C was lower in men (11.1%) than in women (26.4%) (Table 1). The percentages of subjects treated with lipid-lowering drugs were 9.3% for men and 5.4% for women. The prevalence of obesity was 10.9% for men and 10.7% for women, and metabolic syndrome was found in 9.8% and 8.5%, respectively. Hepatic steatosis was suspected in 23.2% of men and 8.9% of women. The frequency of smoking was 26.8% for men and 21.8% for women; mean alcohol consumption was 18 g and 4 g per day, and sedentary lifestyle 61.1% and

Relationships Between HDL-C Levels and Population Characteristics Table 2 (men) and Table 3 (women) show the relationships between the three HDL-C groups (HDL5, HDLm, HDL95) and medical history, clinical and biochemical findings, nutritional habits, smoking habits, sedentary lifestyle, and deprivation. For both genders, there was a linear trend with increasing HDL-C levels for family history of hypercholesterolemia, diabetes, and cardiovascular disease, most of nutritional habits and sedentary lifestyle. The percentage

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Rouvre et al. LOW HDL-C: PREVALENCE AND RISK FACTORS

TABLE 1. Characteristics of the population studied expressed as mean (standard deviation) or percentage Men (n Z 18,483) Biometry Age (yr) Waist circumference (cm) BMI (kg/m2) BMI >30 kg/m2 Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Antihypertensive treatment Biochemistry Fasting plasma glucose (mg/dL) Treatment for hyperglycemia Diabetes* Cholesterol (mg/dL) HDL-C (mg/dL) HDL-C !40/50 mg/dL (men/women) LDL-C (mg/dL) Triglycerides (mg/dL)y Lipid-lowering treatment GGT (IU/l)y Fatty liver indexz Fatty liver index >60 Metabolic syndromex White blood cells (109/l)y Nutritional habits Energy intake (kcal/day) Proteins (g/day) Alcohol (g/day) Sucrose (g/day) Lipids (g/day) Calcium (mg/day) Cholesterol (mg/day) Social variables Sedentary lifestylek Smoking{ EPICES score# EPICES score >30# Oral contraceptives and HRT

Women (n Z 22,047)

44.6 (14.2) 89.4 (11.1) 25.4 (3.8) 10.9% 135 (15) 80 (10) 9.0%

42.9 (14.4) 79.1 (12.0) 24.1 (4.7) 10.7% 125 (16) 76 (10) 7.6%

95.1 (15.5) 1.6% 3.3% 209.5 (39.6) 51.7 (11.4) 11.1%

89.1 (13.7) 0.9% 1.6% 208.1 (38.4) 59.3 (14.3) 26.4%

137.9 (33.3) 82 (61–117) 9.3% 29 (20–46) 37 (27) 23.2% 9.8% 65 (56–77)

133.2 (31.8) 68 (52–92) 5.4% 18 (14–26) 19 (23) 8.9% 8.5% 67 (57–80)

2331 (357) 89 (11) 18 (19) 55 (23) 93 (17) 1048 (206) 404 (71)

1670 (199) 69 (7) 4 (8) 33 (17) 69 (10) 922 (149) 307 (48)

61.1% 26.8% 15.3 (15.7) 12.3% d

63.4% 21.8% 16.1 (16.3) 13.9% 23.2%

BMI Z body mass index; GGT Z gamma glutamyl transferase; HDL-C Z high density lipoprotein-cholesterol; HRT Z hormone replacement therapy; LDL-C Z low density lipoprotein-cholesterol. *Fasting plasma glucose >126 mg/dL or treatment. y Expressed as the median (interquartile range). z Prediction index for hepatic steatosis (21). x NCEP ATP III definition (27). k Physical activity (sport practice) less than once a week. { Current smokers or subjects who had smoked within the previous year. # Deprivation score (deprivation when score >30) (18).

of women taking estrogen treatment was not different in the three groups after adjustment. In the HDL5 group for both genders, sedentary lifestyle, smoking and diabetes were more frequent (p ! 0.0001), waist circumference, triglyceride levels, fatty liver index, WBC count, and deprivation score were higher for both men and women, and alcohol consumption and total

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energy intake (men only) were lower (p ! 0.0001). After adjustments on smoking and alcohol consumption, only total energy intake was no longer significant in relation to HDL5. Table 4 shows the adjusted odds ratios of variables included in the sex-specific logistic regression models with HDL5 as the dependent variable. Most predictive variables were the same for both genders (i.e. waist circumference, alcohol intake, smoking habits, deprivation, high triglyceride levels, WBC level) excepted family history of hypercholesterolemia for men and diabetes for women.

DISCUSSION Evolution of HDL-C According to Age and Gender In this observational study, we demonstrated an increase in HDL-C levels with age from 16 to 54 years and then a plateau for both genders from 55 to 79 (Figures 1a and 1b). These findings were different from those reported in earlier publications in which HDL-C levels increased in men from 50 to 93 years of age (Rancho-Bernardo study) but did not increase in women of the same age range (22). Our results confirmed findings already published in the SYMFONIE, INTERGENE, and GOT-MONICA studies (13, 23). The curves for these populations and our own were remarkably similar for men. The slopes were the same for women but were upshifted in the SYMFONIE study, due to the lower percentage of deprived women. In addition, HDL-C (measured by nuclear magnetic resonance spectroscopy) increased with age in the Framingham study (24). We found a transient increase in HDL-C in perimenopausal women (40–52 years), as already reported by Kim et al. (25). The low percentage of women treated with estrogen in this transitional period (16.5%) in our population should be emphasized. The prevalence of low HDL-C defined by NCEP-ATP III was 11.1% for men and 26.4% for women in our study, decreasing with age between 16 to 19 and greater than or equal to 70 years with the same slope in both genders (Figure 1C). Most studies using the same criteria have reported a higher prevalence of low HDL-C in women, although the percentages were very variable: 7% versus 10% (men vs. women) in a previous study, with a decreasing prevalence with age in a French population aged 18–80 and a lower prevalence of deprivation in women, as already discussed (13). Similar differences in low HDL-C levels between genders have been reported in other countries: 60% versus 80% in the Philippines (16), 25% versus 48% in Korea (15), 35% versus 39% in the United States (NHANES Study 1988–1994) (12), and 23% versus 31% in a recent study (NHANES Study 2003–2004) (14). These differences in

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TABLE 2. Relationship between HDL-C levels and biochemical, biometric, and behavioral data expressed as mean (standard deviation) or percentage in men HDL-C <5th Percentile (n Z 843) Age (yr) Medical history Family history of hypercholesterolemia Family history of diabetes Family history of cardiovascular diseasez Biometry Waist circumference (cm) Waist circumference O102 cm BMI (kg/m2) BMI >30 kg/m2 Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Antihypertensive treatment Blood pressure >130/85 mm Hg Biochemistry Fasting plasma glucose (mg/dL) Fasting plasma glucose >110 mg/dL Treatment for hyperglycemia Diabetes** Cholesterol (mg/dL) LDL-C (mg/dL) Triglycerides (mg/dL)yy Triglycerides >150 mg/dL Lipid-lowering treatment GGTyy (IU/l) Fatty liver indexx Fatty liver index >60 Metabolic syndrome{{ White blood cells (109/l)yy Nutritional habits Daily breakfast Snacking O2 times/day Meat O200 g/day Oil O2 times/day Daily dairy products Bread O200 g/day Sweet drinks O0.5l/day Few fruits and vegetables{ Energy intake (kcal/day) Proteins (g/day) Alcohol O30 g/day Sucrose (g/day) Lipids (g/day) Calcium (mg/day) Cholesterol (mg/day) Social variables Sedentary lifestylexx Smokingk EPICES scorezz

45.6 (14.2) 22.9% 19.2% 44.0% 94.1 (11.7) 22.9% 26.9 (4.1) 21.5% 136 (16) 80 (10) 16.4% 69.7%

7% Medians (n Z 1382) 44.1 (14.7) 27.9% 13.9% 39.1% 89.5 (10.7) 11.1% 25.4 (3.6) 10.5% 136 (16) 80 (10) 8.9% 68.0%

O95th Percentile (n Z 854)

p Value*

p Valuey trend test

0.03 !0.0001 0.0009

0.05 0.39 0.81

0.67 !0.0001 !0.0001

!0.0001 !0.0001 !0.0001 !0.0001 0.80 0.28 !0.0001 0.72

0.03 0.10 0.01 0.16 0.99 0.50 0.03 0.58

!0.0001 !0.0001 !0.0001 !0.0001 0.002 0.0005 !0.0001 0.0007 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 0.04 !0.0001 !0.0001 !0.0001 !0.0001

p Value adjusted for smoking and alcohol

44.2 (14.4) 26.6% 10.8% 35.1% 83.3 (9.3) 3.4% 23.2 (3.0) 2.6% 136 (16) 80 (10) 6.1% 68.3%

98.0 (20.8) 13.4% 4.9% 7.6% 170.7 (31.0) 111.6 (27.9) 107 (78–151) 25.6% 14.6% 29 (21–46) 49 (28) 37.3% 45.5% 70 (59–84)

95.4 (16.8) 7.8% 1.2% 3.4% 210.4 (38.6) 140.3 (33.3) 85 (63–119) 14.3% 10.2% 30 (21–47) 37 (27) 22.9% 6.9% 65 (57–76)

94.3 (14.5) 7.6% 1.2% 2.3% 229.6 (39.3) 134.7 (35.4) 59 (47–76) 2.5% 6.1% 29 (20–49) 22 (22) 8.8% 2.3% 61 (53–73)

!0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 0.006 !0.0001 !0.0001 !0.0001 !0.0001

0.23 0.01 0.0004 0.03 !0.0001 !0.0001 0.003 0.82 0.90 0.003 0.04 0.92 !0.0001 0.94

79.8% 4.7% 5.0% 1.8% 61.9% 12.5% 11.9% 43.4% 2277 (320) 88 (11) 14.4% 58 (27) 90 (15) 1018 (201) 393 (65)

82.1% 3.6% 4.4% 0.8% 67.9% 9.7% 8.7% 44.1% 2331 (371) 89 (11) 23.9% 56 (26) 93 (17) 1052 (208) 404 (70)

80.7% 1.9% 4.3% 1.5% 65.2% 8.6% 8.1% 38.4% 2383 (370) 89 (11) 31.9% 55 (22) 94 (17) 1051 (211) 410 (77)

0.38 0.02 0.77 0.10 0.02 0.02 0.02 0.02 !0.0001 0.03 !0.0001 0.17 0.0002 0.0008 !0.0001

0.19 0.72 0.79 0.04 0.01 0.46 0.23 0.08 0.97 0.17 0.63 0.36 0.13 0.02 0.53

0.41 0.02 0.50 0.81 0.04 0.18 0.31 0.89 0.33 0.06 !0.0001kk 0.42 0.002 0.003 0.0001

71.2% 35.6% 20.2 (19.3)

59.7% 24.4% 14.5 (14.6)

54.1% 23.7% 15.7 (16.8)

!0.0001 !0.0001 !0.0001

0.11 0.002 0.02

!0.0001 !0.0001kk !0.0001

BMI Z body mass index; GGT Z gamma glutamyl transferase; HDL-C Z high density lipoprotein-cholesterol; LDL-C Z low density lipoprotein-cholesterol. *General linear model analysis of variance or c2 tests. y Linear regression analysis (linear trend if p > 0.05). z Hypertension, myocardial infarction or cerebral hemorrhage. x Prediction index for hepatic steatosis. k Current smokers or subjects who had smoked within the previous year. { Once a day or less. **Fasting plasma glucose>126 mg/dL or treatment. yy Median (interquartile range), log-transformed for the test. zz Deprivation score (deprivation when score >30). xx Physical activity (sport practice) less than once a week. kk No adjustment for alcohol or no adjustment for smoking. {{ NCEP ATP III definition.

HDL-C <5th Percentile (n Z 970) 43.1 (14.7) 25.9% 23.9% 45.5% 88.4 (15.3) 46.3% 27.7 (6.3) 32.7% 128 (17) 77 (10) 14.0% 50.5%

O95th Percentile (n Z 1091)

42.3 (14.5)

43.0 (14.4)

31.0% 16.5% 42.0%

34.0% 13.8% 41.2%

78.3 (11.2) 16.9% 23.9 (4.4) 9.4% 124 (16) 75 (9) 7.5% 37.7%

74.1 (9.2) 7.8% 22.3 (3.4) 3.0% 125 (16) 75 (10) 4.9% 38.7%

p Value*

p Value trend testy

0.0003 !0.0001 0.12

0.51 0.07 0.44

0.001 !0.0001 0.006

!0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001

!0.0001 !0.0001 !0.0001 !0.0001 0.0008 0.03 0.04 0.0001

!0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001

88.6 (15.7) 2.4% 0.5% 1.1% 206.4 (35.1) 134.1 (30.6) 68 (53–89) 3.6% 5.5% 18 (13–25) 17.4 (21.1) 6.7% 3.5% 66 (56–78)

87.6 (8.8) 1.2% 0.2% 0.6% 238.1 (37.7) 131.6 (33.0) 57 (46–74) 1.9% 4.9% 18 (13–25) 10.3 (14.0) 2.7% 1.0% 63 (54–75)

!0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001 !0.0001

!0.0001 !0.0001 0.0003 !0.0001 0.56 !0.0001 !0.0001 !0.0001 0.02 0.0002 !0.0001 !0.0001 !0.0001 0.02

84.3% 4.4% 2.0% 1.8% 70.6% 1.3% 7.0% 33.2% 1665 (197) 69 (7) 1.6% 35 (21) 69 (10) 920 (161)

86.3% 3.2% 2.3% 0.9% 74.1% 0.8% 3.5% 32.1% 1674 (202) 69 (7) 2.6% 33 (17) 69 (10) 925 (149)

90.1% 2.0% 1.1% 0.8% 78.5% 0.6% 2.8% 27.7% 1681 (196) 69 (7) 5.3% 31 (13) 69 (10) 931 (145)

0.0005 0.02 0.08 0.06 0.0004 0.21 !0.0001 0.01 0.38 0.98 !0.0001 0.0001 0.24 0.32

0.43 0.94 0.11 0.35 0.78 0.65 0.05 0.32 0.91 0.90 0.21 0.27 0.22 0.87

0.03 0.02 0.89 0.20 0.006 0.33 0.005 0.34 0.43 0.77 !0.0001kk 0.0002 0.56 0.48 (Continued)

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94.6 (23.4) 11.2% 3.8% 6.7% 176.1 (33.7) 118.9 (28.4) 88 (65–126) 16.1% 10.3% 21 (15–32) 39.1 (32.0) 29.7% 42.5% 73 (62–88)

p Value adjusted for smoking and alcohol

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Age (years) Medical history Family history of hypercholesterolemia Family history of diabetes Family history of cardiovascular diseasez Biometry Waist circumference (cm) Waist circumference O88 cm BMI (kg/m2) BMI >30 kg/m2 Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Antihypertensive treatment Blood pressure >130/85 mm Hg Biochemistry Fasting plasma glucose (mg/dL) Fasting plasma glucose >110 mg/dL Treatment for hyperglycemia Diabetes** Cholesterol (mg/dL) LDL-C (mg/dL) Triglycerides (mg/dL)yy Triglycerides >150 mg/dL Lipid-lowering treatment GGT (IU/l)yy Fatty liver indexx Fatty liver index >60 Metabolic syndrome{{ White blood cells (109/l)yy Nutritional habits Daily breakfast Snacking O2 times/day Meat O200 g/day Oil O2 times/day Daily dairy products Bread O200 g/day Sweet drinks O0.5 l/day Few fruits and vegetables{ Energy intake (kcal/day) Proteins (g/day) Alcohol O20 g/day Sucrose (g/day) Lipids (g/day) Calcium (mg/day)

7% Medians (n Z 1319)

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TABLE 3. Relationship between HDL-C levels and biochemical, biometric, and behavioral data expressed as mean (standard deviation) or percentage in women

BMI Z body mass index; GGT Z gamma glutamyl transferase; HDL-C Z high density lipoprotein-cholesterol; HRT Z hormone replacement therapy; LDL-C Z low density lipoprotein-cholesterol. *General linear model analysis of variance or c2 tests. y Linear regression analysis (linear trend if p > 0.05). z Hypertension, myocardial infarction or cerebral hemorrhage. x Prediction index for hepatic steatosis. k Current smokers or subjects who had smoked within the previous year. { Once a day or less. **Fasting plasma glucose>126 mg/dL or treatment. yy Median (interquartile range), log-transformed for the test. zz Deprivation score (deprivation when score >30). xx Physical activity (sport practice) less than once a week. kk No adjustment for alcohol or no adjustment for smoking. {{ NCEP ATP III definition.

!0.0001 !0.0001kk !0.0001 0.02 0.08 0.44 0.0003 0.006 !0.0001 !0.0001 !0.0001 0.009 61.7% 22.0% 16.0 (15.7) 25.2% 75.9% 29.5% 22.7 (20.7) 19.8%

53.6% 17.0% 13.8 (14.1) 22.5%

0.24 0.27 309 (51)

Cholesterol (mg/day) Social variables Sedentary lifestylexx Smokingk EPICES scorezz Oral contraceptives and HRT

308 (48)

305 (48)

p Value trend testy p Value* O95th Percentile (n Z 1091) 7% Medians (n Z 1319) <5th Percentile (n Z 970)

HDL-C TABLE 3. (Continued)

0.43

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p Value adjusted for smoking and alcohol

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prevalence could be explained by ethnic groups and genetic backgrounds, variety of ages, food intake habits, intensity of PA, etc. (26). The prevalence of low HDL-C was more frequent in women (Figure 1C), despite the mean HDL-C level being higher in women. This paradoxical result could be explained by the high threshold chosen for American women and the different behavioral components of the populations studied (27). A great deal of discussion has already been published regarding the validity of NCEP-ATP III thresholds, depending on the population studied. For instance, the World Health Organization suggested different thresholds of waist circumference in Asians (28). Methodological differences between laboratories when evaluating HDL-C levels could also contribute to these differences (29). Figure 1C presents also the prevalence of HDL-C!40 mg/ dL for both genders. Risk Factors Associated With Low HDL-C Most of the risk factor parameters varied significantly for the three HDL-C classes (HDL5, HDLm, and HDL95). Total cholesterol and HDL-C levels increased with age for both genders, but the HDL-C/cholesterol ratio decreased (30). A family history of hypercholesterolemia was strongly and positively associated with HDL-C levels only for women, possibly explained by their greater knowledge of family health history. As expected, FPG was inversely linked to HDL-C level. The WBC count was inversely linked to HDL-C level for both genders. This finding underlines the importance of the inflammatory process in metabolic syndrome. High WBC counts were also associated with metabolic syndrome observed in the NHANES cohort (31) and were negatively correlated with HDL-C cholesterol in the study by Tian et al. (32) associated with worsening of glucose tolerance; this could be interpreted as an inflammatory marker, as suggested in the SYMFONIE study (13). The fatty liver index was inversely related to HDL-C. Non-alcoholic fatty liver disease is considered to be the hepatic expression of metabolic syndrome (33). Hepatic steatosis should be investigated whenever low HDL-C levels are found. Hypertension was negatively associated with HDL-C levels after adjustment for alcohol consumption and smoking and the role played by low HDL-C in hypertension has been recently underlined by Angeli et al. (34). It has been shown that moderate alcohol consumption (!34 g alcohol/day) decreases blood pressure and increases HDLC (35). As previously described, we found excess body weight and waist circumference in the HDL5 group (36). In a study involving 12 pairs of monozygotic twins, prolonged

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TABLE 4. Logistic regression model with HDL5 (HDL-C <5th percentile) as the dependent variable OR (95% CI)

Waist circumference (1 SD) Diabetes* Smokingy Triglycerides >150 mg/dL or treatment White blood cells (1 SD)z Family history of hypercholesterolemia 0 ! alcohol < 30/20 g/day (men/women) Alcohol O 30/20 g/day (men/women) EPICES score >30x

Men

Women

1.44 (1.32–1.58) 1.30 (0.88–1.92) 1.63 (1.33–2.01) 1.77 (1.44–2.16)

1.71 (1.58–1.84) 1.88 (1.22–2.88) 1.45 (1.17–1.79) 1.76 (1.40–2.21)

1.16 (1.05–1.28) 0.79 (0.64–0.97)

1.15 (1.05–1.27) 0.85 (0.70–1.03)

0.50 (0.41–0.62)

0.75 (0.62–0.89)

0.30 (0.23–0.40)

0.38 (0.19–0.75)

1.61 (1.27–2.03)

1.32 (1.05–1.65)

CI Z confidence interval; HDL-C Z high density lipoprotein-cholesterol; OR Z odds ratio; SD Z standard deviation. *Fasting plasma glucose >126 mg/dL or treatment. y Current smokers or subjects who had smoked within the previous year. z Log-transformed. x Deprivation when EPICES deprivation score >30.

overfeeding was reported to induce a decrease in HDL-C and weight gain (37). The main dietary influences on HDL-C levels include alcohol intake, total fat intake, and trans fatty acids (36, 38). As shown in previous studies, we found that alcohol consumption was positively related to HDL-C levels (35, 39, 40). A meta-analysis of 25 studies found that consumption of 30 g of alcohol/day increased HDL-C by about 4 mg/dL (41). Intake of saturated fatty acids increases HDL-C levels, whereas polyunsaturated fatty acids have the opposite effect, but we did not evaluate this (42). In the HDL5 group, sucrose intake and consumption of sweet drinks were higher for women with a similar tendency in men. Intake of carbohydrates is negatively related to low HDL-C levels (43, 44). In the present study, a positive link was shown between HDL-C groups and calcium consumption and dairy products. Studies conducted on selected populations or focusing on calcium density or calcium supplementation have reported similar associations (45–48). Positive correlations were found between HDL-C and calcium density in normal women but not in men (45), and between HDL-C and calcium intake in overweight and obese women (46). It has also been demonstrated that calcium supplementation results in an increase in HDL-C level of about 7% in normal older women (47) but not in men (48). These results and our own indicate a role of calcium intake in reduction of lipogenesis and stimulation of lipolysis in mice as described by Zemel et al. (49). Smoking was negatively associated with HDL-C (Table 2 and Table 3) in our study, matching previous results. Moffatt

125

et al. (50) demonstrated that women who smoke had 15%– 20% lower HDL-C levels than nonsmokers, and HDL-C values improved to normal levels within 30–60 days of ceasing smoking (51). A meta-analysis of cross-sectional studies on the association of lipid profiles and cigarette smoking status revealed that smokers had higher serum concentrations of total cholesterol and triglycerides, and lower serum concentrations of HDL-C than nonsmokers (52). We emphasize the important role of smoking in lowering HDL-C levels (Table 4). There was a huge proportion of subjects with sedentary lifestyle (71% of men and 76% of women) in the HDL5 group but our definition of sedentary lifestyle was based on a single question. Intensive exercise has been shown to bring about significant improvements in HDL-C (8, 9). An increase in HDL-C can be achieved by lifestyle changes (ceasing smoking, aerobic exercise, weight loss, and dietary control) and drug treatment (53). Deprivation was negatively associated with HDL-C in our study. A multi-country study reported that HDL-C varied inversely with years of education for Chinese, Polish, and Russian men, but directly for white men living in the United States. The differences in lipid levels between men with more versus fewer years of schooling were not explained by age, BMI, smoking, alcohol consumption, or blood pressure medication. Findings were less consistent for women (54). Psychosocial deprivation evaluated with the EPICES score was found to be an independent determinant of metabolic syndrome in non-obese people of particularly low economic status in France (55). A similar link was reported in Finland in a random population-based sample (56). A low HDL-C level was most consistently found to be associated with low socio-economic status in Swedish women (57). The strengths of this study were the large number of subjects of both genders and the wide age range considered. All biochemical analyses were carried out in the same laboratory. Data were collected by well-trained nurses and physicians using standardized procedures. However, this study presents some limitations. The population studied was not completely representative of the French population because participants were volunteers for a health check-up and enrolled from the centerwestern part of France. In the French law, the collection of ethnicity data is limited to genetic studies that have to get a forward assessment of the ‘‘Commission Nationale Informatique et Liberte´s’’ (CNIL). Nevertheless, our population was essentially made up of Caucasians subjects. Total carbohydrate intake and distinctions between various types of lipid intake were not evaluated. No correction was made for lipid-lowering drugs, but the percentage of treated subjects was fairly low (9.3% of men and 5.4% of women). Finally, we did not consider the influence of genetic factors

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that modulate the HDL-C rate (APO-A1 gene mutation, ABCA deficit, LCAT deficit).

CONCLUSION This study demonstrated that the prevalence of low HDL-C (NCEP-ATP III) was 11% for French men and 26% for French women. There was a relationship between HDL-C level and smoking, dietary habits, sedentary lifestyle, and deprivation for both genders. These four parameters are modifiable to obtain a positive effect on weight and insulin resistance. Besides lowering LDL-C, increasing HDL-C is another major target for the prevention of cardiovascular risk as well as for the correction of other components of metabolic syndrome. Despite the complexity of lifestyle modifications, patients with low levels of HDL-C should be encouraged to increase physical activity on a regular basis, to stop smoking and achieve stable weight reduction, and to follow the calcium and sucrose intake recommendations. An appropriate prevention policy should focus on reducing smoking and abdominal obesity, particularly in deprived subjects. REFERENCES 1. Assmann G, Schulte H, von Eckardstein A, Huang Y. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis. 1996;124(Suppl):S11–S20. 2. Despres JP, Lemieux I, Dagenais GR, Cantin B, Lamarche B. HDL-cholesterol as a marker of coronary heart disease risk: the Quebec cardiovascular study. Atherosclerosis. 2000;153:263–272. 3. Briel M, Ferreira-Gonzalez I, You JJ, Karanicolas PJ, Akl EA, Wu P, et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ. 2009;338:b92. 4. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62:707–714. 5. Barter P, Gotto AM, Larosa JC, Maroni J, Szarek M, Grundy SM, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357:1301–1310. 6. Connelly PW, Petrasovits A, Stachenko S, MacLean DR, Little JA, Chockalingam A. Prevalence of high plasma triglyceride combined with low HDL-C levels and its association with smoking, hypertension, obesity, diabetes, sedentariness and LDL-C levels in the Canadian population. Canadian Heart Health Surveys Research Group. Can J Cardiol. 1999;15:428–433. 7. Tall AR. Plasma high density lipoprotein. Metabolism and relationship to atherosclerosis. J Clin Invest. 1990;86:379–384. 8. Couillard C, Despre´s JP, Lamarche B, Bergeron J, Gagnon J, Leon AS, et al. Effects of endurance exercise training on plasma HDL cholesterol levels depend on levels of triglycerides: evidence from men of the health risk factors, exercise training and genetics (HERITAGE) family study. Arterioscler Thromb Vasc Biol. 2001;21:1226–1232. 9. Slentz CA, Houmard JA, Johnson JL, Bateman LA, Tanner CJ, McCartney JS, et al. Inactivity, exercise training and detraining, and

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