Studies of Caucasian subjects have indicated additive effects of the D allele in females, but studies of Asian subjects have shown different results. Although many previous metaanalysis studies investigating ACE I/D polymorphisms and CKD have been reported, but no studies have considered moderate effects of gender in our knowledge. This study focused on general population without genetic abnormality or rare disorder, and we wanted to compare the risk of CKD in people with major allele or minor allele on ACE I/D. In addition, gender-dependent effects of ACE I/D polymorphisms on CKD risk was investigated. This study showed that CKD risk was higher in D allele carriers than in I allele carriers, and there was no strong evidence that analyses using different model assumptions might produce dissimilar results. Heterogeneity was higher in the Asian population than in the Caucasian population. Interaction between ACE I/D polymorphisms and hypertension exerted an additive effect on CKD risk. A gender-dependent effect of ACE I/D polymorphisms on CKD risk was clearly apparent in Asians but not in Caucasians. The DD genotype showed higher gene expression and serum ACE levels than the ID genotype, followed by the II genotype. High blood ACE levels may increase blood angiotensin II levels, and individuals with higher angiotensin II levels may have a higher CKD risk. Previous studies showed that the association between ACE I/D polymorphisms and CKD risk might not be dominant or LY2157299 recessive. Previous metaanalysis studies showed the supported results. We also observed the apparent linear association between numbers of D allele and odds ratios compared the II genotype in genotype analyses. The assumption of the allele type model in this association might be more reasonable, and it may thus be true that individuals carrying the D allele have a higher CKD risk. Hypertension in some patients is due to a dysfunction of RAS such as abnormal secretion of renin, causing increased blood angiotensin I levels. D allele carriers had higher ACE levels than I allele carriers, leading to more efficient conversion of angiotensin I to angiotensin II,LY294002 resulting in CKD. The mechanism may be an additive effect of hypertension and the D allele. An additive effect was significant in the nondiabetic group but not in the diabetic nephropathy subgroups. The blood levels of advanced glycation end products diabetic patients may be high, possibly causing blood pressure increases. We accordingly hypothesize that the probability of hypertension because of a dysfunction of RAS was higher in the nondiabetic nephropathy subgroup than in the diabetic nephropathy subgroup. Thus, the interaction between ACE I/D polymorphisms and hypertension was significant only in the nondiabetic nephropathy subgroup. This hypothesis may require further studies for confirmation. We found a significant gender-dependent effect of ACE I/D polymorphisms on CKD risk in Asians. In previous studies in Asians, the ORs of the additive effect on the DD genotype of males were 2.94 and 1.41 in Japanese and Koreans, respectively. Another study in Japan also reported a positive additive effect of the DD genotype of males. Studies of Caucasians reported contrary results, with an interaction OR of 0.42 in Pakistan. Another two studies in France and Mexico also showed an additive effect between the DD genotype and female gender but not male gender.