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

Author
item ELBERS, CLARA - UNIVERSITY OF PENNSYLVANIA
item GUO, YIRAN - THE CHILDREN'S HOSPITAL OF PHILADELPHIA
item TRAGANTE, VINICIUS - UNIVERSITY MEDICAL CENTER UTRECHT
item VAN IPEREN, ERIK - UNIVERSITY OF AMSTERDAM
item LANKTREE, MATTHEW - UNIVERSITY OF WESTERN ONTARIO
item CASTILLO, BERTA ALMOGUERA - THE CHILDREN'S HOSPITAL OF PHILADELPHIA
item CHEN, FANG - UNIVERSITY OF VIRGINIA
item YANEK, LISA - JOHNS HOPKINS UNIVERSITY
item WOJCZYNSKI, MARY - UNIVERSITY OF ALABAMA
item LI, YUN - THE CHILDREN'S HOSPITAL OF PHILADELPHIA
item FERWERDA, BART - UNIVERSITY OF PENNSYLVANIA
item BALLANTYNE, CHRISTIE - BAYLOR COLLEGE
item BUXBAUM, SARAH - JACKSON STATE UNIVERSITY
item CHEN, YII-DER - CEDARS-SINAI MEDICAL CENTER
item CHEN, WEI-MIN - UNIVERSITY OF VIRGINIA
item CUPPLES, L. ADRIENNE - BOSTON UNIVERSITY
item CUSHMAN, MARY - UNIVERSITY OF VERMONT
item DUAN, YANAN - WASHINGTON UNIVERSITY
item DUGGAN, DAVID - TRANSLATIONAL GENOMICS RESEARCH INSTITUTE
item EVANS, MICHELE - NATIONAL INSTITUTES OF HEALTH (NIH)
item FERNANDES, JYOTIKA - MEDICAL UNIVERSITY OF SOUTH CAROLINA
item FORNAGE, MYRIAM - UNIVERSITY OF TEXAS
item GARCIA, MELISSA - NATIONAL INSTITUTES OF HEALTH (NIH)
item GARVEY, W - UNIVERSITY OF ALABAMA
item GLAZER, NICOLE - BOSTON UNIVERSITY
item GOMEZ, FELICIA - UNIVERSITY OF PENNSYLVANIA
item HARRIS, TAMARA - NATIONAL INSTITUTES OF HEALTH (NIH)
item HALDER, INDRANI - UNIVERSITY OF PITTSBURGH
item HOWEVER, VIRGINIA - UNIVERSITY OF ALABAMA
item KELLER, MARGAUX - NATIONAL INSTITUTES OF HEALTH (NIH)
item KAMBOH, M - UNIVERSITY OF PITTSBURGH
item KOOPERBERG, CHARLES - FRED HUTCHINSON CANCER RESEARCH CENTER
item KRITCHEVSKY, STEPHEN - UNIVERSITY OF TENNESSEE
item LACROIX, ANDREA - FRED HUTCHINSON CANCER RESEARCH CENTER
item LIU, KIANG - NORTHWESTERN UNIVERSITY
item LIU, YONGMEI - WAKE FOREST UNIVERSITY
item MUSUNURU, KIRAN - BROAD INSTITUTE OF MIT/HARVARD
item NEWMAN, ANNE - UNIVERSITY OF PITTSBURGH
item ONLAND-MORET, CHARLOTTE - UNIVERSITY MEDICAL CENTER UTRECHT
item ORDOVAS, JOSE - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY
item PETER, INGA - MOUNT SINAI SCHOOL OF MEDICINE
item POST, WENDY - JOHNS HOPKINS UNIVERSITY
item REDLINE, SUSAN - BRIGHAM & WOMEN'S HOSPITAL
item REIS, STEVEN - UNIVERSITY OF PITTSBURGH
item SAXENA, RICHA - MASSACHUSETTS GENERAL HOSPITAL
item SCHREINER, PAMELA - UNIVERSITY OF MINNESOTA
item VOLCIK, KELLY - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item WANG, XINGBIN - UNIVERSITY OF PITTSBURGH
item YUSUF, SALIM - MCMASTER UNIVERSITY
item ZONDERLAND, ALAN - NATIONAL INSTITUTES OF HEALTH (NIH)
item ANAND, SONIA - MCMASTER UNIVERSITY
item BECKER, DIANE - JOHNS HOPKINS UNIVERSITY
item PSATY, BRUCE - UNIVERSITY OF WASHINGTON
item RADER, DANIEL - UNIVERSITY OF PENNSYLVANIA
item REINER, ALEX - FRED HUTCHINSON CANCER RESEARCH CENTER
item RICH, STEPHEN - UNIVERSITY OF VIRGINIA
item ROTTER, JEROME - CEDARS-SINAI MEDICAL CENTER
item SALE, MICHELE - UNIVERSITY OF VIRGINIA
item TSAI, MICHAEL - UNIVERSITY OF MINNESOTA
item BORECKI, INGRID - WASHINGTON UNIVERSITY
item HEGELE, ROBERT - UNIVERSITY OF WESTERN ONTARIO
item KATHIRESAN, SEKAR - BROAD INSTITUTE OF MIT/HARVARD
item NALLS, MICHAEL - NATIONAL INSTITUTES OF HEALTH (NIH)
item TAYLOR, HERMAN - JACKSON STATE UNIVERSITY
item HAKONARSON, HAKON - THE CHILDREN'S HOSPITAL OF PHILADELPHIA
item SIVAPALARATNAM, SUTHESH - ACADEMIC MEDICAL CENTER
item ASSELBERGS, FOLKERT - UNIVERSITY MEDICAL CENTER UTRECHT
item DRENOS, FOTIOS - UNIVERSITY COLLEGE LONDON
item WILSON, JAMES - UNIVERSITY OF MISSISSIPPI MEDICAL CENTER
item KEATING, BRENDAN - THE CHILDREN'S HOSPITAL OF PHILADELPHIA

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.