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, Li, Kawah, Casas, Juan Pablo, Sofat, Reecha, Kumari, Meena, Rodriguez, Santiago, Johnson, Toby, Newhouse, Stephen J., Dominiczak, Anna, Samani, Nilesh J., Caulfield, Mark, Sever, Peter, Stanton, Alice, Shields, Denis C., Padmanabhan, Sandosh, Melander, Olle, Hastie, Claire, Delles, Christian, Ebrahim, Shah, Marmot, Michael G., Smith, George Davey, Lawlor, Debbie A., Munroe, Patricia B., Day, Ian N., Kivimaki, Mika, Whittaker, John, Humphries, Steve E. and Hingorani, Aroon D. (2009) Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American Journal of Human Genetics, 85 5: 628-642. doi:10.1016/j.ajhg.2009.10.014

Author Talmud, Philippa J.
Drenos, Fotios
Shah, Sonia
Shah, Tina
Palmen, Jutta
Verzilli, Claudio
Gaunt, Tom R.
Pallas, Jacky
Lovering, Ruth
Li, Kawah
Casas, Juan Pablo
Sofat, Reecha
Kumari, Meena
Rodriguez, Santiago
Johnson, Toby
Newhouse, Stephen J.
Dominiczak, Anna
Samani, Nilesh J.
Caulfield, Mark
Sever, Peter
Stanton, Alice
Shields, Denis C.
Padmanabhan, Sandosh
Melander, Olle
Hastie, Claire
Delles, Christian
Ebrahim, Shah
Marmot, Michael G.
Smith, George Davey
Lawlor, Debbie A.
Munroe, Patricia B.
Day, Ian N.
Kivimaki, Mika
Whittaker, John
Humphries, Steve E.
Hingorani, Aroon D.
Title Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
Publication date 2009-11-13
Year available 2009
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2009.10.014
Open Access Status Not yet assessed
Volume 85
Issue 5
Start page 628
End page 642
Total pages 15
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
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, HMGCR, 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, BAZ1B, 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 × 10-6), BMPR2 (p < 2.3 × 10-7), BCL3/PVRL2 (flanking APOE; p < 4.4 × 10-8), and SMARCA4 (flanking LDLR; p < 2.5 × 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 [∼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.
Keyword Genetics & Heredity
Genetics & Heredity
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID PG/07/133/24260
NHLBI 33014
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 118 times in Thomson Reuters Web of Science Article | Citations
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