Combining geographic region with meta-analysis to map the potential association between three genetic polymorphisms and coronary artery disease

Background: Coronary artery disease (CAD) is a complex trait influenced by genetic and environmental factors. Geographic isolation and natural selection present fundamental forces to diversify genetic backgrounds during human evolution and migration. In this study, we attempted to assess whether human geographic isolation affects the genetic predisposition of CAD. Methods: We first included 21 genetic association studies of the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T and CAD from 16 geographic regions consisting of 9,008 participants and performed a meta-analysis based on the distributions of these studies. Results: It was found that the positive signals for the association of C677T with CAD were mainly enriched in the regions of northern Africa (pooled OR=1.73, 95% CI=1.45-2.06, Z=3.17, P<0.0001) and India (pooled OR=1.61, 95% CI=1.30 2.00, Z=4.38, P<0.0001). To validate the potential geographic effects on the genetic polymorphism of CAD, we then carried out two additional metaanalyses involving 30 and 13 studies on genetic associations of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) and APOA5 gene T1131C polymorphisms for CAD consisting of 22,190 and 12,322 participants, respectively. We found that the associations of T1131C with CAD were concentrated in East Asia (pooled OR=1.35, 95% CI =1.22-1.49, Z=6.00, P<10-5), whereas the associations of I/D polymorphism with CAD were clustering in Europe and America (pooled OR=1.20, 95% CI=1.04-1.39, Z=2.49, P=0.01) and Turkey (pooled OR=1.33, 95% CI=1.05-1.69, Z=2.40, P=0.02). Conclusions: Our results showed that geographic isolation might have potential effects on the genetic polymorphism of human complex diseases, such as CAD.