Amerindian-specific regions under positive selection harbour new lipid variants in Latinos

Nat Commun. 2014 Jun 2;5:3983. doi: 10.1038/ncomms4983.

Abstract

Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican-Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Apolipoprotein A-V
  • Apolipoproteins A / genetics
  • Case-Control Studies
  • Chromosomes, Human, Pair 11 / genetics
  • Chromosomes, Human, Pair 8 / genetics
  • Dyslipidemias / genetics
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Haplotypes
  • Humans
  • Hypercholesterolemia / genetics*
  • Hypertriglyceridemia / genetics*
  • Indians, North American / genetics*
  • Lipoprotein Lipase / genetics
  • Logistic Models
  • Male
  • Mexico / ethnology
  • Middle Aged
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / genetics
  • Obesity / genetics*
  • Polymorphism, Single Nucleotide
  • Protein Kinases / genetics
  • Young Adult

Substances

  • APOA5 protein, human
  • Apolipoprotein A-V
  • Apolipoproteins A
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • RORA protein, human
  • Protein Kinases
  • KIAA0999 protein, human
  • LPL protein, human
  • Lipoprotein Lipase

Associated data

  • dbGaP/PHS000618.V1.P1