Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration

Aspasia Angelakopoulou, Tina Shah, Reecha Sofat, Sonia Shah, Diane J Berry, Jackie Cooper, Jutta Palmen, Ioanna Tzoulaki, Andrew Wong, Barbara J Jefferis, Nikolas Maniatis, Fotios Drenos, Bruna Gigante, Rebecca Hardy, Ross C Laxton, Karin Leander, Anna Motterle, Iain A Simpson, Liam Smeeth, Andy ThomsonClaudio Verzilli, Diana Kuh, Helen Ireland, John Deanfield, Mark Caulfield, Chris Wallace, Nilesh Samani, Patricia B Munroe, Mark Lathrop, F Gerry R Fowkes, Michael Marmot, Peter H Whincup, John C Whittaker, Ulf de Faire, Mika Kivimaki, Meena Kumari, Elina Hypponen, Chris Power, Steve E Humphries, Philippa J Talmud, Jackie Price, Richard W Morris, Shu Ye, Juan P Casas, Aroon D Hingorani

Research output: Contribution to journalArticle (Academic Journal)peer-review

75 Citations (Scopus)

Abstract

AIMS: To evaluate the associations of emergent genome-wide-association study-derived coronary heart disease (CHD)-associated single nucleotide polymorphisms (SNPs) with established and emerging risk factors, and the association of genome-wide-association study-derived lipid-associated SNPs with other risk factors and CHD events.

METHODS AND RESULTS: Using two case-control studies, three cross-sectional, and seven prospective studies with up to 25 000 individuals and 5794 CHD events we evaluated associations of 34 genome-wide-association study-identified SNPs with CHD risk and 16 CHD-associated risk factors or biomarkers. The Ch9p21 SNPs rs1333049 (OR 1.17; 95% confidence limits 1.11-1.24) and rs10757274 (OR 1.17; 1.09-1.26), MIA3 rs17465637 (OR 1.10; 1.04-1.15), Ch2q36 rs2943634 (OR 1.08; 1.03-1.14), APC rs383830 (OR 1.10; 1.02, 1.18), MTHFD1L rs6922269 (OR 1.10; 1.03, 1.16), CXCL12 rs501120 (OR 1.12; 1.04, 1.20), and SMAD3 rs17228212 (OR 1.11; 1.05, 1.17) were all associated with CHD risk, but not with the CHD biomarkers and risk factors measured. Among the 20 blood lipid-related SNPs, LPL rs17411031 was associated with a lower risk of CHD (OR 0.91; 0.84-0.97), an increase in Apolipoprotein AI and HDL-cholesterol, and reduced triglycerides. SORT1 rs599839 was associated with CHD risk (OR 1.20; 1.15-1.26) as well as total- and LDL-cholesterol, and apolipoprotein B. ANGPTL3 rs12042319 was associated with CHD risk (OR 1.11; 1.03, 1.19), total- and LDL-cholesterol, triglycerides, and interleukin-6.

CONCLUSION: Several SNPs predicting CHD events appear to involve pathways not currently indexed by the established or emerging risk factors; others involved changes in blood lipids including triglycerides or HDL-cholesterol as well as LDL-cholesterol. The overlapping association of SNPs with multiple risk factors and biomarkers supports the existence of shared points of regulation for these phenotypes.

Original languageEnglish
Pages (from-to)393-407
Number of pages15
JournalEuropean Heart Journal
Volume33
Issue number3
DOIs
Publication statusPublished - Feb 2012

Keywords

  • Adult
  • Aged
  • Biological Markers
  • Body Mass Index
  • Case-Control Studies
  • Coronary Disease
  • Diabetes Mellitus, Type 2
  • Diabetic Cardiomyopathies
  • Female
  • Genome-Wide Association Study
  • Humans
  • Lipids
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Risk Factors

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