Association of Rs13118928 and Rs1828591 Polymorphisms in HHIP Gene with COPD Susceptibility: A Meta-Analysis of Case-Control Studies

In recent years, investigators have been striving to explore the pathogenesis of chronic obstructive pneumonia disease (COPD). Hedgehog Interacting Protein (HHIP) has been identified as a candidate susceptibility gene. Our aim is to synthesize and include all evidences to get a more comprehensive result. We searched 6 online databases- PubMed, Web of Science, Cochrane Library, Wanfang, EMBASE, CNKI. All included studies were published before October 1, 2021. We used Newcastle-Ottawa scale (NOS) to evaluate the bias of each study. Meta-analysis methods were conducted to evaluate the pooled result. A total of 14 comparative studies were included in this meta-analysis, for rs13118928 polymorphism, significant associations were observed in 5 genetic models, (A vs. G, OR=1.18, 95CI%=[1.07-1.30], P=0.0006; AA vs. GG, OR=1.56, 95CI%=[1.22-2.00], P=0.0004; AG vs. GG, OR=1.28, 95CI%=[1.05-1.55], P=0.01; AA+AG vs. GG, OR=1.36, 95CI%=[1.12-1.65], P=0.002; AA vs. AG+GG, OR=1.18, 95CI%=[1.05-1.33], P=0.006). as for rs1828591, there were also significant associations detected in the overall population, (A vs. G, OR=1.12, 95CI%=[1.05-1.19], P=0.0003; AA vs. GG, OR=1.27, 95CI%=[1.04-1.56], P=0.02; AG vs. GG, OR=1.25, 95CI%=[1.03-1.51], P=0.02; AA+AG vs. GG, OR=1.26, 95CI%=[1.04-1.53], P=0.02; AA vs. AG+GG, OR=1.10, 95CI%=[1.01-1.19], P=0.03). This meta-analysis showed that the A allele in both rs13118928 and rs1828591 was turn out to be the risk allele in developing COPD. The result of Codominant genetic model, Dominant genetic model and Recessive genetic model remain the same.

MTHFR Polymorphism Is Associated With Severe Methotrexate-Induced Toxicity in Osteosarcoma Treatment

BackgroundPrevious studies have revealed the critical role of methylene tetrahydrofolate reductase (MTHFR) polymorphisms in response to high-dose methotrexate (MTX)-induced toxicity in osteosarcoma patients. However, the conclusions remain controversial. In this setting, we performed a meta-analysis to determine their association more precisely.MethodEligible studies were searched and screened in PubMed, Web of Science, Cochrane Library, Clinical-Trials.gov, Embase, and China National Knowledge Infrastructure (CNKI) following specific inclusion and exclusion criteria. The required information was retrieved and collected for subsequent meta-analysis. Association between MTHFR polymorphism and MTX toxicity was evaluated by odds ratios (ORs).ResultsSeven studies containing 585 patients were enrolled and analyzed in this meta-analysis. Overall, the MTX related grade 3-4 liver toxicity was significantly associated with MTHFR rs1801133 allele (T vs. C: OR=1.61, 95%CI=1.07-2.42, P=0.024), homozygote (TT vs. CC: OR=2.11, 95%CI=1.06-4.21, P=0.011), and dominant genetic model (TT/TC vs. CC: OR=3.15, 95%CI=1.30-7.60, P=0.035) in Asian population. Meanwhile, close associations between MTX mediated grade 3-4 mucositis and MTHFR rs1801133 polymorphism were identified in allele contrast (T vs. C: OR=2.28, 95%CI=1.49-3.50, P<0.001), homozygote comparison (TT vs. CC: OR=4.07, 95%CI=1.76-9.38, P=0.001), heterozygote comparison (TC vs. CC: OR=2.55, 95%CI=1.20-5.42, P=0.015), recessive genetic model (TT vs. TC/CC: OR=2.09, 95%CI=1.19-3.67, P=0.010), and dominant genetic model (TT/TC vs. CC: OR=2.97, 95%CI=1.48-5.96, P=0.002). Additionally, kidney toxicity was corelated with the heterozygote comparison (TC vs. CC: OR=2.63, 95%CI=1.31-5.29, P=0.007) of rs1801133 polymorphism.ConclusionThe MTHFR rs1801133 polymorphism was significantly associated with severer liver toxicity induced by high-dose MTX treatment in the Asian population. In the meantime, patients with MTHFR rs1801133 polymorphism were predisposed to MTX- related mucositis.

Polymorphisms of the KCNS1, COMT and OPRM1 genes and development of postoperative pain in patients with osteoarthritis who underwent total knee or hip replacement

Postoperative pain (POP) is a serious complication that reduces the result of total knee (TKA) or hip arthroplasty (THA) in patients with osteoarthritis (OA). The search for predictors of postoperative pain is an actual problem.The aim of the study – to assessing relationship the polymorphisms of the KCNS1, COMT and OPRM1 genes and the development of POP in OA patients who underwent TKA or THA.Material and methods. The study group consisted of 95 patients with OA knee or hip (64.6% of women, 65.4±9.0 years) who underwent TKA (47.8%) or THA (52.2%). The presence of POP was determined when pain in the area of surgical intervention ≥40 mm (100 mm visual analog scale, VAS) persisted or appeared 3 and 6 months after surgery. All patients underwent genotyping of polymorphisms of the genes KCNS1 (rs734784), COMT (rs6269, rs4633) and OPRM1 (rs1799971) by polymerase chain reaction in real time using original sequence-specific primers and samples labeled with various fluorescent labels. Registration and interpretation of the obtained results were carried out on the DT-96 amplifier (DNA-Technology LLC, Russia).Results. POP was observed in 32.6% of patients who underwent TKA or THA. The frequency of POP after TKA and THA was 30.2% and 34.0% (p=0.882). Statistical analysis revealed no differences in the frequencies of the genotypes of the studied genes (p>0,05). The presence of a homozygous genotype of the GG polymorphism of the KCNS1 gene (rs734784) was associated with the presence of POP in accordance with the recessive genetic model (GG vs AA+AG; odds ratio (OR) – 3.96 [95% confidence interval (CI): 1.51; 10.37]; p=0.005). The presence of the mutant allele T (TT+CT) in the genotype of the COMT polymorphism (rs4633) reduced the risk of POP compared to the carrier of the CC genotype (OR=0.32 [95% CI: 0.12; 0.83]; p=0.02) in accordance with the dominant genetic model. There was no significant correlation between the development of POP and the carrier of different genotypes and alleles of the COMT (rs6269) and OPRM1 (rs1799971) genes.Conclusions. There is a statistically significant association the polymorphism of the KCNS1 (rs734784) and COMT (rs4633) genes and the development of chronic POP in patients who underwent TKA or THA. Further studies of the genetic predisposition to POP are required on more clinical material.

MTHFR A1298C gene polymorphism on stroke risk: an updated meta-analysis

Background Previous studies have shown the effect of MTHFR A1298C gene polymorphism on stroke risk. But the results of published studies remained inconclusive and controversial. So we conducted a meta-analysis to accurately estimate the potential association between MTHFR A1298C gene polymorphism and stroke susceptibility. Methods A systematic literature search on Embase, Pubmed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI) and WanFang electronic database identified 40 articles including 5725 cases and 8655 controls. Strength of association was evaluated by pooled odds ratio (OR), 95% confidence interval (CI) and p value. Funnel plots and Begger’s regression test were applied for testing the publication bias. Statistical analysis of all data was performed by Stata 12.0. Results The meta-analysis results indicated a significant relationship between MTHFR gene A1298C polymorphisms and stoke risk under the C allelic genetic model (OR = 1.19, 95%CI = 1.07–1.32, p = 0.001), dominant genetic model (OR = 1.19, 95%CI = 1.06–1.33, p = 0.004) and recessive genetic model (OR = 1.43, 95%CI =1.15–1.77, p = 0.001). In subgroup analysis, we discovered obvious correlation in three genetic model of Asian, stroke type, adult by ethnicity, population, stroke type, source of control and case size. Additionally, in studies of control from hospital and case size equal 100, obvious correlation was also found in the three genetic model. Conclusions Our meta-analysis results indicated that there was evidence to support the correlation between MTHFR A1298C polymorphism and stroke susceptibility, especially in adults and ischemic stroke.

The Association of CTLA-4 rs231775 and rs3087243 Polymorphisms With Latent Autoimmune Diabetes in Adults: A Meta-analysis

BackgroundPolymorphisms rs231775 and rs3087243 of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) gene have been associated with risk of latent autoimmune diabetes in adults (LADA). However, the results were inconsistent. The purpose of this study was to quantitatively assess the relationship between polymorphisms rs231775 and rs3087243 of CTLA-4 and LADA in a larger pooled population by performing a meta-analysis. MethodsSystematic search for eligible studies was conducted in PubMed, Web of Science, and Embase. Case-control studies containing genotype frequencies of polymorphisms rs231775 or rs3087243 of CTLA-4 gene were selected, and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the associations between polymorphisms of CTLA-4 and LADA in allelic genetic model, dominant genetic model, and recessive genetic model. ResultsA total of eleven studies, in which five studies reported rs231775, two studies reported rs3087342, and four studies reported both rs231775 and rs3087243, were identified. Among them, one study wasn’t included in the following meta-analysis because the distribution of genotypes in the control group didn’t comply with Hardy-Weinberg equilibrium. Significant associations with susceptibility to LADA were detected for rs231775 (785 cases and 3435 controls, allelic genetic model OR 1.53, 95%CI 1.22-1.92; dominant genetic model OR 2.16, 95%CI 1.43-3.28; recessive genetic model OR 1.49, 95%CI 1.13-1.97) and for rs3087243 (820 cases and 4824 controls, allelic genetic model OR 1.26, 95%CI 1.03-1.55; dominant genetic model OR 1.11, 95%CI 0.88-1.40; recessive genetic model OR 1.41, 95%CI 1.07-1.86) in overall population. Further subgroup analyses for ethnicity (Asian, Caucasian, and African) have also indicated the positive association between rs231775 and LADA. As for rs3087243, subgroup analyses detected the association between polymorphism and LADA in Caucasian population under recessive model. ConclusionsPolymorphisms rs231775 and rs3087243 of CTLA-4 gene are potential risk factors for LADA and may serve as novel genetic biomarkers of LADA.

Lack of Association between CYP1A1 3801T > C Polymorphism and Idiopathic Male Infertility in Algerian Population

<p><strong>Background and Objective:</strong> Ongoing research suggests that cytochrome P4501A1 (CYP1A1) 3801T &gt; C polymorphism may be correlated with human male infertility but the reported results are conflicting. Hence, this case-control study was conducted in Algerian population to determine the frequency of this polymorphism and its relationship to male infertility.<br /><strong>Methods:</strong> This study included 173 subjects grouped into two categories: controls (84) and patients (89) with abnormal semen analysis parameters. Genomic DNA from the patients and controls was extracted and PCR-restriction fragment length polymorphism was used to genotype the 3801T &gt; C CYP1A1 polymorphism.<br /><strong>Results:</strong> In the control group, the frequency of homozygous wild-type TT, heterozygous TC, and mutant homozygous CC genotypes of the CYP1A1 T &gt; C polymorphism was 84.52%, 13.10%, and 2.38%, respectively, while infertile men had 77.53%, 20.22%, and 2.25%, respectively. There was no correlation between the 3801T &gt; C CYP1A1 variant and male infertility. Furthermore, the rs4646903 C allele was not a risk factor in the dominant genetic model.<br /><strong>Conclusion:</strong> The 3801T &gt; C polymorphism cannot be considered as a risk factor for male infertility in Algerian population. Our results need to be validated and confirmed through prospective studies with a larger number of patients.</p> <p>&nbsp;</p>

Associations of Metabolic Genes (GSTT1, GSTP1, GSTM1) and Blood Mercury Concentrations Differ in Jamaican Children with and without Autism Spectrum Disorder

We investigated interactive roles of three metabolic glutathione S-transferase (GST) genes (GSTP1, GSTT1, and GSTM1) and autism spectrum disorder (ASD) status in relation to blood Hg concentrations (BHC) of Jamaican children. We used data from 266 children (2-8 years) with ASD and their 1:1 age- and sex-matched typically developing (TD) controls. After adjusting General Linear Models for child’s age, socioeconomic status, consumption of leafy vegetables, fried plantain, canned fish, and the interaction between GSTP1 and GSTT1, we found significant interactions between GSTP1 and ASD status in relation to BHC either in a co-dominant or dominant genetic model for GSTP1(P < 0.001, P = 0.007, respectively). In the co-dominant model for the Ile105Val GSTP1 polymorphism, geometric mean (GM) BHC in ASD cases with genotype Ile/Ile were significantly higher than in cases with the Ile/Val genotype (0.73 vs. 0.48 µg/L, P = 0.01). In contrast, in TD controls with the Ile/Val genotype GM BHC were significantly higher than in those with the Ile/Ile genotype (0.72 vs. 0.49 µg/L, P = 0.03) or the Val/Val genotype (0.72 vs. 0.51 µg/L, P = 0.04). Although our findings are consistent with the role of GSTP1 in detoxification of Hg, replication in other populations is warranted.

Determination of risk predictors of statokinetic development delay and polymorphism of GSTP1, GSTT1, GSTM1, ACE, AGT2R1 AND ENOS genes in premature children with very low and extremely low birth weight

World statistics and scientific research show that premature birth of children is accompanied by a high risk of not only somatic, but also neurological pathology and mental disorders development. Therefore, the clinical prognostic model development for the research of delayed infant statokinetic development, which was born prematurely, may be the basis for creating a preventive program of early intervention. Purpose — to determine the clinical and genetic delayed statokinetic development formation determinants of children born with a body weight less than 1500 g; to develop an algorithm for early prediction of adverse effects. Materials and methods. A cohort prospective study was conducted, which included 155 children with very low and extremely low body weight. Their statokinetic development at 6, 12, 18, 24 and 36 months of adjusted age was studied and the determinants were established. Genetic methods included studies of the GSTP1, GSTT1, GSTM1, ACE, AGT2R1, and eNOS genes polymorphism. Results. It was defined that at 24 months of adjusted age 19% have delayed statokinetic development, at 36 months — 16% of examined children have very low and extremely low body weight. Important predictors that contribute a delayed statokinetic development were severe intraventricular hemorrhages, anemia in the second year of life, significant delay in physical development at 6 months and socio-economic status of the family. The greatest delay in the motor sphere was found in children with a dominant genetic model (GG+AG vs. AA) of the GSTP1 gene. Conclusions. The developed model for predicting motor developmental delay at an early age has a high specificity (92.44%) and moderate sensitivity (53.33%), which indicates the possibility of its use for forecasting and personalized method of treatment. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of these Institutes. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: prediction, statokinetic development, very low body weight, extremely low body weight, premature babies, premature infants.

Meta-analytic method reveal a significant association of theBDNF Val66Met variant with smoking persistence based on a large samples

Although numerous genetic studies have reported the link between Val66Met in BDNF gene with smoking, the findings remain controversial, mainly due to small-to-moderate sample sizes. The main aim of current investigation is to explore whether the variant of Val66Met has any genetic functions in the progress of smoking persistence. The Val-based dominant genetic model considering Val/* (namely, Val/Val + Val/Met) and Met/Met as two genotypes with comparison of the frequency of each genotype in current smokers and never smokers. There were seven genetic association articles including eight independent datasets with 10,160 participants were chosen in current meta-analytic investigation. In light of the potent effects of ethnicity on homogeneity across studies, we carried out separated meta-analyses according to the ancestry origin by using the wide-used tool of Comprehensive Meta-analysis software (V 2.0). Our meta-analyses results indicated that the Val66Met polymorphism was significantly linked with smoking persistence based on either all the chosen samples (N = 10,160; Random and fixed models: pooled OR = 1.23; 95% CI = 1.03–1.46; P value = 0.012) or Asian samples (N = 2,095; Fixed model: pooled OR = 1.25; 95% CI = 1.01–1.54; P value = 0.044; Random model: pooled OR = 1.25; 95% CI = 1.001–1.56; P value = 0.049). No significant clue of bias in publications or heterogeneity across studies was detected. Thus, we conclude that the Val66Met (rs6265) variant conveys genetic susceptibility to maintaining smoking, and smokers who carry Val/* genotypes have a higher possibility of maintaining smoking than those having Met/Met genotype.

Sequence analysis and variant identification at the APOC3 gene locus indicates association of rs5218 with BMI in a sample of Kuwaiti’s

Background APOC3 is important in lipid transport and metabolism with limited studies reporting genetic sequence variations in specific ethnic groups. The present study aimed to analyze the full APOC3 sequence among Kuwaiti Arabs and test the association of selected variants with lipid levels and BMI. Methods Variants were identified by Sanger sequencing the entire APOC3 gene in 100 Kuwaiti Arabs. Variants and their genotypes were fully characterized and used to construct haplotype blocks. Four variants (rs5128, rs2854117, rs2070668, KUAPOC3N3 g.5196 A > G) were selected for testing association with serum lipid levels and BMI in a cohort (n = 733). Results APOC3 sequence (4.3 kb) of a Kuwaiti Arab was deposited in Genbank (accession number KJ437193). Forty-two variants including 3 novels were identified including an “A” insertion at genomic positions 116,700,599–116,700,600 (promoter region) and two substitutions in intron 1 at genomic positions 116,700,819 and 116,701,159. Only three variants, (rs5128, rs2854117, and rs2070668) were analyzed for association of which rs5128 showed a trend for association with increased BMI, TG and VLDL levels that was further investigated using multivariate analysis. A significant association of rs5128 with BMI (p < 0.05) was observed following a dominant genetic model with increased risk by an OR of 4.022 (CI: 1.13–14.30). Conclusion The present study is the first to report sequence analysis of APOC3 in an Arab ethnic group. This study supports the inclusion of rs5128 as a marker for assessing genetic risk to dyslipidemia and obesity and the inclusion of the novel variant g.5196 A > G for population stratification of Arabs.