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Physical activity modifies the effect of LPL, LIPC, and CETP polymorphisms on HDL-C levels and the risk of myocardial infarction in women of European ancestry.

ABSTRACT: Recent genome-wide association studies have identified common variants associated with high-density lipoprotein cholesterol (HDL-C). Whether these associations are modified by physical activity, which increases HDL-C levels and reduces the risk of cardiovascular disease, is uncertain.In a prospective cohort study of 22 939 apparently healthy US women of European ancestry, we selected 58 single nucleotide polymorphisms (SNPs) in 9 genes that demonstrated genome-wide association (P<5×10(-8)) with HDL-C levels and sought evidence of effect modification according to levels of physical activity. Physical activity modified the effects on HDL-C of 7 SNPs at 3 loci, and the strongest evidence of effect was observed for rs10096633 at lipoprotein lipase (LPL), rs1800588 at hepatic lipase (LIPC), and rs1532624 at cholesteryl ester transfer protein (CETP) (each P-interaction<0.05). The per-minor-allele increase in HDL-C for rs1800588 at LIPC and rs1532624 at CETP was greater in active than inactive women, whereas the reverse was observed for rs10096633 at LPL. Minor-allele carrier status at the LPL SNP was associated with a reduced risk of myocardial infarction in active (hazard ratio, 0.51; 95% confidence interval 0.30-0.86) but not among inactive women (hazard ratio 1.13; 95% confidence interval 0.79 to 1.61; P-interaction=0.007). By contrast, carrier status at the CETP SNP was associated with a reduced risk of myocardial infarction regardless of activity level (hazard ratio, 0.72; 95% confidence interval, 0.57 to 0.92; P-interaction=0.71). No association between LIPC SNP carrier status and myocardial infarction risk was noted.The effects of common variants in the LPL, LIPC, and CETP genes on HDL-C levels are modified by physical activity. For a common variant in LPL, the impact on myocardial infarction varied by activity level, whereas the effects of a common variant in CETP on myocardial infarction risk did not.

SUBMITTER: Ahmad T

PROVIDER: S-EPMC3053582 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Physical activity modifies the effect of LPL, LIPC, and CETP polymorphisms on HDL-C levels and the risk of myocardial infarction in women of European ancestry.

Ahmad Tariq T Chasman Daniel I DI Buring Julie E JE Lee I-Min IM Ridker Paul M PM Everett Brendan M BM

Circulation. Cardiovascular genetics 20110120 1

<h4>Background</h4>Recent genome-wide association studies have identified common variants associated with high-density lipoprotein cholesterol (HDL-C). Whether these associations are modified by physical activity, which increases HDL-C levels and reduces the risk of cardiovascular disease, is uncertain.<h4>Methods and results</h4>In a prospective cohort study of 22 939 apparently healthy US women of European ancestry, we selected 58 single nucleotide polymorphisms (SNPs) in 9 genes that demonstr ...[more]

PMID: 21252145

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Project description:Cardiovascular risk factors and atherosclerosis precursors were examined in 365 Turkish children and adolescents. Study participants were recruited at five different state schools. We tested single and multi-locus effects of six polymorphisms from five candidate genes, chosen based on prior known association with lipid levels in adults, for association with low (?10th percentile) high density lipoprotein cholesterol (HDL-C) and high (?90th percentile) triglycerides (TG), and the related continuous outcomes. We observed an association between CETP variant rs708272 and low HDL-C (allelic p=0.020, genotypic p=0.046), which was supported by an independent analysis, PRAT (PRAT control p=0.027). Sex-stratified logistic regression analysis showed that the B2 allele of rs708272 decreased odds of being in the lower tenth percentile of HDL-C measurements (OR=0.36, p=0.02) in girls; this direction of effect was also seen in boys but was not significant (OR=0.64, p=0.21). Logistic regression analysis also revealed that the T allele of rs6257 (SHBG) decreased odds of being in the top tenth percentile of TG measurements in boys (OR=0.43, p=0.03). Analysis of lipid levels as a continuous trait revealed a significant association between rs708272 (CETP) and LDL-C levels in males (p=0.02) with the B2B2 genotype group having the lowest mean LDL-C; the same direction of effect was also seen in females (p=0.05). An effect was also seen between rs708272 and HDL-C levels in girls (p=0.01), with the B2B2 genotype having the highest mean HDL-C levels. Multi-locus analysis, using quantitative multifactor dimensionality reduction (qMDR) identified the previously mentioned CETP variant as the best single locus model, and overall model, for predicting HDL-C levels in children. This study provides evidence for association between CETP and low HDL-C phenotype in children, but the results appear to be weaker in children than previous results in adults and may also be subject to gender effects.

Project description:Polymorphisms in and around the Cholesteryl Ester Transfer Protein (CETP) gene have been associated with HDL levels, risk for coronary artery disease (CAD), and response to therapy. The mechanism of action of these polymorphisms has yet to be defined. We used mRNA allelic expression and splice isoform measurements in human liver tissues to identify the genetic variants affecting CETP levels. Allelic CETP mRNA expression ratios in 56 human livers were strongly associated with several variants 2.5-7 kb upstream of the transcription start site (e.g., rs247616 p = 6.4 × 10(-5), allele frequency 33%). In addition, a common alternatively spliced CETP isoform lacking exon 9 (?9), has been shown to prevent CETP secretion in a dominant-negative manner. The ? 9 expression ranged from 10 to 48% of total CETP mRNA in 94 livers. Increased formation of this isoform was exclusively associated with an exon 9 polymorphism rs5883-C>T (p = 6.8 × 10(-10)) and intron 8 polymorphism rs9930761-T>C (5.6 × 10(-8)) (in high linkage disequilibrium with allele frequencies 6-7%). rs9930761 changes a key splicing branch point nucleotide in intron 8, while rs5883 alters an exonic splicing enhancer sequence in exon 9.The effect of these polymorphisms was evaluated in two clinical studies. In the Whitehall II study of 4745 subjects, both rs247616 and rs5883T/rs9930761C were independently associated with increased HDL-C levels in males with similar effect size (rs247616 p = 9.6 × 10(-28) and rs5883 p = 8.6 × 10(-10), adjusted for rs247616). In an independent multiethnic US cohort of hypertensive subjects with CAD (INVEST-GENE), rs5883T/rs9930761C alone were significantly associated with increased incidence of MI, stroke, and all-cause mortality in males (rs5883: OR 2.36 (CI 1.29-4.30), p = 0.005, n = 866). These variants did not reach significance in females in either study. Similar to earlier results linking low CETP activity with poor outcomes in males, our results suggest genetic, sex-dependent CETP splicing effects on cardiovascular risk by a mechanism independent of circulating HDL-C levels.

Dataset Information

Physical activity modifies the effect of LPL, LIPC, and CETP polymorphisms on HDL-C levels and the risk of myocardial infarction in women of European ancestry.

Publications

Physical activity modifies the effect of LPL, LIPC, and CETP polymorphisms on HDL-C levels and the risk of myocardial infarction in women of European ancestry.

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