The effect of hematocrit and hemoglobin on the risk of ischemic heart disease: A Mendelian randomization study.
Hematocrit and hemoglobin affect viscosity, and have been considered as risk factors for ischemic heart disease (IHD), although observations are inconsistent; randomized controlled trials targeting hematocrit or hemoglobin have not been definitive. To clarify their role, the risk of IHD was assessed according to genetically determined hematocrit and hemoglobin. We applied single nucleotide polymorphisms (SNPs) strongly determining hematocrit and hemoglobin, from a genome wide association study, to a large case (64,746) control (130,681) study of coronary artery disease, CARDIoGRAMplusC4D, to obtain unconfounded estimates using instrumental variable analysis by combining the Wald estimators for each SNP taking into account any correlation between SNPs using weighted generalized linear regression. Hematocrit was positively associated with IHD, odds ratio (OR) 1.07 per %, 95% confidence interval (CI) 1.03 to 1.11, before and after excluding SNPs from gene regions directly functionally relevant to IHD. However, hematocrit was not associated with IHD (OR 0.99, 0.94 to 1.04) after also excluding SNPs associated with lipids at genome wide significance. Hemoglobin was not associated with IHD (OR 1.06 per g/dL, 0.97 to 1.15) which was similar (OR 1.02, 0.94 to 1.11) after excluding SNPs from gene regions directly functionally relevant to IHD. Hemoglobin was negatively associated with IHD after also excluding SNPs associated with lipids at genome wide significance (OR 0.86, 0.78 to 0.94). In conclusion, hematocrit shares genetic determinants with IHD, but whether the genes contribute to IHD via hematocrit or other mechanisms is not entirely clear. Higher Hemoglobin is unlikely to cause IHD.
School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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Zhong
School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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Lin
School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; CUNY School of Public Health and Health Policy, New York, USA. Electronic address: cms1@hku.hk.
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Schooling
D055106:Genome-Wide Association Study; D005838:Genotype; D006400:Hematocrit; D006454:Hemoglobins; D006801:Humans; D057182:Mendelian Randomization Analysis; D017202:Myocardial Ischemia / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D006454:Hemoglobins
Coronary artery disease; Hematocrit; Hemoglobin; Mendelian randomization analysis