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Triacylglycerol-Lowering Effect of Docosahexaenoic Acid Is Not Influenced by Single-Nucleotide Polymorphisms Involved in Lipid Metabolism in Humans.
AbuMweis, SS, Panchal, SK, Jones, PJH
Lipids. 2018;(9):897-908
Abstract
The triacylglycerol (TAG)-lowering effects of long-chain n-3 fatty acids, and in particular docosahexaenoic acid (DHA), are well documented, although these effects manifest large interindividual variability. The objective of this secondary analysis is to investigate whether common single-nucleotide polymorphisms (SNP) in genes involved in DHA synthesis and TAG metabolism are associated with the responsiveness of blood lipids, lipoprotein, and apolipoprotein concentration to dietary treatment by DHA supplied in high-oleic canola oil (HOCO). In a randomized, crossover-controlled feeding trial, 129 subjects with metabolic syndrome received high-oleic canola oil (HOCO) and high-oleic canola oil supplemented with DHA (HOCO-DHA), each for 4 weeks. During the HOCO-DHA phase, the intake of DHA ranged from 1 to 2.5 g/day. The subjects were genotyped for apolipoprotein E (APOE) isoforms, and SNP including FADS1-rs174561, FADS2-rs174583, ELOVL2-rs953413, ELOVL5-rs2397142, CETP-rs5882, SCD1-rs2234970, PPARA-rs6008259, and LIPF-rs814628 were selected as important genes controlling fatty acid metabolism. Overall, consumption of HOCO-DHA oil reduced blood concentrations of TAG by 24% compared to HOCO oil. The reduction in TAG was independent of genetic variations in the studied genes. Similarly, no treatment-by-gene interactions were evident in the response to other lipids, lipoproteins, or apolipoproteins to DHA supplementation. Nevertheless, a lower interindividual variation in the TAG response to DHA supplementation compared to other studies was observed in this analysis. The TAG-lowering effect of a supplemental body-weight-based dose of DHA was not influenced by genetic variations in APOE, FADS1, FADS2, ELOVL2, ELOVL5, CETP, SCD1, PPARA, and LIPF.
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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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ADCY9 Genetic Variants and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease: A Nested Case-Control Study.
Nissen, SE, Pillai, SG, Nicholls, SJ, Wolski, K, Riesmeyer, JS, Weerakkody, GJ, Foster, WM, McErlean, E, Li, L, Bhatnagar, P, et al
JAMA cardiology. 2018;(5):401-408
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IMPORTANCE A pharmacogenetic analysis of dalcetrapib, a cholesteryl ester transfer protein inhibitor, reported an association between a single-nucleotide polymorphism (SNP) in the ADCY9 gene (rs1967309) and reduction in major adverse cardiovascular events despite a neutral result for the overall trial. OBJECTIVE To determine whether the association between the SNP in the ADCY9 gene and a reduction in major adverse cardiovascular events could be replicated for another cholesteryl ester transfer protein inhibitor, evacetrapib, in patients with high-risk vascular disease. DESIGN, SETTING, AND PARTICIPANTS A nested case-control study examining the rs1967309 SNP in 1427 cases and 1532 matched controls selected from the 12 092-patient Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial, a randomized, double-blind, placebo-controlled phase 3 trial conducted in patients with high-risk vascular disease randomized from October 2012 through December 2013. The genotyping was conducted from January 2017 to March 2017, and the data analyses were conducted from July 2017 to November 2017. EXPOSURES Evacetrapib, 130 mg, or matching placebo. MAIN OUTCOMES AND MEASURES The primary analyses used a conditional logistic regression model to assess the odds ratio (OR) for major adverse cardiovascular events for evacetrapib compared with placebo for each genotype. The basic model included adjustment for age, sex, and the top 5 principal components. An additional model included cardiovascular risk factors to adjust for potential bias in selecting control patients. The primary major adverse cardiovascular event end point was the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS For patients with the AA genotype reported to demonstrate a beneficial effect from dalcetrapib, the OR for evacetrapib compared with placebo was 0.88 (95% CI, 0.69-1.12). For patients with the AG genotype, the OR was 1.04 (95% CI, 0.90-1.21). For patients with the GG genotype reported to show evidence for a harmful effect from dalcetrapib, the OR for evacetrapib was 1.18 (95% CI, 0.98-1.41). The interaction P value among the 3 genotypes was P = .17 and the trend P value was P = .06. When adjusted for cardiovascular risk factors, the OR for evacetrapib was 0.93 (95% CI, 0.73-1.19) for the AA genotype, 1.05 (95% CI, 0.91-1.22) for the AG genotype, and 1.02 (95% CI 0.85-1.24) for the GG genotype; interaction P = .71 and trend P = .59. CONCLUSIONS AND RELEVANCE Pharmacogenetic analysis did not show a significant association between the ADCY9 SNP (rs1967309) and cardiovascular benefit or harm for the cholesteryl ester transfer protein inhibitor evacetrapib.
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Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant.
Shepherd, C, Zhu, D, Skelton, AJ, Combe, J, Threadgold, H, Zhu, L, Vincent, TL, Stuart, P, Reynard, LN, Loughlin, J
Arthritis & rheumatology (Hoboken, N.J.). 2018;(10):1577-1587
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OBJECTIVE To identify the functional single-nucleotide polymorphisms (SNPs) and mechanisms conferring increased risk of hand osteoarthritis (OA) at the ALDH1A2 locus, which is a retinoic acid regulatory gene. METHODS Tissue samples from 247 patients with knee, hip, or hand OA who had undergone joint surgery were included. RNA-sequencing analysis was used to investigate differential expression of ALDH1A2 and other retinoic acid signaling pathway genes in cartilage. Expression of ALDH1A2 in joint tissues obtained from multiple sites was quantified using quantitative reverse transcription-polymerase chain reaction. Allelic expression imbalance (AEI) was measured by pyrosequencing. The consequences of ALDH1A2 depletion by RNA interference were assessed in primary human chondrocytes. In silico and in vitro analyses were used to pinpoint which, among 62 highly correlated SNPs, could account for the association at the locus. RESULTS ALDH1A2 expression was observed across multiple joint tissue samples, including osteochondral tissue from the hand. The expression of ALDH1A2 and of several retinoic acid signaling genes was different in diseased cartilage compared to non-diseased cartilage, with ALDH1A2 showing lower levels in OA cartilage. Experimental depletion of ALDH1A2 resulted in changes in the expression levels of a number of chondrogenic markers, including SOX9. In addition, reduced expression of the OA risk-conferring allele was witnessed in a number of joint tissues, with the strongest effect in cartilage. The intronic SNP rs12915901 recapitulated the AEI observed in patient tissues, while the Ets transcription factors were identified as potential mediators of this effect. CONCLUSION The ALDH1A2 locus seems to increase the risk of hand OA through decreased expression of ALDH1A2 in joint tissues, with the effect dependent on rs12915901. These findings indicate a mechanism that may now be targeted to modulate OA risk.
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[Meta-analysis on relationship between the Chinese maternal MTHFR gene polymorphism(C677T) and neural tube defects in offspring].
Zhang, C, Huo, J, Sun, J, Huang, J, Piao, W, Yin, J
Wei sheng yan jiu = Journal of hygiene research. 2018;(2):312-317
Abstract
OBJECTIVE To explore the association between maternal MTHFR gene polymorphism( C677T) and neural tube defects in offspring through Meta-analysis in China. METHODS CNKI, Pub Med, Web of Science, Chinese Wan Fang Data databases, CBM, VIP for published articles were searched from the time of Database establishment to July 5 th 2017. The search strategy was based on combinations of the English and/or Chinese keywords, 'MTHFR'and 'folate pathway'and 'polymorphism'or 'SNP'and'NTDs or Neural Tube Defects'. References of reviews and retrieved studies were also scanned. All the case-control studies about MTHFR gene C677T polymorphism and susceptibility of neural tube defect were collected, which were fulfilled the followinginclusion criteria: case-control study and cohort study design, presentation of data necessary for calculating odds ratios( ORs). Data were extracted from studies and analyzed by Rev Man 5. 3 software. RESULTS A total of 13 papers were selected, including1500 patients and 1654 controls. Meta-analysis result showed that the combined odds ratio values of neural tube defect for offspring with maternal TT, TT + CT and T allele genotypes were 1. 94, 1. 65 and 1. 39, respectively. CONCLUSION The present Meta-analysis suggests that MTHFR C677T is significantly associated with maternal risk for NTDs in the Chinese population, supplemental folic acid supplementation based on MTHFR polymorphisms will be an important means to further reduce the birth defects of newborns.
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Influence of FTO rs9939609 and Mediterranean diet on body composition and weight loss: a randomized clinical trial.
Di Renzo, L, Cioccoloni, G, Falco, S, Abenavoli, L, Moia, A, Sinibaldi Salimei, P, De Lorenzo, A
Journal of translational medicine. 2018;(1):308
Abstract
BACKGROUND The Mediterranean diet (MeD) plays a key role in the prevention of obesity. Among the genes involved in obesity, the Fat mass and obesity-associated gene (FTO) is one of the most known, but its interaction with MeD remained uncertain so far. METHODS We carried out a study on a sample of 188 Italian subjects, analyzing their FTO rs9939609 alleles, and the difference in body composition between the baseline and a 4-weeks nutritional intervention. The sample was divided into two groups: the control group of 49 subjects, and the MeD group of 139 subjects. RESULTS We found significant relations between MeD and both variation of total body fat (ΔTBFat) (p = 0.00) and gynoid body fat (p = 0.04). ∆TBFat (kg) demonstrated to have a significant relation with the interaction diet-gene (p = 0.04), whereas FTO was associated with the variation of total body water (p = 0.02). CONCLUSIONS MeD demonstrated to be a good nutritional treatment to reduce the body fat mass, whereas data about FTO remain uncertain. Confirming or rejecting the hypothesis of FTO and its influence on body tissues during nutritional treatments is fundamental to decide whether its effect has to be taken into consideration during both development of dietetic plans and patients monitoring. Trial Registration ClinicalTrials.gov Id: NCT01890070. Registered 01 July 2013, https://clinicaltrials.gov/ct2/show/NCT01890070.
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Methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to epilepsy.
Rai, V, Kumar, P
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2018;(12):2033-2041
Abstract
BACKGROUND Methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism was reported as risk factor for multiple diseases due to its role in conversion of homocysteine to methionine. The aim of the present meta-analysis was to find out the validity of association of C677T polymorphism with epilepsy susceptibility. METHODS Pubmed, Science Direct, Springer Link and Google Scholar, databases were searched for relevant studies up to January, 31, 2018. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were performed using five genetic models. All statistical analysis was done by MetaAnalyst and Mix programs. RESULTS Except recessive model, significant association was found between MTHFR C677T polymorphism and epilepsy risk in other four genetic models (T vs C: OR = 1.29, 95% CI = 1.08-1.52, p = 0.004; TT vs CC: OR = 1.48, 95% CI = 1.19-1.82, p = 0.0003; TT + CT vs CC: OR = 1.20, 95% CI = 1.05-1.38, p = 0.008; TT vs CT + CC: OR = 1.35, 95% CI = 1.11-1.62, p = 0.002). Similarly, in the subgroup analysis based on ethnicity, significant association was found in Asian (T vs C: OR = 1.85; 95% CI = 1.15-2.99; p = 0.03) and Caucasian populations (TT vs CC: OR = 1.38; 95% CI = 1.10-1.1.73; p = 0.005). No evidence of heterogeneity and publication bias was detected in present meta-analysis. CONCLUSION In conclusion, results of present meta-analysis suggested that 677T allele of MTHFR is significantly increases the epilepsy susceptibility.
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Analysis of variant rs3794087 in SLC1A2 and Parkinson's disease in a Chinese Han population: A case-control study and meta-analysis.
Cheng, Y, Mao, CY, Liu, YT, Li, F, Yang, J, Liu, H, Zhang, C, Wang, YL, Wu, J, Shi, CH, et al
Neuroscience letters. 2018;:165-168
Abstract
Recently, a genome-wide association study of a Caucasian population identified variant rs3794087 in intron 4 of the SLC1A2 gene, which may increase the risk of essential tremor (ET). Considering the overlap in the pathological features and clinical manifestations of ET and Parkinson's disease (PD), several studies on the association between rs3794087 and PD were later performed in other populations. However, results about the role of SLC1A2 rs3794087 in PD were inconsistent. We thus performed a case-control study in a Chinese Han population to investigate the role of SLC1A2 rs3794087 in Chinese patients with PD. Overall, 1096 subjects comprising 546 patients with PD and 550 control subjects were genotyped. A meta-analysis of the data obtained from the current sample-set and those available from prior studies was performed. Taking all patients and controls into consideration, rs3794087 was found to have no significant effect on PD susceptibility in analyses using allelic (p = .486), genotype (p = .736), additive (p = .764), dominant (p = .438), and recessive (p = .878) genetic models. The results of the meta-analysis were in agreement with our findings (the pooled OR was 0.97 and 95% CI = 0.85, 1.10). Our study suggested that rs3794087 does not lead to an increased risk of PD in the Chinese Han population. The role of single nucleotide polymorphism rs3794087 in the development of PD remains to be further studied.
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CETP and LCAT Gene Polymorphisms Are Associated with High-Density Lipoprotein Subclasses and Acute Coronary Syndrome.
Vargas-Alarcon, G, Perez-Mendez, O, Herrera-Maya, G, Garcia-Sanchez, C, Martinez-Rios, MA, Peña-Duque, MA, Posadas-Sanchez, R, Posadas-Romero, C, Escobedo, G, Fragoso, JM
Lipids. 2018;(2):157-166
Abstract
We evaluated whether CETP and LCAT gene polymorphisms are statistically associated with the high-density lipoprotein (HDL) size distribution, the cholesterol level of HDL subclasses, and the acute coronary syndrome (ACS) susceptibility. Two CETP gene polymorphisms (rs4783961 and rs708272) and one LCAT polymorphism (rs2292318) were genotyped by 5' exonuclease TaqMan assays in 619 patients with ACS and 607 control individuals. For HDL analysis, a subgroup of 100 healthy individuals was recruited; the HDL subclasses were separated via ultracentrifugation and polyacrylamide gradient gel electrophoresis under native conditions. Under a dominant model, the G allele of the rs708272 polymorphism was associated with an increased risk of ACS (odds ratios [OR] = 1.45, corrected p-value [pCDom ] = 0.036). The linkage disequilibrium analysis showed that one of the eight possible combinations was associated with the risk of developing ACS (OR = 1.52, pC = 0.02), which suggests that it may contribute to coronary atherosclerosis. The rs708272 G allele carriers had a lower concentration of cholesterol associated with the HDL2a and HDL3a subclasses when compared with subjects carrying the A allele. Carriers of LCAT rs2292318 A allele showed a lower concentration of high-density lipoprotein-cholesterol (HDL-C) in comparison to the GG genotype; the cholesterol associated with the each one of the five HDL subclasses was significantly lower in rs2292318 A than in GG subjects. In summary, this study demonstrates that the rs708272 polymorphism is associated with a heightened risk of developing ACS. In addition, we report the association of the rs708272 and rs2292318 polymorphisms with HDL-C levels and HDL subclasses.