Location: Boston, MassachusettsTitle: Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations Author
|Van Iperen, Erik|
|Castillo, Berta Almoguera|
|Cupples, L. Adrienne|
Submitted to: PLoS One
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/22/2012
Publication Date: 12/7/2012
Citation: Elbers, C.C., Guo, Y., Tragante, V., Van Iperen, E.P., Lanktree, M.B., Castillo, B., Chen, F., Yanek, L.R., Wojczynski, M.K., Li, Y.R., Ferwerda, B., Ballantyne, C.M., Buxbaum, S.G., Chen, Y.I., Chen, W., Cupples, L., Cushman, M., Duan, Y., Duggan, D., Evans, M.K., Fernandes, J., Fornage, M., Garcia, M., Garvey, W.T., Glazer, N., Gomez, F., Harris, T.B., Halder, I., However, V.J., Keller, M., Kamboh, M.I., Kooperberg, C., Kritchevsky, S.B., Lacroix, A., Liu, K., Liu, Y., Musunuru, K., Newman, A.B., Onland-Moret, C.N., Ordovas, J.M., Peter, I., Post, W., Redline, S., Reis, S.E., Saxena, R., Schreiner, P.J., Volcik, K.A., Wang, X., Yusuf, S., Zonderland, A.B., Anand, S.S., Becker, D.M., Psaty, B., Rader, D.J., Reiner, A.P., Rich, S.S., Rotter, J.I., Sale, M.M., Tsai, M.Y., Borecki, I.B., Hegele, R.A., Kathiresan, S., Nalls, M.A., Taylor, H.A., Hakonarson, H., Sivapalaratnam, S., Asselbergs, F.W., Drenos, F., Wilson, J.G., Keating, B.J. 2012. Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations. PLoS One. DOI: 10.1371/journal.pone.0050198. Interpretive Summary: Lipoproteins are spherical particles that carry lipids, particularly cholesterol and triglyceride, in the blood. There is a well-established association between dyslipidemias, or disorders of lipoprotein metabolism, and coronary heart disease (CHD). Elevated levels of blood cholesterol, especially low-density lipoprotein cholesterol (LDL-C), and low levels of high-density lipoprotein cholesterol (HDL-C) increase risk for CHD. Blood levels of these lipids are determined by both genetic and environmental factors. We recently performed large-scale meta-analysis of genome-wide studies and identified over 100 regions in the genome, which are significant predictors of blood lipid traits. However, most populations investigated have been of European origin and our knowledge of other ethnicities remains limited. The objective of this work was to perform dense genotyping of about 2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using a gene chip containing about 50,000 Single-nucleotide polymorphisms (variation in a lone nucleotide in a DNA sequence or SNP). Our analyses confirmed 16 lipid genetic regions previously established in European populations. Initial discovery and follow-up in 7,000 additional African American samples, confirmed two novel regions: one defined by the rs5030359 polymorphism within the ICAM1 gene that was associated with total cholesterol (TC) and LDL-C and another mutation known as rs3211938 within the CD36 gene that was associated with HDL-C levels. In conclusion, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of the ICAM1 and CD36 associations.
Technical Abstract: Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of circa 2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom circa 50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p=8.8×10-7 and p=1.5×10-6 respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p=13.5×10-12). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.