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Catechol-O-methyltransferase gene Val158Met polymorphism and obsessive compulsive disorder susceptibility: a meta-analysis.
Kumar, P, Rai, V
Metabolic brain disease. 2020;(2):241-251
Abstract
Obsessive-compulsive disorder (OCD) is a common psychiatric disorder that affects approximately 1-3% of the general population. It is characterized by disabling obsessions (intrusive unwanted thoughts) and/or compulsions (ritualized repetitive behaviors). Catechol-O-methyltransferase (COMT) enzyme has an important role in inactivation of dopamine and higher dopamine levels may be implicated in OCD, hence COMT gene is a suitable candidate for OCD. Several case-control studies have evaluated the role of COMT Val 158Met (rs4680;472G- > A) polymorphism as a risk factor for OCD but the results remained inconclusive, hence present meta-analysis was designed to find out correct assessment. All studies that investigated the association of COMT gene Val158Met polymorphism with OCD risk, were considered in the present meta-analysis. Statistical analysis was performed with the software program MetaAnalyst. In the current meta-analysis, 14 case-control studies with 1435 OCD cases and 2753 healthy controls were included. The results indicated significant association between COMT Val158Met polymorphism and OCD risk using allele contrast, homozygote and dominant models (ORA vs G = 1.14; 95% CI = 1.02-1.27; p = 0.01; ORAAvs.GG = 1.33; 95% CI = 1.09-1.62, p = 0.004; ORAA + AGvs.GG = 1.14; 95% CI = 1.0-1.32; p = 0.04). In subgroup analysis based on case gender, meta-analysis of male cases showed significant association using all five genetic models (ORAAvsGG = 1.99; 95%CI = 1.42-2.59; p = <0.001; ORAA + AGvs.GG = 1.59; 95% CI = 1.20-2.10; p = 0.001), but did not show any association between COMT Val 158Met polymorphism and OCD risk in females. In conclusion, results of present meta-analysis supports that the COMT Val158Met polymorphism is a risk factor for OCD especially for males.
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BMI-associated gene variants in FTO and cardiometabolic and brain disease: obesity or pleiotropy?
Ganeff, IMM, Bos, MM, van Heemst, D, Noordam, R
Physiological genomics. 2019;(8):311-322
Abstract
Obesity is a causal risk factor for the development of age-related disease conditions, which includes Type 2 diabetes mellitus, cardiovascular disease, and dementia. In genome-wide association studies, genetic variation in FTO is strongly associated with obesity and has been described across different ethnic backgrounds and life stages. To date, much work has been devoted on determining the biological mechanisms via which FTO affects body weight regulation and ultimately contributes to age-related cardiometabolic and brain disease. The main hypotheses of the involved biological mechanisms include the involvement of FTO in habitual food intake and energy expenditure. In this narrative review, our overall aim is to provide an overview on how FTO gene variants could increase the risk of developing age-related disease conditions. Specifically, we will discuss the state of the literature based on the different hypotheses how FTO regulates body weight and ultimately contributes to cardiometabolic disease and brain disease.
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Role of CTLA4 A49G polymorphism in systemic lupus erythematosus and its geographical distribution.
Kailashiya, V, Sharma, HB, Kailashiya, J
Journal of clinical pathology. 2019;(10):659-662
Abstract
CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) or CD152 is an inhibitory receptor expressed constitutively on CD4+ CD25+ T regulatory lymphocytes and transiently on activated CD4+ and CD8+ T lymphocytes. Its inhibitory function promotes long-lived anergy in immune cells and prevents autoimmunity. Therefore, it plays a crucial role in T cell-mediated autoimmunity, and thus in susceptibility to autoimmune diseases, including systemic lupus erythematosus (SLE). It is encoded by CTLA4 gene in humans. AtoG polymorphism at position +49 of CTLA4 gene is the only polymorphism which changes amino acid sequence from alanine to threonine in the leader sequence, which may affect the function of CTLA-4. Association of CTLA4 polymorphisms with SLE has been investigated in several reports in different ethnic populations from different countries, which have shown highly inconsistent findings. In this review, we have compiled previous studies which have reported the association of CTLA4 A49G polymorphism in SLE and its geographical distribution.
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The roles of endothelial nitric oxide synthase gene polymorphisms in diabetes mellitus and its associated vascular complications: a systematic review and meta-analysis.
Dong, J, Ping, Y, Wang, Y, Zhang, Y
Endocrine. 2018;(2):412-422
Abstract
PURPOSE The roles of endothelial nitric oxide synthase (eNOS) gene polymorphisms in diabetes mellitus (DM) were intensively analyzed, but the results of these studies were inconsistent. Therefore, we performed this study to better assess the relationship between eNOS genetic variations and DM. METHODS Eligible studies were searched in PubMed, Medline, Embase, and Web of Science. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess correlations between eNOS polymorphisms and DM. RESULTS A total of 91 studies were finally included in our analyses. Significant associations with the susceptibility to DM were detected for the rs891512, rs1799983, rs2070744, and rs869109213 polymorphisms. As for vascular complications in DM, significant associations with the susceptibility to diabetic nephropathy were detected for the rs1799983 and rs2070744 polymorphisms. In addition, we also found that the rs1799983 polymorphism was significantly associated with the susceptibility to peripheral artery disease, whereas the rs2070744 polymorphism was significantly associated with the susceptibility to coronary artery disease in DM patients. Further subgroup analyses on the basis of type of disease and ethnicity of participants showed similar positive results. CONCLUSIONS In conclusion, our findings indicate that rs891512, rs1799983, rs2070744, and rs869109213 polymorphisms may serve as genetic biomarkers of DM, while rs1799983, rs2070744, and rs869109213 polymorphisms may contribute to the development of vascular complications in DM.
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Associations between common ion channel single nucleotide polymorphisms and sudden cardiac death in adults: A MOOSE-compliant meta-analysis.
Liu, X, Shi, J, Xiao, P
Medicine. 2018;(38):e12428
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Abstract
BACKGROUND We sought to identify common ion channel single nucleotide polymorphisms (SNPs) associated with the occurrence of sudden cardiac death (SCD) to predict the incidence of SCD in clinical settings. METHODS This study involved a systematic review and meta-analysis of ion channel SNPs and risk of SCD in adults. We searched public databases for studies published up to September 19, 2017. We examined relationships between SNPs in common ion channel genes and the incidence of SCD. RESULTS We collected data for 22 trials that included a total of 4149 patients who experienced SCD or had a high risk of SCD and assessed these data in our meta-analysis. An allelic model showed that rs11720524 in SCN5A clearly protected against SCD (odds ratio [OR]: 0.76; 95% confidence interval [95% CI]: 0.67-0.85; P < .001). Subgroup analysis showed that rs11720524 in SCN5A protected against SCD in Europeans and Caucasians but not in Koreans. The allelic model indicated that rs12296050 in KCNQ1 also had significant protective effects against SCD (OR: 0.85; 95% CI: 0.76-0.96; P = .007). Moreover, this model demonstrated that rs2283222 in KCNQ1 had a significant negative relationship with SCD (OR: 0.73; 95% CI: 0.62-0.85; P < .001). Rs12296050 in KCNQ1 protected against SCD in Koreans and Americans. Our results also showed that rs790896 in RYR2 was negatively associated with SCD in a dominant model (OR: 0.66; 95% CI: 0.45-0.97; P = .033). CONCLUSIONS Rs11720524 in SCN5A is negatively related to SCD in Europeans and Caucasians, and rs12296050 and rs2283222 in KCNQ1 and rs790896 in RYR2 clearly have protective effects against SCD.
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Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis.
Harrison, SC, Holmes, MV, Burgess, S, Asselbergs, FW, Jones, GT, Baas, AF, van 't Hof, FN, de Bakker, PIW, Blankensteijn, JD, Powell, JT, et al
JAMA cardiology. 2018;(1):26-33
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Abstract
IMPORTANCE Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease. OBJECTIVE To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk. DESIGN, SETTING, AND PARTICIPANTS Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016. EXPOSURES Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). MAIN OUTCOMES AND MEASURES The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk. RESULTS Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10-9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10-5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10-7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C-reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C-raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10-7). Finally, the LDL-C-lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C-lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.92-1.02; P = .28). CONCLUSIONS AND RELEVANCE The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA.
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Whole-exome sequencing identifies unique mutations and copy number losses in calcifying fibrous tumor of the pleura: report of 3 cases and review of the literature.
Mehrad, M, LaFramboise, WA, Lyons, MA, Trejo Bittar, HE, Yousem, SA
Human pathology. 2018;:36-43
Abstract
Calcifying fibrous tumor of the pleura (CFTP) is a rare mesenchymal tumor of unknown pathogenesis. The diagnosis often requires exclusion of other common entities. Our aim was to determine if genomic changes were associated with CFTP that could contribute to mechanisms underlying tumorigenesis. Three cases of CFTP with their corresponding uninvolved control lung tissue were identified. Two patients were male, and 1 was female (age range, 21-32 years). Tumors were multifocal in 2 cases and solitary in 1. Immunohistochemistry for STAT6, BCL-2, CD34, cytokeratin AE1/AE3, calretinin, desmin, S100, ALK, and β-catenin was used. All immunohistochemistries were negative in CFTPs. DNA was isolated from all 3 pairs of CFTPs and matching normal lungs for whole-exome sequencing. Damaging, tumor-specific, coding variants were identified in 3 genes including multiple heterozygotic, de novo mutations in the Zinc Finger Protein 717 (ZNF717), fascioscapulohumeral muscular dystrophy-1 (FRG1) and cell division cycle 27 (CDC27) genes. Whole-exome sequencing revealed statistically significant, focal, tumor-specific copy number losses among all CFTPs including a large (302 kb) loss at 6p22.2 comprising 32 genes of the histone cluster 1 family and the hemochromatosis (HFE) gene. This is the first study to evaluate the molecular pathogenesis of CFTP and to identify novel deleterious mutations in ZN717, FRG1, and CDC27 genes as well as significant copy number losses on 8 chromosomes with a large loss common to all samples on chromosome 6. These mutations deleteriously altered coding domains in a manner predicted to be damaging to protein function and may contribute to CFTP tumorigenesis.
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Nine genetic polymorphisms associated with power athlete status - A Meta-Analysis.
Weyerstraß, J, Stewart, K, Wesselius, A, Zeegers, M
Journal of science and medicine in sport. 2018;(2):213-220
Abstract
OBJECTIVES In this study the association between genetic polymorphisms and power athlete status with possible interference by race and sex was investigated to identify genetic variants favourable for becoming a power athlete. DESIGN This meta-analysis included both, case-control and Cohort studies. METHODS Databases of PubMed and Web of Science were searched for studies reporting on genetic polymorphisms associated with the status of being a power athlete. Thirty-five articles published between 2008 and 2016 were identified as eligible including a total number of 5834 power athletes and 14,018 controls. A series of meta-analyses were conducted for each of the identified genetic polymorphisms associated with power athlete status. Odds ratios (ORs) based on the allele and genotype frequency with corresponding 95% confidence intervals (95%CI) were calculated per genetic variant. Heterogeneity of the studies was addressed by Chi-square based Q-statistics at 5% significance level and a fixed or random effects model was used in absence or presence of heterogeneity respectively. Stratified analyses were conducted by race and sex to explore potential sources of heterogeneity. RESULTS Significant associations were found for the genetic polymorphisms in the ACE (rs4363, rs1799752), ACTN3 (rs1815739), AGT (rs699), IL6-174 (rs1800795), MnSOD (rs1799725), NOS3 (rs1799983, rs2070744) and SOD2 (rs4880) genes. CONCLUSIONS Nine genetic polymorphisms have been identified in the meta-analyses to have a significant association with the status of being a power athlete. Nevertheless, more research on the investigated genes needs to be done to draw comprehensive conclusions.
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SCN1A rs3812718 polymorphism is associated with epilepsy: An updated meta-analysis.
Zhi, H, Wu, C, Yang, Z
Epilepsy research. 2018;:81-87
Abstract
To clarify the association between SCN1A rs3812718 polymorphism and epilepsy, we performed an updated meta-analysis. PubMed, Science Direct, Embase, Springer, Google Scholar, and Cochrane databases were searched before January 20, 2018. Odds ratios and 95% confidence intervals were used to assess the strength of associations. Finally, simply eight studies were included in this meta-analysis and all together recruited 7184 individuals, and they consisted of 3595 cases and 3589 controls. Based on the quality evaluation with the NOS, the overall quality of eight studies was scored from seven to eight which indicated good quality. A significant association between SCN1A rs3812718 polymorphism and the risk of epilepsy was detected in the homozygote comparison (OR = 1.64, 95% CI, 1.25-2.15, P = .001, P(BON) = 0.004), and dominant model (OR = 1.36, 95% CI, 1.08-1.72, P < .001, P(BON) < 0.001), but not in heterozygote comparison (OR = 1.22, 95% CI, 0.98-1.53, P = .003, P(BON) = 0.001), and recessive model (OR = 1.35, 95% CI, 1.22-1.49, P = .104, P(BON) = 0.104). In conclusion, our results suggest that SCN1A rs3812718 polymorphism is associated with the risk of epilepsy.
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The Association of Vitamin D Receptor Gene Polymorphism with Lung Cancer Risk: An Update Meta-analysis.
Yu, ZH, Chen, M, Zhang, QQ, Hu, X
Combinatorial chemistry & high throughput screening. 2018;(10):704-710
Abstract
The association between vitamin D receptor (VDR) genetic polymorphism and lung cancer risk has been evaluated by the previous meta-analyses. Due to the emergence of novel studies and inappropriate inclusion of overlapping populations, an updated meta-analysis on recent evidences is necessarily needed. We comprehensively searched databases of PubMed, Web of Science and Chinese National Knowledge Infrastructure and finally obtained 7 eligible studies according to the inclusion criteria. Four positions on VDR gene, namely ApaI (rs7975232), BsmI (rs1544410), FokI (rs10735810) and TaqI (rs731236), were considered in this investigation. Data pooling found no significant association of lung cancer risk with ApaI or FokI. In contrast, it was indicated that the BsmI A allele was negatively related to the lung cancer risk, compared with the G allele (OR = 0.51, 95% CI = 0.33-0.79). Individuals with BsmI AA (OR = 0.53, 95% CI = 0.26-1.11) and AG genotypes (OR = 0.46, 95% CI = 0.30-0.71) showed decreased risk of lung cancer, compared with those of GG genotype. Regarding the TaqI polymorphism, the T allele carriers were at increased risk of lung cancer (OR = 1.25, 95% CI = 1.04-1.50). Compared with the TaqI TC+CC genotype, the TT genotype was positively associated with lung cancer risk (OR = 1.42, 95% CI = 1.11-1.82). No publication bias was identified in any of the analysis. In conclusion, VDR genetic polymorphism may be correlated to lung cancer risk. Given limited number of the included studies, more observations are warranted to draw a safer conclusion.