Evaluation of gene-obesity interaction effects on cholesterol levels: A genetic predisposition score on HDL-cholesterol is modified by obesity

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• 作者：Claudia Lamina^a ; Lukas Forer^a ; ^b ; Sebastian Schö ; nherr^a ; ^b ; Barbara Kollerits^a ; Janina S. Ried^c ; Christian Gieger^c ; Annette Peters^d ; ^e ; H.-Erich Wichmann^f ; ^g ; ^h ; Florian Kronenberg^a ; ^{Florian.Kronenberg@i-med.ac.at}
• 关键词：Lipids ; Genetic predisposition score ; SNP ; Interaction ; Polymorphism ; HDL cholesterol
• 刊名：Atherosclerosis
• 出版年：2012
• 出版时间：December, 2012
• 年：2012
• 卷：225
• 期：2
• 页码：363-369
• 全文大小：461 K

文摘

Objective

Effect modification by obesity or obesity-related phenotypes (e.g. physical activity and diet) was observed in some candidate gene studies on lipids. We aimed to evaluate gene-obesity interaction effects on HDL (HDL-C), LDL (LDL-C) and total cholesterol (TC) levels using genetic predisposition scores.

Methods

We derived imputed genotypes for 104 SNPs in 84 lipid-associated loci in the population-based studies KORA F3 (n?=?1406) and KORA F4 (n?=?1515). We inferred specific unbiased weights for each SNP from linear regression estimates in KORA F4. Weighted genotypic predisposition SNP-scores were then calculated for each lipid trait in KORA F3. Interaction terms of SNP-scores with each of the obesity parameters (BMI, waist-hip-ratio, waist circumference) were included in age- and sex-adjusted linear regression models on HDL-C, LDL-C and TC.

Results

All three SNP-scores were shown to be highly associated with their respective lipid levels (p?=?1.11?¡Á?10^?47 for HDL-C, p?=?3.25?¡Á?10^?19 for LDL-C and 1.53?¡Á?10^?13 for TC). BMI, WHR and waist?circumference modified the effect of the weighted HDL-C SNP-score on HDL-C significantly (all?interaction p-values?<?0.0062). No interaction term was significant for LDL-C or TC. Accounting for gene-obesity interaction substantially increased the proportion of HDL-C variance explained by 3-3.5 % .

Conclusion

Our investigation revealed a significant interaction effect between obesity parameters and a SNP-score on HDL-C: the combined effect of HDL-C-increasing alleles on HDL-C is attenuated with increasing levels of obesity-relevant parameters. Future studies aiming to detect new genetic variants or to model genetic predictions of HDL-C levels should take obesity or obesity associated parameters into account.