Genes determining cholesterol levels

Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci

Asselbergs FW et al.
The American Journal of Human Genetics 2012; http://dx.doi.org/10.1016/j.ajhg.2012.08.032

Background

Both genetic and environmental factors determine cholesterol levels in the blood [1]. There is a clear relationship between abnormalities in plasma lipid levels and cardiovascular disease [2,3]. Plasma lipid and lipoprotein levels are highly heritable (40-60%)[4].
Genetic associations have been studied before. In this meta-analysis, a team of international researchers analyzed approximately 50,000 genetic variants in some 2100 genes with a role in heart disease by a dense gene-centric approach. They viewed these genes in more than 65,000 people and repeated the performance in an independent survey of 25,000 people, they compared it also with previous research of another 100,000 people.
Four hospitals coordinated the large international study, called the International IBC Lipid Genetics Consortium. This consortium consists of 180 researchers worldwide, from which two from the Netherlands, UMC Utrecht and AMC Amsterdam. In addition, the Children's Hospital of Philadelphia and the Institute of Cardiovascular Sciences at University College London.

Main results

• 21 new genes were identified that affect lipid levels in the blood
• The relationship between changes in 49 newly found genes with plasma lipid levels was confirmed

Conclusion

A focused genotyping approach can further increase the understanding of heritability of plasma lipids. The newly found genes constitute a valuable target for the development of new cholesterol-lowering drugs.

References

1. Berenson, G.S., Srinivasan, S.R., Bao, W., et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N. Engl. J. Med. 1998:338;1650–1656.
2. Arsenault, B.J., Boekholdt, S.M., and Kastelein, J.J. Lipid parameters for measuring risk of cardiovascular disease. Nat Rev Cardiol 2011: 8;197–206.
3. Di Angelantonio, E., Sarwar, N., Perry, P., et al.; Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009:302;1993–2000.
4. Weiss, L.A., Pan, L., Abney, M., Ober, C. The sexspecific genetic architecture of quantitative traits in humans. Nat. Genet. 2006:38;218–222.

Abstract

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ~50,000 SNP genotyping array (the ITMAT-Broad- CARe array) covering ~2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids