Abstract 13720: Extreme Ends Approach Identifies Novel eQTL Genes for Low HDL-C
Inverse correlation between HDL-cholesterol level and atherosclerosis has been established. To identify potentially novel, rare variants contributing to exceptionally high or low serum HDL-cholesterol levels, we genotyped 450 Finns (Illumina370K) from EUFAM population sample, either having extremely high (>90 %) or low (<10 %) HDL-C levels. Out of these, subcutaneous fat biopsies were obtained from 54 individuals, and their global expression profiles were analyzed using Affymetrix microarrays.
The two best low HDL-C associating SNPs were located at CETP, as in previous studies. However, the 3rd and 10th best hits (rs7766109, p=10-5 and rs4959377, p=3.45x10-5) were located within F13A1, a coagulation factor with no previously reported associations with serum lipid levels. We tested 54 additional SNPs within the F13A1 region and detected associations for 10 of them, all of them located within introns 3-5. The associations of F13A1 SNPs in introns 3-5 for HDL-C were replicated in a Finnish population sample with normal distribution of HDL (n=11,290).
To obtain functional evidence for our genetic link between HDL level and F13A1 we measured F13A1 transcript levels in fat biopsies and observed them to be higher in adipose tissue of individuals with low HDL (p=0.007). Furthermore, we identified a cis-eQTL by demonstrating the dose-dependent effect of rs7766109 genotype on both F13A1 expression and HDL-levels (p=0.004). To further explore the role of F13A1 in metabolic derangements, we recruited 5 insulin sensitive females with high HDL-C levels and 5 insulin resistant females from the Helsinki University Central Hospital. We obtained surgical biopsies from their subcutaneous adipose tissue before and after a euglycemic insulin clamp. F13A1 transcript level was 6-fold higher in IR subjects compared to IS individuals (p=0.003). Moreover, an insulin-induced decrease in F13A1 expression was observed in IR (p=0.047) but not in IS subjects. Here we show the value of extreme phenotypes and the combination of global SNP and expression analysis in the identification of new, potentially high impact genes regulating serum lipid levels and metabolism.
- © 2013 by American Heart Association, Inc.