Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL

Abstract

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 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.

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Figure 1: Schematic of the ANGPTL4 gene with location of nonsynonymous sequence variations identified in the upper and lower quartiles of Dallas Heart Study.
Figure 2: Proportion of nonsynonymous and synonymous sequence variants in European Americans, African Americans and Hispanics in the Dallas Heart Study.
Figure 3: Prevalence of the ANGPTL4[E40K] allele among individuals with low and high plasma triglyceride levels in the Dallas Heart Study and ARIC study.

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Acknowledgements

The authors thank the Joint Genome Institute's production sequencing group, T. Hyatt, K. Moller Hansen, M. Refstrup, W.S. Schackwitz, J. Martin and A. Ustaszewska for excellent technical assistance and J. Schageman, C. Lee and K. Lawson for statistical analyses. We are indebted to the staff and participants of the Dallas Heart Study, the ARIC study and the CCHS for their important contributions. We thank J. Goldstein and M. Brown for discussions. This work was supported by grants from the Donald W. Reynolds Foundation, the US National Institutes of Health, the Danish Medical Research Council, The Danish Heart Foundation and the Research Fund at Rigshospitalet (Copenhagen University Hospital). Research conducted at the E.O. Lawrence Berkeley National Laboratory and the Joint Genome Institute was performed under the Berkeley Program for Genomic Applications, funded by the US National Heart, Lung, and Blood Institute (HL066681) and Department of Energy Contract DE-AC02-05CH11231 (University of California).

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Correspondence to Helen H Hobbs or Jonathan C Cohen.

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Supplementary information

Supplementary Fig. 1

Location and frequency of sequence variations identified in ANGPTL4. (PDF 159 kb)

Supplementary Table 1

Oligonucleotide primers used for amplification and sequencing of ANGPTL4. (PDF 13 kb)

Supplementary Table 2

Distribution of nonsynonymous and synonymous sequence variants in the Dallas Heart Study. (PDF 19 kb)

Supplementary Table 3

Nonsynonymous ANGPTL4 alleles in individuals with high and low BMI, HDL-C and plasma insulin levels in the Dallas Heart Study. (PDF 22 kb)

Supplementary Table 4

Association between sequence variants in ANGPTL4 and plasma triglyceride levels in the Dallas Heart Study. (PDF 92 kb)

Supplementary Table 5

Association between ANGPTL4[E40K] genotype and plasma triglyceride levels in African Americans and Hispanics. (PDF 86 kb)

Supplementary Table 6

Tests for neutrality of mutations in the Dallas Heart Study. (PDF 33 kb)

Supplementary Note (PDF 17 kb)

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Romeo, S., Pennacchio, L., Fu, Y. et al. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat Genet 39, 513–516 (2007). https://doi.org/10.1038/ng1984

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