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United States Department of Agriculture

Agricultural Research Service

Research Project: NUTRITION, OBESITY, CARDIOVASCULAR HEALTH AND GENOMICS

Location: Boston, Massachusetts

Title: Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations)

Author
item Elbers, Clara
item Guo, Yiran
item Tragante, Vinicius
item Van Iperen, Erik
item Lanktree, Matthew
item Castillo, Berta Almoguera
item Chen, Fang
item Yanek, Lisa
item Wojczynski, Mary
item Li, Yun
item Ferwerda, Bart
item Ballantyne, Christie
item Buxbaum, Sarah
item Chen, Yii-der
item Chen, Wei-min
item Cupples, L. Adrienne
item Cushman, Mary
item Duan, Yanan
item Duggan, David
item Evans, Michele
item Fernandes, Jyotika
item Fornage, Myriam
item Garcia, Melissa
item Garvey, W
item Glazer, Nicole
item Gomez, Felicia
item Harris, Tamara
item Halder, Indrani
item However, Virginia
item Keller, Margaux
item Kamboh, M
item Kooperberg, Charles
item Kritchevsky, Stephen
item Lacroix, Andrea
item Liu, Kiang
item Liu, Yongmei
item Musunuru, Kiran
item Newman, Anne
item Onland-moret, Charlotte
item Ordovas, Jose
item Peter, Inga
item Post, Wendy
item Redline, Susan
item Reis, Steven
item Saxena, Richa
item Schreiner, Pamela
item Volcik, Kelly
item Wang, Xingbin
item Yusuf, Salim
item Zonderland, Alan
item Anand, Sonia
item Becker, Diane
item Psaty, Bruce
item Rader, Daniel
item Reiner, Alex
item Rich, Stephen
item Rotter, Jerome
item Sale, Michele
item Tsai, Michael
item Borecki, Ingrid
item Hegele, Robert
item Kathiresan, Sekar
item Nalls, Michael
item Taylor, Herman
item Hakonarson, Hakon
item Sivapalaratnam, Suthesh
item Asselbergs, Folkert
item Drenos, Fotios
item Wilson, James
item Keating, Brendan

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.

Last Modified: 8/24/2016
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