Searching for the Causal Variants of the Association Between Hypertriglyceridemia and the Genome-Wide Association Studies-Derived Signals? Take a Look in the Native American Populations.

Abstract

Genome-wide association studies (GWAS) have made possible the identification of >175 loci that affect plasma lipid levels. Its results have been crucial to identify roles of new players in lipid metabolism (ie, apolipoprotein A5) or even to postulate potential treatment targets (ie, apolipoprotein C-III). However, a large proportion of the GWAS results has not been translated in clinically useful information because a large proportion of responsible single nucleotide polymorphisms (SNPs) are located either in noncoding regions or in genes without an obvious participation in any metabolic pathway.1 This is the case of the association between rs964184 and plasma triglycerides concentrations. This highly significant association has been a constant finding in the GWAS reports, regardless the sample size or the study sample composition.2 The frequency of the risk allele (G) varies between populations from 12% in whites to 27% in Mexicans. Also, it is common in Japanese (31%) and in Native American communities located in Central Mexico (≈50%). This SNP is nearby the 3′ untranslated region of the zinc finger gene ( ZPR1 ) and close to APOA5 . However, the identification of the functional variant that explains the association has not been possible. See Article by Hsueh et al The study of ethnic groups not included in the discovery cohorts, some methodological approaches (ie, admixture mapping or inception by descent [IBD] mapping), and deep genotyping are among the potential approaches to identify the variants responsible for a GWAS signal.3 The study of the Native American populations is an option because this group has not included in the majority of the lipids-related GWAS. The greater susceptibility of the populations derived from the Native American founding groups for having hypertriglyceridemia is well documented.4 These groups include the Amerindian communities living in Canada and the United States, mestizos living in the …