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Gene-centric Association Signals for Lipids and Apolipoproteins Identified via the HumanCVD BeadChip

Talmud, Philippa J.; Drenos, Fotios; Shah, Sonia; Shah, Tina; Palmen, Jutta; Verzilli, Claudio; Gaunt, Tom R.; Pallas, Jacky; Lovering, Ruth and Li, Kawah, et al. (2009) In American Journal of Human Genetics 85(5). p.628-642
Abstract
Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n = 5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p < 10(-5), with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HWGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with... (More)
Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n = 5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p < 10(-5), with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HWGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with triglycerides in GCKR, BAZIB, MLXIPL, LPL, and APOA5-A4-C3-A1. For 48 SNPs in previously unreported loci that were significant at p < 10(-4) in Whitehall II, in silico analysis including the British Women's Heart and Health Study, BRIGHT, ASCOT, and NORDIL studies (total n > 12,500) revealed previously unreported associations of SH2B3 (p < 2.2 x 10(-6)), BMPR2 (p < 2.3 x 10(-7)), BCL3/PVRL2 (flanking APOE; p < 4.4 x 10(-8)), and SMARCA4 (flanking LDLR; p < 2.5 x 10(-7)) with LDL cholesterol. Common alleles in these genes explained 6.1%-14.7% of the variance in the five lipid-related traits, and individuals at opposite tails of the additive allele score exhibited substantial differences in trait levels (e.g., > 1 mmol/L in LDL cholesterol [similar to 1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically. (Less)
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American Journal of Human Genetics
volume
85
issue
5
pages
628 - 642
publisher
Cell Press
external identifiers
  • wos:000271916500010
  • scopus:72149100752
ISSN
0002-9297
DOI
10.1016/j.ajhg.2009.10.014
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English
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2009-12-28 15:25:39
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@article{3efaeff4-5eb5-4d40-8246-75f3495eb383,
  abstract     = {Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n = 5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p &lt; 10(-5), with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HWGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with triglycerides in GCKR, BAZIB, MLXIPL, LPL, and APOA5-A4-C3-A1. For 48 SNPs in previously unreported loci that were significant at p &lt; 10(-4) in Whitehall II, in silico analysis including the British Women's Heart and Health Study, BRIGHT, ASCOT, and NORDIL studies (total n &gt; 12,500) revealed previously unreported associations of SH2B3 (p &lt; 2.2 x 10(-6)), BMPR2 (p &lt; 2.3 x 10(-7)), BCL3/PVRL2 (flanking APOE; p &lt; 4.4 x 10(-8)), and SMARCA4 (flanking LDLR; p &lt; 2.5 x 10(-7)) with LDL cholesterol. Common alleles in these genes explained 6.1%-14.7% of the variance in the five lipid-related traits, and individuals at opposite tails of the additive allele score exhibited substantial differences in trait levels (e.g., &gt; 1 mmol/L in LDL cholesterol [similar to 1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically.},
  author       = {Talmud, Philippa J. and Drenos, Fotios and Shah, Sonia and Shah, Tina and Palmen, Jutta and Verzilli, Claudio and Gaunt, Tom R. and Pallas, Jacky and Lovering, Ruth and Li, Kawah and Casas, Juan Pablo and Sofat, Reecha and Kumari, Meena and Rodriguez, Santiago and Johnson, Toby and Newhouse, Stephen J. and Dominiczak, Anna and Samani, Nilesh J. and Caulfield, Mark and Sever, Peter and Stanton, Alice and Shields, Denis C. and Padmanabhan, Sandosh and Melander, Olle and Hastie, Claire and Delles, Christian and Ebrahim, Shah and Marmot, Michael G. and Smith, George Davey and Lawlor, Debbie A. and Munroe, Patricia B. and Day, Ian N. and Kivimaki, Mika and Whittaker, John and Humphries, Steve E. and Hingorani, Aroon D.},
  issn         = {0002-9297},
  language     = {eng},
  number       = {5},
  pages        = {628--642},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Gene-centric Association Signals for Lipids and Apolipoproteins Identified via the HumanCVD BeadChip},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2009.10.014},
  volume       = {85},
  year         = {2009},
}