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The –250G>A Promoter Variant in Hepatic Lipase Associates with Elevated Fasting Serum High-Density Lipoprotein Cholesterol Modulated by Interaction with Physical Activity in a Study of 16,156 Danish Subjects

Steno Diabetes Center (N.G., C.H.A., M.K.A., K.B.-J., T.H., O.P.), 2820 Gentofte, Denmark; Department of Medicine (M.K.A.), University of Helsinki and Helsinki University Central Hospital, FIN-00290 Helsinki, Finland; Department of Biostatistics (A.A.), University of Copenhagen, DK-1017 Copenhagen, Denmark; Departments of General Practice (A.S., T.L.) and Clinical Pharmacology (O.S.), and Faculty of Health Sciences (K.B-J., O.P.), University of Aarhus, DK-8000 Aarhus, Denmark; Research Centre for Prevention and Health (K.B.-J., T.J.), Glostrup University Hospital, DK-2600 Glostrup, Denmark; and Department of Endocrinology and Diabetes (O.S.), Aarhus University Hospital, DK 8200 Aarhus, Denmark

Address all correspondence and requests for reprints to: Niels Grarup, Steno Diabetes Center, Niels Steensens Vej 1, NLC2.14, 2820 Gentofte, Denmark. E-mail: ngrp{at}steno.dk.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Hepatic lipase plays a pivotal role in the metabolism of high-density lipoprotein (HDL) and low-density lipoprotein by involvement in reverse cholesterol transport and the formation of atherogenic small dense low-density lipoprotein.

Objectives: The objective was to investigate the impact of variants in LIPC on metabolic traits and type 2 diabetes in a large sample of Danes. Because behavioral factors influence hepatic lipase activity, we furthermore examined possible gene-environment interactions in the population-based Inter99 study.

Design: The LIPC –250G>A (rs2070895) variant was genotyped in the Inter99 study (n = 6070), the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care Denmark screening cohort of individuals with risk factors for undiagnosed type 2 diabetes (n = 8662), and in additional type 2 diabetic patients (n = 1,064) and glucose-tolerant control subjects (n = 360).

Results: In the Inter99 study, the A allele of rs2070895 associated with a 0.057 mmol/liter [95% confidence interval (CI) 0.039–0.075] increase in fasting serum HDL-cholesterol (HDL-c) (P = 8 x 10^–10) supported by association in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care study [0.038 mmol/liter per allele (95% CI 0.024–0.053); P = 2 x 10^–7). The allelic effect on HDL-c was modulated by interaction with self-reported physical activity (P_interaction = 0.002) because vigorous physically active homozygous A-allele carriers had a 0.30 mmol/liter (95% CI 0.22–0.37) increase in HDL-c compared with homozygous G-allele carriers.

Conclusions: We validate the association of LIPC promoter variation with fasting serum HDL-c and present data supporting an interaction with physical activity implying an increased effect on HDL-c in vigorous physically active subjects carrying the –250 A allele. This interaction may have potential implications for public health and disease prevention.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Hepatic lipase (HL) is an enzyme primarily synthesized by hepatocytes with the capacity to catalyze the hydrolysis of triglycerides and phospholipids in most lipoprotein subtypes, thereby altering lipoprotein size and density (1). HL is involved in reverse cholesterol transport by its ability to stimulate hepatic high-density lipoprotein (HDL) cholesterol (HDL-c) ester uptake and hydrolysis (2). However, it is also implicated in the remodeling of triglyceride-rich lipoprotein particles and thereby the formation of atherogenic small dense low-density lipoprotein (LDL) (3, 4). Studies in genetically modified rodents demonstrate that overexpression of the gene encoding HL, Lipc, leads to a marked reduction in plasma HDL-c (5, 6), an observation supported by studies in humans showing an inverse correlation between HL activity and plasma HDL-c (7).

In humans, LIPC is located on chromosome 15q15–22 and consists of nine exons spanning 137 kb. Two common LIPC promoter variants [–514C>T (rs1800588) and –250G>A (rs2070895)], which are in almost perfect linkage disequilibrium (R² > 96%) (8), have been widely studied in relation to HL activity and lipoprotein metabolism. The minor alleles of these promoter variants have been associated with a diminished transcriptional activity in vitro (9) and a 15–45% decrease in plasma HL activity (10). Still, it remains to be settled which variant is functional. Besides genetic regulation, environmental factors such as dietary fat intake (11), obesity (12), and physical activity (13, 14) influence the HL activity. Association of the –514 minor T allele with increased plasma HDL-c has been demonstrated in a metaanalysis, including almost 24,000 subjects (15), and modification of this association by interaction with dietary fat intake and visceral obesity has been demonstrated (16, 17). Two previous reports have reported conflicting results about a potential association of the LIPC –250G>A variant with type 2 diabetes. In a study of 490 subjects with impaired glucose tolerance (IGT), homozygous carriers of the –250 G allele had an increased risk of conversion to overt type 2 diabetes (18), contradicted by a study including 770 IGT subjects demonstrating increased risk of conversion in –250 homozygous A-allele carriers (19). Coding variation in LIPC, including a common nonsynonymous Ser215Asn variant, has only been sporadically investigated, demonstrating no evident effect on lipoprotein metabolism or metabolic traits (10, 20).

Thus, we aimed to investigate the impact of variants in LIPC on fasting serum lipids, type 2 diabetes, and cardiovascular risk factors in a large sample of Danes. Because behavioral factors influence HL activity, we furthermore examined possible gene-environment interactions in the population-based Inter99 study including 5585 individuals. Because fasting lipid levels are affected by plasma glucose levels, we further investigated a potential modifying effect of glucose tolerance status. We genotyped the –250G>A promoter variant and the only common nonsynonymous variant (Ser215Asn) in LIPC in 16,156 Danish subjects.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Studies of quantitative metabolic traits were performed in the Inter99 cohort, which is a population-based, randomized, nonpharmacological intervention study of middle-aged subjects for the prevention of ischemic heart disease, conducted at the Research Centre for Prevention and Health in Glostrup, Copenhagen (ClinicalTrials.gov identification no. NCT00289237) (21). The Inter99 study involved 6070 participants who were characterized by an oral glucose tolerance test as subjects with normal glucose tolerance (n = 4522), impaired fasting glycemia (n = 503), IGT (n = 693), or screen-detected and treatment-naive type 2 diabetes (n = 252). Patients with treated type 2 diabetes (n = 100) were not included, and subjects treated with lipid-lowering drugs (n = 89) were excluded in all analyses of fasting serum lipids.

Further studies of quantitative traits were performed in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care (ADDITION) Study, Denmark (ClinicalTrials.gov identification no. NCT00237548) (22). The ADDITION study is a population-based, high-risk screening, and intervention study for type 2 diabetes in general practice. The 8662 participants with available DNA and who participated in the screening included 1626 subjects with screen-detected and untreated type 2 diabetes, and 7036 nondiabetic subjects.

The case-control studies of type 2 diabetes included all type 2 diabetic cases and all glucose-tolerant control subjects from the Inter99 cohort (352 cases, 4522 controls) and the ADDITION study (1626 cases), as well as samples recruited from the outpatient clinic at Steno Diabetes Center (1064 cases, 360 controls). All control subjects had normal fasting glycemia and were glucose tolerant after an oral glucose tolerance test. Diabetes was diagnosed according to the World Health Organization 1999 criteria (23). Exclusion of atypical type 2 diabetic cases was done as previously described (24).

Phenotypical characteristics of all study subgroups are given in supplemental Table 1, which is published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org, and the exact numbers of subjects genotyped for each variant are given in the respective tables.

All participants were of Danish nationality, and informed written consent was obtained from all subjects before participation. The studies were approved by the Ethical Committees of Copenhagen and Aarhus, and were in accordance with the principles of the Helsinki Declaration II.

Biochemical and anthropometric measures

In all study groups, height and weight were measured in light indoor clothing and without shoes, and body mass index (BMI) was calculated as weight (kg)/height² (m²). Waist circumference was measured in the upright position midway between the iliac crest and the lower costal margin, and hip circumference was measured at its maximum. Blood samples were drawn after a 12-h overnight fast.

In the Inter99 study, plasma glucose was analyzed by a glucose oxidase method (Granutest; Merck, Darmstadt, Germany). Serum triglycerides and total serum cholesterol and HDL-c were analyzed using enzymatic colorimetric methods (GPO-PAP and CHOD-PAP; Roche Molecular Biochemicals, Mannheim, Germany). LDL-cholesterol (LDL-c) was calculated using Friedewald’s equation. Non-HDL-c was calculated as total cholesterol minus HDL-c. Insulin sensitivity was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR) index (25).

In the ADDITION study, fasting blood glucose was measured on capillary whole blood using a HemoCue B-glucose analyzer (HemoCue AB, Ängelholm, Sweden). The Hitachi 971 system (Roche Diagnostics GmbH, Mannheim, Germany) was used to measure total serum cholesterol and serum HDL-c by enzymatic tests.

Behavioral data in the Inter99 study

Physical activity was assessed by a self-administered standardized questionnaire (21, 26). Based on information on physical activity both at work and during leisure time, subjects were categorized as being either: vigorous physically active (n = 446), moderate physically active (n = 3459), or physically inactive (n = 2070). The group of physically inactive was either not physically active at work and during leisure time, only minor physically active at work (sitting/walking) combined with no activity during leisure time, or physically inactive at work combined with minor activity during leisure time (sitting/walking/cycling). Subjects graded as moderate physically active either did minor physical activity both at work and during leisure time, or moderate activity at work (walking stairways) or during leisure time (sport). Vigorous physically active subjects were very active at work (heavy work) and/or during leisure time (competitive sport) or moderately active both at work and during leisure time. Smoking status was categorized as "daily or occasional smokers," "previous smokers," and "never-smokers."

Dietary data were based on a food frequency questionnaire evaluating dietary intake 1 month before examination, including 168 questions on food items and beverages (27). The amount of macronutrients was calculated as energy percentages. These were included in the analyses as both continuous and categorical variables stratified on the mean value of the population. Alcohol consumption was graded as "no intake," "moderate intake," or "high intake." High intake was defined as above sex-specific median for the population (>6.9 g/d for women and > 13.9 g/d for men).

Genotyping

Genotyping of the LIPC –250G>A polymorphism (rs2070895) was conducted using chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (DNA Mass-ARRAY; Sequenom, San Diego, CA) of PCR-generated primer extension products as described earlier (28). The LIPC Ser215Asn (rs6083) polymorphism was genotyped using TaqMan allelic discrimination (KBioscience, Herts, UK). The genotyping success rates were 95 and 98%, and no mismatches were observed in 451 and 469 samples, respectively, genotyped in duplicates. The distributions of genotypes for both variants were in Hardy-Weinberg equilibrium in the population-based Inter99 cohort (P = 0.09 and P = 0.2, respectively).

Statistical analysis

A general linear model was used for testing quantitative traits in relation to genotype adjusting for the effect of sex and age for measures of obesity (BMI, waist circumference, and waist-to-hip ratio) and for the effect of sex, age, and BMI for serum lipids. Analysis of serum lipids in the Inter99 cohort was further tested adjusting for the effect of age, sex, BMI, physical activity (three groups), smoking status (three groups), alcohol consumption (three groups), and insulin sensitivity (HOMA-IR). Serum triglyceride was logarithmically transformed before analysis. Assuming a linear interaction, we evaluated the gene-environment interaction using a general linear model, comparing a model including gene-environment interaction parameters with a model lacking the interaction terms by an ANOVA test (2 df) with adjustment for the effect of sex, age, and BMI or age, sex, BMI, alcohol consumption (three groups), smoking status (three groups), and insulin sensitivity (HOMA-IR).

In the association studies of type 2 diabetes, logistic regression was used to examine differences in genotypes assuming an additive, dominant or recessive model with adjustment for sex, age, and BMI. Heterogeneity in the case-control material was evaluated by comparing allele frequencies within cases or controls ascertained from different cohorts separately. These analyses were performed using the ² test. No evidence of heterogeneity was observed. All statistical analyses were performed using RGui, version 2.6.1 (available at http://www.r-project.org), and a P value less than 0.05 was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We observed no linkage disequilibrium between the –250G>A (rs2070895) and Ser215Asn (rs6083) variants (D’ = 0.05; R² = 0).

In 5585 treatment-naive middle-aged subjects of the population-based Inter99 study, the –250G>A variant showed a highly significant association with a 0.057 mmol/liter [95% confidence interval (CI) 0.039–0.075] increase in fasting serum HDL-c per A allele (P = 8 x 10^–10), which was reproduced in the ADDITION study of 8407 high-risk individuals [0.038 mmol/liter per allele (95% CI 0.024–0.053); P = 2 x 10^–7] (Table 1). Furthermore, the –250 A-allele carriers had an increased fasting serum total cholesterol in both the Inter99 and ADDITION studies [Inter99: 0.074 mmol/liter per allele (0.029–0.12), P = 0.001; ADDITION: 0.055 mmol/liter per allele (0.016–0.094), P = 0.006], and associated nominally with fasting serum triglyceride levels in Inter99 (P = 0.04) (Table 1). The associations with HDL-c and total cholesterol in the Inter99 cohort were similar in an analysis additionally adjusted for the effect of smoking status, self-reported physical activity, alcohol consumption, and degree of insulin sensitivity, as assessed by the HOMA-IR [HDL-c: 0.055 mmol/liter per allele (0.040–0.070), P = 2 x 10^–12; total cholesterol: 0.082 mmol/liter per allele (0.037–0.13), P = 4 x 10^–4]. However, the –250G>A genotype did not associate with the non-HDL-c fraction of total cholesterol in the Inter99 or ADDITION cohorts (P = 0.3 and P = 0.4, respectively).

View larger version (22K): [in this window] [in a new window]   FIG. 1. Modifying effect of self-reported physical activity on the impact of the LIPC –250G>A genotype on fasting serum HDL-c in the population-based Inter99 study. Subjects were divided according to self-reported physical activity and stratified according to the LIPC –250G>A (rs2070895) genotype. The bars are estimates of differences in mean HDL-c levels between heterozygous carriers and homozygous G-allele carriers, and between homozygous A-allele carriers and homozygous G-allele carriers, respectively. Error bars are SE. We tested for interaction effects using linear models with or without interaction parameters for physical activity compared by an ANOVA test (Pinteraction = 0.002).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
HL plays a crucial role in hepatic lipid metabolism, and is involved in both reverse cholesterol transport and remodeling of triglyceride-rich lipoprotein particles and, thereby, the formation of atherogenic small dense LDLs (4).

In the present study, we investigated two carefully selected variants in LIPC in relation to metabolic traits in 16,156 Danish subjects. In a population-based cohort and a study of individuals at high risk for undiagnosed type 2 diabetes, we find strong associations with an allele-dependent increase in fasting serum HDL-c of 0.057 and 0.038 mmol/liter, respectively. The observed association with HDL-c is in line with results of a metaanalysis of the –514C>T (rs1800588) variant (R² = 0.97 with the –250G>A variant) of almost 24,000 subjects showing an increase in plasma HDL-c of 0.09 mmol/liter in homozygous minor T-allele carriers compared with homozygous major C-allele carriers (15). Although we observed association with total cholesterol in two cohorts, the lack of association with non-HDL-c indicates that the association with total cholesterol is driven by differences in HDL-c.

Interestingly, we demonstrated that the effect of the –250G>A variant on HDL-c was modified by interaction with self-reported physical activity in the population-based Inter99 study. Vigorous physically active homozygous A-allele carriers had a 0.30 mmol/liter (95% CI 0.22–0.37) increase in HDL-c compared with homozygous G-allele carriers, whereas no major effect of an active lifestyle was seen comparing heterozygous carriers with homozygous G-allele carriers. The precise mechanism behind this putative biological interaction is not known. Because exercise regulates HL activity (13, 14), it is possible that a direct regulatory effect of exercise on LIPC expression is influenced by the –250G>A promoter polymorphism or by a promoter variant in high linkage disequilibrium. Thus, the observed interaction seems biologically plausible. The observed increase in HDL-c may be of clinical relevance because a study has shown that a 0.026 mmol/liter decrease in HDL-c is associated with a 3% higher risk of cardiovascular disease (CVD) (29). Although low HDL-c is a well-established risk factor for CVD (30, 31), the association of LIPC promoter variants with the risk of CVD appears to be a paradox showing the highest CVD risk in minor allele carriers also associated with elevated HDL-c (8, 32). This contradiction may be due to a HL-induced modulation of the two-sided antiinflammatory or proinflammatory state of the HDL particle (33), a balance that is actually influenced by physical activity (34). Therefore, the present findings need validation in lifestyle intervention studies to assess possible implications for public health care.

Observations of the Framingham Heart Study demonstrated a significant gene-diet interaction of the –514C>T (rs1800588) LIPC promoter variant with total dietary intake of fat on HDL-c levels in 2130 subjects (16) contradicted by a subsequent study of 752 men (35). In the present report, we were unable to replicate this interaction analyzing 5585 population-sampled middle-aged subjects. Population-specific disparities in food consumption and differences in dietary data assessment may account for this inconsistency.

We consider characterization of interactions between gene variants and environmental and behavioral factors of crucial importance in the search for the genetic background of metabolic traits. However, inadequate statistical power and the lack of validity in assessment of behavioral factors severely impede finding and replicating true biological interactions (36).

A slight increase in measures of obesity was observed for rs6083 Asn-allele carriers in the population-based Inter99, yet no association was seen in the ADDITION cohort of high-risk individuals. Differences in the cohorts studied, or statistical type I or II errors may account for this inconsistency.

Two previous reports have indicated an association of the –250G>A variant with type 2 diabetes (18, 19). No evidence of association with type 2 diabetes in a cross-sectional design was observed in the present study. Based on CIs of effect sizes of type 2 diabetes, we can exclude an odds ratio above 1.13 per allele assuming an additive model.

In conclusion, we validate the association of the –250G>A variant LIPC promoter with serum HDL-c in two large cohorts and present data supporting a gene-environment interaction with physical activity implying an increased serum HDL-c elevating effect of the –250 A allele in vigorous physically active subjects. This interaction calls for validation in lifestyle intervention studies.

	Acknowledgments

 
We thank A. Forman, I.-L. Wantzin, and M. Stendal for technical assistance, and G. Lademann for secretarial support.

	Footnotes

 
The study was supported by grants from the Lundbeck Foundation Centre of Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care, Danish Health Research Council, The European Union (Hepatic and Adipose Tissue and Functions in the Metabolic Syndrome, Grant LSHM-CT-2005-018734), Danish Council for Strategic Research (Danish Obesity Research Centre, Grant 2101-06-0005), the Faculty of Health Sciences of Aarhus University, the Danish Clinical Intervention Research Academy, and the Danish Diabetes Association. The Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care trial was supported by the National Health Services in the counties of Copenhagen, Aarhus, Ringkøbing, Ribe and South Jutland in Denmark, Danish Research Foundation for General Practice, Danish Centre for Evaluation and Health Technology Assessment, The diabetes fund of the National Board of Health, The Danish Medical Research Council, The Aarhus University Research Foundation and Novo Nordisk Foundation. Furthermore, the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care trial has been given unrestricted grants from Novo Nordisk AS, Novo Nordisk Scandinavia AB, ASTRA Denmark, Pfizer Denmark, GlaxoSmithKline Pharma Denmark, SERVIER Denmark A/S, and HemoCue Denmark A/S.

Disclosure Summary: K.B.-J. holds stock in Novo Nordisk. K.B.-J., A.S., and T.L. have received lecture fees, and T.L. and O.S. consulting fees from commercial sponsors. N.G., C.H.A., M.K.A, A.A., T.J., T.H., and O.P. have nothing to declare.

First Published Online March 25, 2008

Abbreviations: ADDITION, Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care; BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; HDL, high-density lipoprotein; HDL-c, high-density lipoprotein cholesterol; HL, hepatic lipase; HOMA-IR, homeostasis model assessment of insulin resistance; IGT, impaired glucose tolerance; LDL, low-density lipoprotein; LDL-c, low-density lipoprotein cholesterol.

Received December 21, 2007.

Accepted March 17, 2008.

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