The p.R4810K and other rare variants of ring finger protein 213 gene (RNF213) were illustrated as susceptibility variants for moyamoya (MMD) and non-moyamoya intracranial artery stenosis/occlusion disease (ICASO) recently. However, the effect sizes of p.R4810K were in great discrepancy even in studies of the same ethnic population and firm conclusions of other rare variants have been elusive given the small sample sizes and lack of replication. Thus, we performed this study to quantitatively evaluate whether or to what extent the rare variants of RNF213 contribute to MMD and ICASO in different populations. A systematic search of PubMed, EMBASE, ISI web of science, CNKI, and WANFANG DATA was conducted up to 5 September 2017. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random- or fixed-effect models based on the between-study heterogeneity. The subgroup analyses were performed by the ethnicity and family history. Sensitivity and publication bias analysis were performed to test the robustness of associations. All the statistical analyses were conduct using STATA 12.0. Twenty studies including 2353 MMD cases and 5488 controls and 11 studies including 1778 ICASO cases and 3140 controls were included in this study. Pooled ORs indicated that RNF213 p.R4810K significantly increased MMD and ICASO risk in East Asians with great effect sizes of discrepancy (dominant model: odds ratios 184.04, 109.77, and 31.53 and 10.07, 28.52, and 5.59 for MMD and ICASO, respectively, in Japan, Korea, and China). It significantly increased familial MMD risk in Japan, Korea, and China with 5 ~ 36 times larger effect sizes than that for sporadic ones in each country (dominant model ORs 1802.44, 512.42, 1109.02 and 134.35, 99.82, and 30.52, respectively, for familial and sporadic cases). The effect sizes of RNF213 p.R4810K to sporadic MMD were 3 ~ 4 times larger in Japan and Korea than those in China. RNF213 p.R4810K also increased the ICASO risk in Japan and Korea with 2 ~ 4 times larger effect sizes than that in China (dominant model ORs 10.71, 28.52, and 5.59, respectively). Another two rare variants- p.E4950D and p.A5021V significantly increased MMD risk in Chinese population (dominant model ORs 9.06 and 5.01, respectively). Various other rare variants in RNF213 were identified in Japanese, Chinese, European, and Hispanic American populations without association evidence available yet. This meta-analysis shows the critical roles of RNF213 p.R4810K in MMD especially familial MMD and ICASO in Japan, Korea, and China. Except for RNF213 p.R4810K, MMD seems to have more complex determiners in China. Distinct genetic background exists and other environmental or genetic factor(s) may contribute to MMD. Studies focused on delineating the ethnicity-specific factors and pathological role of RNF213 variants in MMD and ICASO are needed.

Background: Variants in organic cation transporter (OCT) genes play a crucial role in metformin pharmacokinetics and are critical for diabetes treatment. However, studies investigating the effect of OCT genetic polymorphisms on metformin response have reported inconsistent results. This review and meta-analysis aimed to evaluate the associations between OCT genetic polymorphisms and metformin response and intolerance in individuals with type 2 diabetes mellitus (T2DM).Method: A systematic search was conducted on PubMed, EMBASE, CNKI, WANFANG DATA, and VIP database for identifying potential studies up to 10 November 2022. The Q-Genie tool was used to evaluate the quality of included studies. Pooled odds ratios (OR) or standardized mean differences (SMD) and 95% confidence intervals (95% CI) were calculated to determine the associations between OCT genetic polymorphisms and metformin response and intolerance that were reflected by glycemic response indexes, such as glycated hemoglobin level (HbA1c%) or change in glycated hemoglobin level (ΔHbA1c%), fasting plasma level (FPG) or change in fasting plasma glucose level (ΔFPG), the effectiveness rate of metformin treatment, and the rate of metformin intolerance. A qualitative review was performed for the variants identified just in one study and those that could not undergo pooling analysis.Results: A total of 30 related eligible studies about OCT genes (SLC22A1, SLC22A2, and SLC22A3) and metformin pharmacogenetics were identified, and 14, 3, and 6 single nucleotide polymorphisms (SNPs) in SLC22A1, SLC22A2, and SLC22A3, respectively, were investigated. Meta-analysis showed that the SLC22A1 rs622342 polymorphism was associated with a reduction in HbA1c level (AA vs. AC: SMD [95% CI] = −0.45 [−0.73–−0.18]; p = 0.001). The GG genotype of the SLC22A1 rs628031 polymorphism was associated with a reduction in FPG level (GG vs. AA: SMD [95 %CI] = −0.60 [−1.04–0.16], p = 0.007; GG vs. AG: −0.45 [−0.67–0.20], p < 0.001). No statistical association was found between the remaining variants and metformin response and intolerance.Conclusion: SLC22A1 rs622342 and rs628031 polymorphisms were potentially associated with glycemic response to metformin. This evidence may provide novel insight into gene-oriented personalized medicine for diabetes.

Background. Vascular endothelial growth factor (VEGF) gene polymorphisms have been shown to be associated with the risk of diabetic retinopathy (DR), but the results were inconsistent. The aim of this study was to systematically assess the associations between VEGF gene polymorphisms and different types of DR (nonproliferative DR and proliferative DR). Methods. Electronic databases PubMed, Embase, Web of Science, CNKI, and WANFANG DATA were searched for articles on the associations between VEGF gene polymorphisms and different types of DR up to November 6, 2019. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and subgroup analyses were conducted by ethnicity. Sensitivity analysis was conducted to assess the stability of the results. Publication bias was assessed by using the Egger regression asymmetry test and visualization of funnel plots. A systematic review was conducted for polymorphisms with a high degree of heterogeneity ( ) or studied in only one study. Results. A total of 13 and 18 studies analyzed the associations between VEGF SNPs and nonproliferative DR (NPDR) as well as proliferative DR (PDR), respectively. There were significant associations between rs2010963 and NPDR in Asian (dominant model: , ); and rs2010963 is associated with PDR in total population (dominant model: , ), either Asian (recessive model: , ) or Caucasian (recessive model: , ). Rs833061 is associated with PDR in Asian (recessive model: ,