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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 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.


  1. Rondinone, C.M. Adipocyte-derived hormones, cytokines, and mediators. Endocrine 29, 81–90 (2006).

    Article  CAS  Google Scholar 

  2. Li, C. Genetics and regulation of angiopoietin-like proteins 3 and 4. Curr. Opin. Lipidol. 17, 152–156 (2006).

    Article  CAS  Google Scholar 

  3. Koster, A. et al. Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism. Endocrinology 146, 4943–4950 (2005).

    Article  CAS  Google Scholar 

  4. Yoshida, K., Shimizugawa, T., Ono, M. & Furukawa, H. Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase. J. Lipid Res. 43, 1770–1772 (2002).

    Article  CAS  Google Scholar 

  5. Xu, A. et al. Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice. Proc. Natl. Acad. Sci. USA 102, 6086–6091 (2005).

    Article  CAS  Google Scholar 

  6. Mandard, S. et al. The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity. J. Biol. Chem. 281, 934–944 (2006).

    Article  CAS  Google Scholar 

  7. Merkel, M., Eckel, R.H. & Goldberg, I.J. Lipoprotein lipase: genetics, lipid uptake, and regulation. J. Lipid Res. 43, 1997–2006 (2002).

    Article  CAS  Google Scholar 

  8. Yu, X. et al. Inhibition of cardiac lipoprotein utilization by transgenic overexpression of Angptl4 in the heart. Proc. Natl. Acad. Sci. USA 102, 1767–1772 (2005).

    Article  CAS  Google Scholar 

  9. Victor, R.G. et al. The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health. Am. J. Cardiol. 93, 1473–1480 (2004).

    Article  Google Scholar 

  10. Browning, J.D. et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40, 1387–1395 (2004).

    Article  Google Scholar 

  11. Grundy, S.M. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am. J. Cardiol. 81, 18B–25B (1998).

    Article  CAS  Google Scholar 

  12. The ARIC Study Investigators. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. Am. J. Epidemiol. 129, 687–702 (1989).

  13. Schnohr, P., Jensen, G., Scharling, H. & Appleyard, M. The Copenhagen City Heart Study. Osterbroundersogelsen. Tables with data from the third examination 1991–94. Eur. Heart J. 3 (Suppl.), H1–H83 (2001).

    Google Scholar 

  14. Tajima, F. Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123, 585–595 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Fu, Y.X. & Li, W.H. Statistical tests of neutrality of mutations. Genetics 133, 693–709 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Collins, F.S. The case for a US prospective cohort study of genes and environment. Nature 429, 475–477 (2004).

    Article  CAS  Google Scholar 

  17. Gibbs, R. Deeper into the genome. Nature 437, 1233–1234 (2005).

    Article  CAS  Google Scholar 

  18. Kotowski, I.K. et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am. J. Hum. Genet. 78, 410–422 (2006).

    Article  CAS  Google Scholar 

  19. Cohen, J. et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37, 161–165 (2005).

    Article  CAS  Google Scholar 

  20. Cohen, J.C. et al. Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels. Proc. Natl. Acad. Sci. USA 103, 1810–1815 (2006).

    Article  CAS  Google Scholar 

  21. Tartaglia, M. et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat. Genet. 39, 75–79 (2007).

    Article  CAS  Google Scholar 

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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).

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