Genetic effects versus bias for candidate polymorphisms in myocardial infarction: case study and overview of large-scale evidence.
Several genetic polymorphisms have been proposed to be associated with myocardial infarction (MI). The authors examined the evidence and biases underlying such associations using a case-study meta-analysis and an overview of large-scale data. In a meta-analysis of 27 studies addressing the association of the angiotensin type 1 receptor (AT1R)+1166A/C polymorphism with MI (10,180 cases, 17,129 controls), the *C allele conferred an increase in MI risk (odds ratio = 1.13 per allele, p = 0.005). However, there was large between-study heterogeneity; the largest study showed no effect, contradicting smaller studies; and studies with blinded genotyping showed no effect. The authors conducted an overview of meta-analyses of genetic associations for MI or coronary artery disease, including at least three studies and 3,000 subjects. In their latest meta-analysis, another 14 polymorphisms were found to have formally significant associations. If true, these associations would already explain 42% of the MI risk for Caucasian populations. Significant between-study heterogeneity was common. Across the 32 largest studies, only two found formally significant results (nine would be expected if each meta-analysis showed a true association). Even with large-scale evidence from meta-analyses, significant associations for MI may be subject to bias. Large-scale single studies and prospective consortia should be used for detecting and validating the genetic determinants of MI.
Ntzani
Evangelia E
EE
Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
Rizos
Evangelos C
EC
Ioannidis
John P A
JP
D000483:Alleles; D015982:Bias; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D006115:Greece / Q000453:epidemiology; D006801:Humans; D009203:Myocardial Infarction / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D012307:Risk Factors
D044140:Receptor, Angiotensin, Type 1