Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL.
Resequencing genes provides the opportunity to assess the full spectrum of variants that influence complex traits. Here we report the first application of resequencing to a large population (n = 3,551) to examine the role of the adipokine ANGPTL4 in lipid metabolism. Nonsynonymous variants in ANGPTL4 were more prevalent in individuals with triglyceride levels in the lowest quartile than in individuals with levels in the highest quartile (P = 0.016). One variant (E40K), present in approximately 3% of European Americans, was associated with significantly lower plasma levels of triglyceride and higher levels of high-density lipoprotein cholesterol in European Americans from the Atherosclerosis Risk in Communities Study and in Danes from the Copenhagen City Heart Study. The ratio of nonsynonymous to synonymous variants was higher in European Americans than in African Americans (4:1 versus 1.3:1), suggesting population-specific relaxation of purifying selection. Thus, resequencing of ANGPTL4 in a multiethnic population allowed analysis of the phenotypic effects of both rare and common variants while taking advantage of genetic variation arising from ethnic differences in population history.
Romeo
Stefano
S
Donald W. Reynolds Cardiovascular Clinical Research Center, the Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
Pennacchio
Len A
LA
Fu
Yunxin
Y
Boerwinkle
Eric
E
Tybjaerg-Hansen
Anne
A
Hobbs
Helen H
HH
Cohen
Jonathan C
JC
D000328:Adult; D001741:Black or African American / Q000235:genetics; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D008076:Cholesterol, HDL / Q000097:blood*; D015331:Cohort Studies; D004734:Energy Metabolism / Q000235:genetics; D005787:Gene Frequency; D008040:Genetic Linkage; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D017422:Sequence Analysis, DNA; D013781:Texas; D014280:Triglycerides / Q000097:blood*; D044465:White People / Q000235:genetics
C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D008076:Cholesterol, HDL; D036341:Intercellular Signaling Peptides and Proteins; D014280:Triglycerides