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1.
The role of testosterone in chronic kidney disease and kidney function in men and women: a bi-directional Mendelian randomization study in the UK Biobank.
Zhao, JV, Schooling, CM
BMC medicine. 2020;(1):122
Abstract
BACKGROUND Chronic kidney disease (CKD) has an apparent sex disparity, with a more rapid progress in men than in women. Whether the well-established sex-specific evolutionary biology trade-off between reproduction and longevity might inform CKD has not previously been considered. Relevant evidence from randomized controlled trials (RCTs) is not available. METHODS We used a bi-directional Mendelian randomization study to obtain unconfounded estimates using the UK Biobank. Single nucleotide polymorphisms (SNPs) that strongly (p value < 5 × 10-8) predicted testosterone in a sex-specific manner were applied to 179,916 white British men (6016 CKD cases) and 212,079 white British women (5958 CKD cases) to obtain sex-specific associations with CKD, albuminuria, and estimated glomerular filtration rate (eGFR). We also used multivariable MR to control for sex hormone binding globulin (SHBG). For validation, we similarly examined their role in hemoglobin and high-density lipoprotein cholesterol (HDL-c). We also assessed the role of kidney function in serum testosterone, by applying eGFR-related SNPs to testosterone in the UK Biobank. RESULTS Genetically predicted testosterone was associated with CKD in men (odds ratio (OR) for bioavailable testosterone 1.17 per standard deviation, 95% confidence interval (CI) 1.03 to 1.33) based on 125 SNPs but not in women (OR 1.02, 95% CI 0.92 to 1.14 for total testosterone) based on 254 SNPs. Multivariable MR allowing for SHBG showed consistent patterns. Genetically predicted bioavailable testosterone in men and women and genetically predicted total testosterone in women increased hemoglobin and lowered HDL-c, as seen in RCTs. Genetically predicted eGFR was not related to serum testosterone in men or in women. CONCLUSIONS Genetically predicted testosterone was associated with CKD and worse kidney function in men, whilst not affected by kidney function. Identifying drivers of testosterone and the underlying pathways could provide new insights into CKD prevention and treatment.
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2.
Probability of change in life: Amino acid changes in single nucleotide substitutions.
Chan, KF, Koukouravas, S, Yeo, JY, Koh, DW, Gan, SK
Bio Systems. 2020;:104135
Abstract
Mutations underpin the processes in life, be it beneficial or detrimental. While mutations are assumed to be random in the bereft of selection pressures, the genetic code has underlying computable probabilities in amino acid phenotypic changes. With a wide range of implications including drug resistance, understanding amino acid changes is important. In this study, we calculated the probabilities of substitutions mutations in the genetic code leading to the 20 amino acids and stop codons. Our calculations reveal an enigmatic in-built self-preserving organization of the genetic code that averts disruptive changes at the physicochemical properties level. These changes include changes to start, aromatic, negative charged amino acids and stop codons. Our findings thus reveal a statistical mechanism governing the relationship between amino acids and the universal genetic code.
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3.
CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose: a systematic review and meta-analysis.
Takeuchi, M, Kobayashi, T, Biss, T, Kamali, F, Vear, SI, Ho, RH, Bajolle, F, Loriot, MA, Shaw, K, Carleton, BC, et al
The pharmacogenomics journal. 2020;(2):306-319
Abstract
Studies on the effect of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with CYP2C9 *1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with CYP2C9 *1/*1 (SMD = -0.610, 95% CI: -0.802 to -0.419, I2 = 0%). Patients with VKORC1-1639GA or AA required a lower warfarin maintenance dose compared with patients with VKORC1-1639GG (SMD = -0.666, 95% CI: -0.887 to -0.445, I2 = 33%). However, no associations were observed between CYP4F2 polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: -0.006 to 0.015, I2 = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that CYP2C9 and VKORC1 variant statuses affect warfarin maintenance dose in children, but not CYP4F2.
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4.
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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Associations between Genotype-Diet Interactions and Weight Loss-A Systematic Review.
Bayer, S, Winkler, V, Hauner, H, Holzapfel, C
Nutrients. 2020;(9)
Abstract
Studies on the interactions between single nucleotide polymorphisms (SNPs) and macronutrient consumption on weight loss are rare and heterogeneous. This review aimed to conduct a systematic literature search to investigate genotype-diet interactions on weight loss. Four databases were searched with keywords on genetics, nutrition, and weight loss (PROSPERO CRD42019139571). Articles in languages other than English and trials investigating special groups (e.g., pregnant women, people with severe diseases) were excluded. In total, 20,542 articles were identified, and, after removal of duplicates and further screening steps, 27 articles were included. Eligible articles were based on eight trials with 91 SNPs in 63 genetic loci. All articles examined the interaction between genotype and macronutrients (carbohydrates, fat, protein) on the extent of weight loss. However, in most cases, the interaction results were not significant and represented single findings that lack replication. The publications most frequently analyzed genotype-fat intake interaction on weight loss. Since the majority of interactions were not significant and not replicated, a final evaluation of the genotype-diet interactions on weight loss was not possible. In conclusion, no evidence was found that genotype-diet interaction is a main determinant of obesity treatment success, but this needs to be addressed in future studies.
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6.
Replication of FTO Gene associated with lean mass in a Meta-Analysis of Genome-Wide Association Studies.
Ran, S, Jiang, ZX, He, X, Liu, Y, Zhang, YX, Zhang, L, Pei, YF, Zhang, M, Hai, R, Gu, GS, et al
Scientific reports. 2020;(1):5057
Abstract
Sarcopenia is characterized by low skeletal muscle, a complex trait with high heritability. With the dramatically increasing prevalence of obesity, obesity and sarcopenia occur simultaneously, a condition known as sarcopenic obesity. Fat mass and obesity-associated (FTO) gene is a candidate gene of obesity. To identify associations between lean mass and FTO gene, we performed a genome-wide association study (GWAS) of lean mass index (LMI) in 2207 unrelated Caucasian subjects and replicated major findings in two replication samples including 6,004 unrelated Caucasian and 38,292 unrelated Caucasian. We found 29 single nucleotide polymorphisms (SNPs) in FTO significantly associated with sarcopenia (combined p-values ranging from 5.92 × 10-12 to 1.69 × 10-9). Potential biological functions of SNPs were analyzed by HaploReg v4.1, RegulomeDB, GTEx, IMPC and STRING. Our results provide suggestive evidence that FTO gene is associated with lean mass.
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7.
In-depth Mendelian randomization analysis of causal factors for coronary artery disease.
Tan, YD, Xiao, P, Guda, C
Scientific reports. 2020;(1):9208
Abstract
Selecting a set of valid genetic variants is critical for Mendelian randomization (MR) to correctly infer risk factors causing a disease. We here developed a method for selecting genetic variants as valid instrumental variables for inferring risk factors causing coronary artery disease (CAD). Using this method, we selected two sets of single-nucleotide-polymorphism (SNP) genetic variants (SNP338 and SNP363) associated with each of the three potential risk factors for CAD including low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c) and triglycerides (TG) from two independent GWAS datasets. We performed in-depth multivariate MR (MVMR) analyses and the results from both datasets consistently showed that LDL-c was strongly associated with increased risk for CAD (β = 0.396,OR = 1.486 per 1 SD (equivalent to 38 mg/dL), 95CI = (1.38, 1.59) in SNP338; and β = 0.424, OR = 1.528 per 1 SD, 95%CI = (1.42, 1.65) in SNP363); HDL-c was strongly associated with reduced risk for CAD (β = -0.315, OR = 0.729 per 1 SD (equivalent to 16 mg/dL), 95CI = (0.68, 0.78) in SNP338; and β = -0.319, OR = 0.726 per 1 SD, 95%CI = (0.66, 0.80), in SNP363). In case of TG, when using the full datasets, an increased risk for CAD (β = 0.184, OR = 1.2 per 1 SD (equivalent to 89 mg/dL), 95%CI = (1.12, 1.28) in SNPP338; and β = 0.207, OR = 1.222 per 1 SD, 95%CI = (1.10, 1.36) in SNP363) was observed, while using partial datasets that contain shared and unique SNPs showed that TG is not a risk factor for CAD. From these results, it can be inferred that TG itself is not a causal risk factor for CAD, but it's shown as a risk factor due to pleiotropic effects associated with LDL-c and HDL-c SNPs. Large-scale simulation experiments without pleiotropic effects also corroborated these results.
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8.
One‑carbon metabolism factor MTHFR variant is associated with saccade latency in Spinocerebellar Ataxia type 2.
Almaguer-Mederos, LE, Jorge-Sainz, Y, Almaguer-Gotay, D, Aguilera-Rodríguez, R, Rodríguez-Labrada, R, Velázquez-Pérez, L, González-Zaldívar, Y, Cuello-Almarales, D, Vázquez-Mojena, Y, Canales-Ochoa, N, et al
Journal of the neurological sciences. 2020;:116586
Abstract
BACKGROUND Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder due to a CAG-repeat expansion. This work is intended to identify modifiers of the clinical phenotype in SCA2, following up on recent genome-wide association analyses that demonstrated the prominent role of DNA-damage repair and methylation for the severity and progression of polyglutamine diseases. In particular, we assessed the impact of MTHFR as rate-limiting enzyme in DNA methylation pathways, which modulates cerebellar neurotransmission and motor neuron atrophy. METHODS A sample of 166 Cuban SCA2 patients and of 130 healthy subjects from the same geographical and ethnic background was selected. The ATXN2 CAG repeat length was determined by PCR followed by polyacrylamide gel electrophoresis. Two amino acid substitutions known to decrease the enzyme activity of MTHFR, encoded by C677T and A1298C polymorphisms, were assessed by PCR/RFLP. RESULTS No significant differences were observed for C677T or A1298C alleles or genotype frequencies between cases and controls, confirming that disease risk in SCA2 does not depend on MTHFR activity. However, MTHFR A1298C genotypes showed a significant association with saccade latency. CONCLUSIONS \MTHFR A1298C polymorphism is associated with saccade latency in SCA2 patients, but not with disease risk, age at onset or maximal saccade velocity. These results provide evidence that folate-mediated one‑carbon metabolism might be important in the physiopathology of SCA2.
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9.
A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis.
Justice, CM, Cuellar, A, Bala, K, Sabourin, JA, Cunningham, ML, Crawford, K, Phipps, JM, Zhou, Y, Cilliers, D, Byren, JC, et al
Human genetics. 2020;(8):1077-1090
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Abstract
Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10-8): rs781716 (P = 4.71 × 10-9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10-8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10-9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10-8, OR = 0.45; P = 3.31 × 10-8, OR = 0.45; P = 1.09 × 10-8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10-8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10-6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821-55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.
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10.
Methylenetetrahydrofolate reductase C677T polymorphism and diabetic retinopathy risk: a meta-analysis of the Chinese population.
Xu, WH, Zhuang, Y, Han, X, Yuan, ZL
The Journal of international medical research. 2020;(1):300060518816834
Abstract
OBJECTIVES This study evaluated associations between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms and diabetic retinopathy (DR) susceptibility within the Chinese population. METHODS Five databases (PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure) were used for literature searches of open access articles from inception through April 2017. RESULTS Eight publications were identified involving 600 DR cases, 363 healthy controls, and 646 nondiabetic retinopathy (NDR) controls. There was a positive association between MTHFR C677T polymorphisms and DR risk within the Chinese population (DR with NDR controls: T vs. C, odds ratio (OR): 2.14, 95% confidence interval (CI): 1.55–2.97; TT vs. CC, OR: 4.19, 95% CI: 2.09–8.41; TT + CT vs. CC, OR: 2.83, 95% CI: 1.86–4.40; TT vs. CC + CT, OR: 2.48, 95% CI: 1.52–4.05. DR with healthy controls: T vs. C, OR: 2.48, 95% CI: 1.99–3.09; TT vs. CC, OR: 4.92, 95% CI: 3.18–7.62; TT + CT vs. CC, OR: 3.22, 95% CI: 2.32–4.48; TT vs. CC + CT, OR: 3.11, 95% CI: 1.83–5.28). The association was similar in South China and North China, when stratifying by geographic areas. CONCLUSION MTHFR C677T polymorphisms increase DR risk within the Chinese population.