Abstract
Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10−7 and p = 1.5×10−6 respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10−12). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.
Highlights
Plasma levels of circulating total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C) and triglycerides (TG) are associated with coronary artery disease (CAD) and are targets for therapeutic intervention [1]
We evaluated for each ethnic group the contribution of the weighted genetic risk score to TC, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and TG in linear regression models adjusting for 10 principal components (PCs)
The current study reports a meta-analysis of lipid association studies in African Americans, Hispanics and East Asians using the IBC array, and has identified two novel loci associated with TC and LDL-C levels and HDL-C levels in African Americans
Summary
Plasma levels of circulating total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C) and triglycerides (TG) are associated with coronary artery disease (CAD) and are targets for therapeutic intervention [1]. To date, .100 lipid-associated loci have been described, using studies mainly based on individuals of European ancestry [3]. Known variants affecting plasma lipid levels explain 10–12% of the total variance and 25–30% of the genetic variance [3] indicating that other loci and independent signals in established loci are likely to contribute to the trait. An important first step towards understanding genetic risk across populations is to establish whether plasma lipid associated loci, identified in Europeans, span across multiple ethnicities or are population-specific. Most of these known lipid loci had the same direction of association in different ethnic groups as in Europeans, despite presumed differences in linkage disequilibrium (LD) between marker and causal variants in each population [6]. Independent association signals in established lipid loci in one ethnicity may be useful to highlight causal signal(s) in other ethnicities
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
