title: Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies.
abstract: BACKGROUND
  Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality.
  
  
  METHODS
  We assessed the -1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20,842 patients with coronary heart disease, 35,206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12,785 incident cases of coronary heart disease during 2.79 million person-years at risk). We analysed -1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy.
  
  
  RESULTS
  The minor allele frequency of -1131T>C was 8% (95% CI 7-9). -1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3.5% [95% CI 2.6-4.6]; 0.053 mmol/L [0.039-0.068]), lower apolipoprotein AI (1.3% [0.3-2.3]; 0.023 g/L [0.005-0.041]), and higher apolipoprotein B (3.2% [1.3-5.1]; 0.027 g/L [0.011-0.043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16.0% (95% CI 12.9-18.7), or 0.25 mmol/L (0.20-0.29), higher (p=4.4x10(-24)). The odds ratio for coronary heart disease was 1.18 (95% CI 1.11-1.26; p=2.6x10(-7)) per C allele, which was concordant with the hazard ratio of 1.10 (95% CI 1.08-1.12) per 16% higher triglyceride concentration recorded in prospective studies. -1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12.2 nmol/L [95% CI 7.7-16.7]; p=9.3x10(-8)) and smaller HDL particle size (0.14 nm [0.08-0.20]; p=7.0x10(-5)), factors that could mediate the effects of triglyceride.
  
  
  CONCLUSIONS
  These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease.
  
  
  BACKGROUND
  British Heart Foundation, UK Medical Research Council, Novartis.
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK. nadeem.sarwar@phpc.cam.ac.uk
authors.forename: Nadeem
authors.initials: N
authors.lastname: Sarwar
authors.forename: Manjinder S
authors.initials: MS
authors.lastname: Sandhu
authors.forename: Sally L
authors.initials: SL
authors.lastname: Ricketts
authors.forename: Adam S
authors.initials: AS
authors.lastname: Butterworth
authors.forename: Emanuele
authors.initials: E
authors.lastname: Di Angelantonio
authors.forename: S Matthijs
authors.initials: SM
authors.lastname: Boekholdt
authors.forename: Willem
authors.initials: W
authors.lastname: Ouwehand
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Danish
authors.initials: D
authors.lastname: Saleheen
authors.forename: Debbie
authors.initials: D
authors.lastname: Lawlor
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: John
authors.initials: J
authors.lastname: Danesh
mesh_terms: D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000097:blood; D001054:Apolipoproteins A / Q000235:genetics; D003327:Coronary Disease / Q000097:blood / Q000235:genetics*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008055:Lipids / Q000097:blood; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL / Q000097:blood / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000097:blood / Q000235:genetics; D057182:Mendelian Randomization Analysis; D010316:Particle Size; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood* / Q000235:genetics
chemical_list: C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A; D008055:Lipids; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides
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