Different Associations Between CDKAL1 Variants and Type 2 Diabetes Mellitus Susceptibility: A Meta-analysis

Background:CDK5 regulatory subunit associated protein 1 like 1 (CDKAL1) is a major pathogenesis-related protein for type 2 diabetes mellitus (T2DM). Recently, some studies have investigated the association of CDKAL1 susceptibility variants, including rs4712523, rs4712524, and rs9460546 with T2DM. However, the results were inconsistent. This study aimed to evaluate the association of CDKAL1 variants and T2DM patients.Methods: A comprehensive meta-analysis was performed to assess the association between CDKAL1 SNPs and T2DM among dominant, recessive, additive, and allele models.Results: We investigated these three CDKAL1 variants to identify T2DM risk. Our findings were as follows: rs4712523 was associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.172; 95% CI: 1.103–1.244; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.464; 95% CI: 1.073–1.996; p = 0.016); rs4712524 was significantly associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.146; 95% CI: 1.056–1.245; p = 0.001), additive model (GG vs AA: OR = 1.455; 95% CI: 1.265–1.673; p < 0.001) recessive model (GG vs AA + AG: OR = 1.343; 95% CI: 1.187–1.518; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.221; 95% CI: 1.155–1.292; p < 0.001); and rs9460546 was associated with an increased risk of T2DM for the allele model (G vs T: OR = 1.215; 95% CI: 1.167–1.264; p = 0.023). The same results were found in the East Asian subgroup for the allele model.Conclusions: Our findings suggest that CDKAL1 polymorphisms (rs4712523, rs4712524, and rs9460546) are significantly associated with T2DM.

The Decisive Case-Control Study Elaborates the Null Association between ADAMTS5 rs226794 and Osteoarthritis in Asians: A Case-Control Study and Meta-Analysis

Background: Osteoarthritis is an important health issue for the elderly. Many studies indicate that genetics is an important risk factor for osteoarthritis, and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is one gene that is most frequently implicated. Many recent studies have examined the relationship between a polymorphism in the ADAMTS5 gene (rs226794) and the risk for developing osteoarthritis without definitive results. Objective: In this case-control study, we examined the correlation between the ADAMTS5 gene polymorphism, rs226794, and knee osteoarthritis. We used a meta-analysis and trial sequential analysis to determine whether ADAMTS5 rs226794 expression increases susceptibility to osteoarthritis. Methods: This study consisted of two parts: a case-control study and a meta-analysis. The case-control study included subjects who underwent knee radiography at the Health Examination Center of the Tri Service General Hospital from 2015 to 2019. The Kellgren–Lawrence (KL) grading system was used as diagnostic criteria. Patients with unsuccessful gene sequencing were excluded. There were 606 subjects in the knee osteoarthritis group (KL ≥ 2) and 564 in the control group (KL < 2). Gene sequencing was performed using iPLEX Gold to determine the association between the gene polymorphism of ADAMTS5 rs226794 and knee osteoarthritis. For the meta-analysis, databases such as PubMed, Embase, and Cochrane were queried to identify studies that examined the relationship between ADAMTS5 rs226794 and osteoarthritis. Next, the findings of the meta-analysis were incorporated with the results of the case-control study and samples from the published studies to estimate the association between the genetic polymorphism and osteoarthritis using an odds ratio and a 95% confidence interval. Results: We found a non-significant association between the G allele and knee OA (crude-OR: 0.93 (95% CI: 0.79–1.10) and adjusted-OR: 1.02 (95% CI: 0.76–1.36) in the allele model) in the present study, and the analysis of other genetic models revealed a similar trend. After including five published studies and our case-control study, the results with 2866 Asians indicated a conclusively null association between ADAMTS5 rs226794 and knee OA) OR: 1.09 (95% CI: 0.93–1.26). The results for Caucasians also revealed a null association (OR: 1.21 (95% CI: 0.81–1.82)). Conclusions: This study indicates that the gene polymorphism, ADAMTS5 rs226794, is not significantly associated with knee osteoarthritis. Additionally, assuming that the cumulative sample size in the allele model is sufficient, we confirmed that the G allele is not a risk factor for osteoarthritis. This study integrated all available evidence to arrive at this conclusion, and it suggests that no additional studies are necessary.

Association Between Insulin-like Growth Factor-1 rs35767 Polymorphism and Type 2 Diabetes Mellitus Susceptibility: A Meta-Analysis

Background: Insulin-like growth factor-1 (IGF-1) has been demonstrated to increase fatty acid β oxidation during fasting, and play an important role in regulating lipid metabolism and type 2 diabetes mellitus (T2DM). The rs35767 (T &gt; C) polymorphism, a functional SNP was found in IGF-1 promoter, which may directly affect IGF-1 expression. However, the inconsistent findings showed on the IGF-1 rs35767 polymorphism and T2DM risk.Methods: We performed a comprehensive meta-analysis to estimate the association between the IGF-1 rs35767 and T2DM risk among four genetic models (the allele, additive, recessive and dominant models).Results: A total 49,587 T2DM cases and 97,906 NDM controls were included in the allele model, a total 2256 T2DM cases and 2228 NDM controls were included in the other three genetic models (the additive; recessive and dominant models). In overall analysis, the IGF-1 rs35767 was shown to be significantly associated with increased T2DM risk for the allele model (T vs. C: OR = 1.251, 95% CI: 1.082–1.447, p = 0.002), additive model (homozygote comparisons: TT vs. CC: OR = 2.433, 95% CI: 1.095–5.405, p = 0.029; heterozygote comparisons: TC vs. CC: OR = 1.623, 95% CI: 1.055–2.495, p = 0.027) and dominant model (TT + CT vs. CC: OR = 1.934, 95% CI: 1.148–3.257, p = 0.013) with random effects model. After omitting Gouda’s study could reduce the heterogeneity, especially in the recessive model (TT vs. CC + CT: I2 = 38.7%, p = 0.163), the fixed effects model for recessive effect of the T allele (TT vs. CC + CT) produce results that were of borderline statistical significance (OR = 1.206, 95% CI: 1.004–1.448, p = 0.045). And increasing the risk of T2DM in Uyghur population of subgroup for the allele model.Conclusion: The initial analyses that included all studies showed statistically significant associations between the rs35767 SNP and type 2 diabetes, but after removing the Gouda et al. study produced results that were mostly not statistically significant. Therefore, there is not enough evidence from the results of the meta-analysis to indicate that the rs35767 SNP has a statistically significant association with type 2 diabetes.

Meta-Analysis of miRNA Variants Associated with Susceptibility to Autoimmune Disease

Purpose. Various studies have shown an association between miRNA polymorphisms and susceptibility to autoimmune disease (AD); however, the results are inconclusive. To evaluate whether miRNA polymorphisms account for a significant risk of AD, a total of 87 articles, including 39431 patients and 56708 controls, were identified to estimate their association with 12 AD subtypes. Methods. Several electronic databases were searched to analyze population-based studies on the relationship between miRNA variants and AD risk. Fixed effects or random effect models were used in the meta-analysis for the risk assessment. Results. In our meta-analysis, miR-146a rs2910164/rs57095329 conferred a marginally elevated risk for AD (allele model, OR = 1.08 , 95% CI: 1.01-1.15, P = 0.019 ; allele model, OR = 1.09 , 95 CI: 1.05-1.15, P < 0.001 , respectively). Furthermore, miR-196a2 rs11614913 was also associated with AD risk (allele model, OR = 0.92 , 95% CI: 0.88-0.97, P = 0.001 ) as well as miR-499 rs3746444 (allele model, OR = 1.16 , 95% CI: 1.03-1.29, P = 0.011 ). In addition, associations were observed between miR-149 rs2292832/miR-27a rs895819 and AD susceptibility in the overall population (allele model, OR = 1.15 , 95% CI: 1.06-1.24, P < 0.001 ; allele model, OR = 1.11 , 95% CI:1.01-1.22, P = 0.043 , respectively). Conclusions. Evidence from our systematic review suggests that miR-146a, miR-196a2, miR-499, miR-149, and miR-27a polymorphisms are associated with susceptibility to AD.

The 10-Repeat 3′-UTR VNTR Polymorphism in the SLC6A3 Gene May Confer Protection Against Parkinson’s Disease: A Meta-analysis

The dopamine transporter (DAT) is encoded by the SLC6A3 gene and plays an important role in the regulation of the neurotransmitter dopamine. The SLC6A3 gene contains several repetition alleles (3–11 repeats) of a 40-base pair variable number of tandem repeats (VNTR) in the 3′-untranslated region (3′-UTR), which may affect DAT expression levels. The 10-repeat (10R) allele could play a protective role against PD. However, inconsistent findings have been reported.Methods: A comprehensive meta-analysis was performed to accurately estimate the association between the 10R allele of the 3′-UTR VNTR in SLC6A3 and PD among four different genetic models.Results: This meta-analysis included a total of 3,142 patients and 3,496 controls. We observed a significant difference between patients and controls for the allele model (10R vs. all others: OR = 0.860, 95% CI: 0.771–0.958, P = 0.006), pseudodominant model (10R/10R + 10R/9R vs. all others: OR = 0.781, 95% CI: 0.641–0.952, P = 0.014) and pseudorecessive model (10R/10R vs. all others: OR = 0.858, 95% CI: 0.760–0.969, P = 0.013) using a fixed effects model. No significant differences were observed under the pseudocodominant model (10R/9R vs. all others: OR = 1.079, 95% CI: 0.945–1.233, P = 0.262). By subgroup analysis, the 10R, 10R/10R and 10R/9R genotypes were found to be significantly different from PD in Asian populations.Conclusion: Our findings suggest that the SLC6A3 10R may be a protective factor in susceptibility to PD.

The rs9340799 polymorphism of the estrogen receptor alpha (ESR1) gene and its association with breast cancer susceptibility

The ESR1 rs9340799 polymorphism has been frequently investigated with regard to its association with breast cancer (BC) susceptibility, but the findings have been inconclusive. In this work, we aimed to address the inconsistencies in study findings by performing a systematic review and meta-analysis. Eligible studies were identified from the Web of Science, PubMed, Scopus, China National Knowledge Infrastructure, VIP and Wanfang databases based on the predefined inclusion and exclusion criteria. The pooled odds ratio (OR) was then calculated under five genetic models: homozygous (GG vs. AA), heterozygous (AG vs. AA), dominant (AG + GG vs. AA), recessive (GG vs. AA + AG) and allele (G vs. A). Combined results from 23 studies involving 34,721 subjects indicated a lack of significant association between the polymorphism and BC susceptibility (homozygous model, OR = 1.045, 95% CI 0.887–1.231, P = 0.601; heterozygous model, OR = 0.941, 95% CI 0.861–1.030, P = 0.186; dominant model, OR = 0.957, 95% CI 0.875–1.045, P = 0.327; recessive model, OR = 1.053, 95% CI 0.908–1.222, P = 0.495; allele model, OR = 0.987, 95% CI 0.919–1.059, P = 0.709). Subgroup analyses by ethnicity, menopausal status and study quality also revealed no statistically significant association (P > 0.05). In conclusion, our results showed that the ESR1 rs9340799 polymorphism was not associated with BC susceptibility, suggesting its limited potential as a genetic marker for BC.

Associations Between Adipokines Gene Polymorphisms and Osteoarthritis: a Meta-analysis

Background: Adipokines gene polymorphisms are speculated to have associations with the risk of osteoarthritis (OA), but evidences remain conflicting. This study therefore aimed to examine the potential associations between adipokines gene polymorphisms and OA.Methods: A systematic search was performed on PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang up to March 31, 2020. Meta-analysis was carried out by focusing on associations between adipokines gene polymorphisms and OA with allele model, dominant model, recessive model, homozygote model, and heterozygote model.Results: The present meta-analysis included 13 studies containing 3,661 OA patients and 4,864 controls for analysis. Significant associations were observed between ADIPOQ rs2241766 and OA in Asians (dominant: OR = 1.35, 95% CI 1.03-1.78; heterozygote: OR = 1.43, 95% CI 1.07-1.19), between LEPR rs1137101 and OA in the overall population (recessive: OR = 0.40, 95% CI 0.21-0.79; homozygote: OR = 0.38, 95% CI 0.18-0.79), between VISFATIN rs4730153 and OA in Asians (allele: OR = 0.58, 95% CI 0.41-0.83; dominant: OR = 0.57, 95% CI 0.39-0.83; heterozygote: OR = 0.59, 95% CI 0.40-0.86), and between VISFATIN rs16872158 and OA in Asians (allele: OR = 1.84, 95% CI 1.26-2.68; dominant: OR = 1.94, 95% CI 1.31-2.89; heterozygote: OR = 1.97, 95% CI 1.31-2.95).Conclusions: Adipokines gene polymorphisms may be associated with OA. In particular, associations were observed in ADIPOQ rs2241766, LEPR rs1137101, VISFATIN rs4730153, and VISFATIN rs16872158 in the present study. PROSPERO registration number: CRD42020187664.

Toll-like receptor 9 and 4 gene polymorphisms in susceptibility and severity of malaria: a meta-analysis of genetic association studies

Background Malaria is still a major public health problem in sub-Saharan Africa and South-east Asia. The clinical presentations of malaria infection vary from a mild febrile illness to life-threatening severe malaria. Toll like receptors (TLRs) are postulated to be involved in the innate immune responses to malaria. Individual studies showed inconclusive findings. This study aimed to assess the role of TLR4 (D299G, T399I) and TLR9 (T1237C, T1486C) in severity or susceptibility of malaria by meta-analysis of data from eligible studies. Methods Relevant case–control studies that assessed the association between TLR 4/9 and malaria either in susceptibility or progression were searched in health-related electronic databases. Quality of included studies was evaluated with Newcastle–Ottawa scale. Pooled analyses for specific genetic polymorphisms were done under five genetic models. Stratified analysis was done by age and geographical region (Asian countries vs non-Asian countries). Results Eleven studies (2716 cases and 2376 controls) from nine endemic countries were identified. Five studies (45.4%) obtained high score in quality assessment. Overall, a significant association between TLR9 (T1486C) and severity of malaria is observed in allele model (OR: 1.26, 95% CI: 1.08–1.48, I2 = 0%) or homozygous model (OR: 1.55, 95% CI: 1.08–2.28, I2 = 0%). For TLR9 (T1237C), a significant association with severity of malaria is observed in in heterozygous model (OR:1.89, 95% CI: 1.11–3.22, I2 = 75%). On stratifications, TLR9 (T1486C) is only significantly associated with a subgroup of children of non-Asian countries under allele model (OR: 1.25, 95% CI: 1.02–1.38), while 1237 is with a subgroup of adults from Asian countries under heterozygous model (OR: 2.0, 95% CI: 1.09–3.64, I2 = 39%). Regarding the susceptibility to malaria, TLR9 (T1237C) is significantly associated only with the children group under recessive model (OR: 2.21, 95% CI: 1.06–4.57, I2=85%) and homozygous model (OR: 1.49, 95% CI: 1.09–2.0, I2 = 0%). For TLR4 (D299G, T399I), none is significantly associated with either severity of malaria or susceptibility to malaria under any genetic models. Conclusions The findings suggest that TLR 9 (T1486C and T1237C) seems to influence the progression of malaria, under certain genetic models and in specific age group of people from specific geographical region. TLR 9 (T1237C) also plays a role in susceptibility to malaria under certain genetic models and only with children of non-Asian countries. To substantiate these, future well designed studies with larger samples across endemic countries are needed.

MIR17HG Polymorphisms Contribute to High Altitude Pulmonary Edema Susceptibility in Chinese Population

Background: High-altitude pulmonary edema (HAPE) is a common acute altitude sickness. The results from existing studies have shown that the occurrence of HAPE is related to genetic factors. Therefore, six locis of MIR17HG were selected to study its effect on HAPE of Chinese population.Methods: All subjects were genotyped by the Agena MassARRAY, and the relationship between polymorphisms on MIR17HG and HAPE risk was evaluated using a χ2 test with an odds ratio (OR) and 95% confidence intervals (CIs) in multiple genetic models.Results: In the allele model, we observed that lower risk (OR = 0.74, p = 0.036) of the A allele for rs7318578 on the MIR17HG compared to the people with the C allele. Logistic regression analysis of four models for all selected MIR17HG SNPs between cases and controls showed significant differences for rs7318578 (OR = 0.74, p = 0.037) and rs17735387 (OR = 1.51, p = 0.036) in the HAPE population. Conclusion: Rs7318578 and rs17735387 on MIR17HG were associated with the genetic susceptibility of HAPE in Chinese population.