Impact of adiposity on risk of female gout among those genetically predisposed: sex-specific prospective cohort study findings over >32 years

2021 ◽  
pp. annrheumdis-2021-221635
Author(s):  
Natalie McCormick ◽  
Chio Yokose ◽  
Na Lu ◽  
Amit D Joshi ◽  
Gary C Curhan ◽  
...  
Keyword(s):  
Genetic Predisposition ◽  
Genetic Risk Score ◽  
Joint Effect ◽  
Health Study ◽  
Nucleotide Polymorphisms ◽  
Additive Interaction ◽  
Individual Factor ◽  
Single Nucleotide ◽  
Excess Adiposity

ObjectivesTo evaluate the joint (combined) association of excess adiposity and genetic predisposition with the risk of incident female gout, and compare to their male counterparts; and determine the proportion attributable to body mass index (BMI) only, genetic risk score (GRS) only, and to their interaction.MethodsWe prospectively investigated potential gene-BMI interactions in 18 244 women from the Nurses’ Health Study and compared with 10 888 men from the Health Professionals Follow-Up Study. GRS for hyperuricaemia was derived from 114 common urate-associated single nucleotide polymorphisms.ResultsMultivariable relative risk (RR) for female gout was 1.49 (95% CI 1.42 to 1.56) per 5 kg/m2 increment of BMI and 1.43 (1.35 to 1.52) per SD increment in the GRS. For their joint association of BMI and GRS, RR was 2.18 (2.03 to 2.36), more than the sum of each individual factor, indicating significant interaction on an additive scale (p for interaction <0.001). The attributable proportions of joint effect for female gout were 42% (37% to 46%) to adiposity, 37% (32% to 42%) to genetic predisposition and 22% (16% to 28%) to their interaction. Additive interaction among men was smaller although still significant (p interaction 0.002, p for heterogeneity 0.04 between women and men), and attributable proportion of joint effect was 14% (6% to 22%).ConclusionsWhile excess adiposity and genetic predisposition both are strongly associated with a higher risk of gout, the excess risk of both combined was higher than the sum of each, particularly among women.

scholarly journals Lack of gene–diuretic interactions on the risk of incident gout: the Nurses’ Health Study and Health Professionals Follow-up Study

2015 ◽  
Vol 74 (7) ◽  
pp. 1394-1398 ◽  
Author(s):  
Ying Bao ◽  
Gary Curhan ◽  
Tony Merriman ◽  
Robert Plenge ◽  
Peter Kraft ◽  
...  
Keyword(s):  
Genetic Predisposition ◽  
Health Professionals ◽  
Risk Scores ◽  
Health Study ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
P Values ◽  
Follow Up Study

BackgroundDiuretic-induced gout might occur only among those with a genetic predisposition to hyperuricaemia, as suggested by a recent study with 108 self-reported gout cases.MethodsWe examined the role of urate genes on the risk of diuretic-induced incident gout in 6850 women from the Nurses’ Health Study (NHS) and in 4223 men from the Health Professionals Follow-up Study (HPFS). Two published genetic risk scores (GRSs) were calculated using urate-associated single-nucleotide polymorphisms for 8 (GRS8) and 29 genes (GRS29).ResultsOur analyses included 727 and 354 confirmed incident gout cases in HPFS and NHS, respectively. The multivariate relative risk (RR) for diuretic use was 2.20 and 1.69 among those with GRS8 < and ≥ the median (p for interaction=0.27). The corresponding RRs using GRS29 were 2.19 and 1.88 (p for interaction=0.40). The lack of interaction persisted in NHS (all p values >0.20) and in our analyses limited to those with hypertension in both cohorts. SLC22A11 (OAT4) showed a significant interaction only among women but in the opposite direction to the recent study.ConclusionsIn these large prospective studies, individuals with a genetic predisposition for hyperuricaemia are not at a higher risk of developing diuretic-induced gout than those without.

Joint effect of multiple prothrombotic genotypes and obesity on the risk of incident venous thromboembolism

2021 ◽  
Author(s):  
Tobias Frischmuth ◽  
Kristian Hindberg ◽  
Maiken Elvestad Gabrielsen ◽  
Ben Michael Brumpton ◽  
Kristian Hveem ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Genetic Risk Score ◽  
Joint Effect ◽  
Additive Effect ◽  
Health Study ◽  
Nucleotide Polymorphisms ◽  
Risk Alleles ◽  
Individual Snps ◽  
Increased Risk ◽  
The Impact

Background: The impact of the combination of obesity and multiple prothrombotic genotypes on venous thromboembolism (VTE) risk remains unclear. Objective: To investigate the joint effect of obesity and a genetic risk score (GRS) comprised of established prothrombotic single nucleotide polymorphisms (SNPs) on VTE risk using a population-based case-cohort. Methods: Cases with incident VTE (n=1,470) and a subcohort (n=12,826) were derived from the Tromsø Study (1994‐2012) and the Trøndelag Health Study (HUNT) (1995‐2008). Participants were genotyped for ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865) and F11 (rs2036914) SNPs. Age- and sex-adjusted hazard ratios (HRs) were estimated according to body mass index (BMI) categories and number of risk alleles for individual SNPs and the GRS (0-1, 2, 3, ≥4 alleles). Results: The combination of obesity (BMI≥30kg/m2) and risk alleles, either as individual SNPs or as a GRS, had an additive effect on VTE risk (i.e. no biological interaction). Obese subjects who were carriers of ≥4 risk alleles had a 2.85-fold (95% confidence intervals [CI] 2.05-3.96) increased risk of overall VTE compared to those with BMI<25kg/m2 and 0-1 risk allele. However, in subgroups, the combination of obesity and ≥4 risk alleles was more pronounced for deep vein thrombosis (DVT) (HR 3.20, 95% CI 2.09-4.90) and unprovoked VTE (HR 3.82, 95% CI 2.25-6.47), suggesting a supra-additive effect. Conclusion: Our findings indicate that the combination of obesity and GRS has an additive effect on the risk of overall VTE. However, it may have a supra-additive effect on the risk of DVT and unprovoked VTE.

Genetic Predisposition to Essential Hypertension in Children: Analysis of 17 Single Nucleotide Polymorphisms

2014 ◽  
Vol 5 (4) ◽  
pp. 307-322
Author(s):  
Sergii V. Goncharov ◽  
Veronika L. Gurianova ◽  
Dmytro O. Stro ◽  
Tatyana I. Drevytska ◽  
Sergii P. Kaplinskii ◽  
...  
Keyword(s):  
Essential Hypertension ◽  
Single Nucleotide Polymorphisms ◽  
Genetic Predisposition ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Hypertension In Children

Association of genetic polymorphism of cytokines and antioxidant enzymes with the development of asbestosis

2020 ◽  
Vol 60 (12) ◽  
pp. 898-903
Author(s):  
Lyudmila P. Kuzmina ◽  
Anastasiya G. Khotuleva ◽  
Evgeniy V. Kovalevsky ◽  
Nikolay N. Anokhin ◽  
Iraklij M. Tskhomariya
Keyword(s):  
Antioxidant Enzymes ◽  
Genetic Polymorphism ◽  
Genetic Predisposition ◽  
Risk Groups ◽  
Dust Exposure ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Gstp1 Gene ◽  
Polymorphic Variants

Introduction. Various industries widely use chrysotile asbestos, which determines the relevance of research aimed at the prevention of asbestos-related diseases. It is promising to assess the role of specific genes, which products are potentially involved in the development and regulation of certain links in the pathogenesis of asbestosis, forming a genetic predisposition to the disease. The study aims to analyze the presence of associations of genetic polymorphism of cytokines and antioxidant enzymes with asbestosis development. Materials and methods. Groups were formed for examination among employees of OJSC "Uralasbest" with an established diagnosis of asbestosis and without lung diseases. For each person included in the study, dust exposure doses were calculated considering the percentage of time spent at the workplace during the shift for the entire work time. Genotyping of single nucleotide polymorphisms of cytokines IL1b (rs16944), IL4 (rs2243250), IL6 (rs1800795), TNFα (rs1800629) and antioxidant enzymes SOD2 (rs4880), GSTP1 (rs1610011), CAT (rs1001179) was carried out. Results. The authors revealed the associations of polymorphic variants A511G IL1b gene (OR=2.457, 95% CI=1.232-4.899) and C47T SOD2 gene (OR=1.705, 95% CI=1.055-2.756) with the development of asbestosis. There was an increase in the T allele IL4 gene (C589T) frequency in persons with asbestosis at lower values of dust exposure doses (OR=2.185, 95% CI=1.057-4.514). The study showed the associations of polymorphism C589T IL4 gene and C174G IL6 gene with more severe asbestosis, polymorphism A313G GSTP1 gene with pleural lesions in asbestosis. Conclusion. Polymorphic variants of the genes of cytokines and antioxidant enzymes, the protein products directly involved in the pathogenetic mechanisms of the formation of asbestosis, contribute to forming a genetic predisposition to the development and severe course of asbestosis. Using the identified genetic markers to identify risk groups for the development and intense period of asbestos-related pathology will optimize treatment and preventive measures, considering the organism's characteristics.

scholarly journals Power of a reproducing kernel-based method for testing the joint effect of a set of single-nucleotide polymorphisms

Genetica ◽  
2012 ◽  
Vol 140 (10-12) ◽  
pp. 421-427 ◽  
Author(s):  
Hong He ◽  
Hongmei Zhang ◽  
Arnab Maity ◽  
Yubo Zou ◽  
James Hussey ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Reproducing Kernel ◽  
Joint Effect ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Causal associations of obesity with chronic kidney disease and arterial stiffness: a Mendelian randomization study

2021 ◽  
Author(s):  
Chaojie Ye ◽  
Lijie Kong ◽  
Zhiyun Zhao ◽  
Mian Li ◽  
Shuangyuan Wang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Standard Deviation ◽  
Kidney Disease ◽  
Single Nucleotide Polymorphisms ◽  
Arterial Stiffness ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Abstract Purpose Observational studies have associated obesity with chronic kidney disease (CKD) and arterial stiffness, but the causality remains unclear. We aimed to investigate the causality of obesity with CKD and arterial stiffness using Mendelian randomization (MR) analysis. Methods We genotyped 14 body mass index (BMI)-associated variants validated in East Asians in 11384 Chinese adults. A genetic risk score based on the 14 variants and the 14 individual single nucleotide polymorphisms were respectively used as instrumental variables (IVs). CKD was defined as estimated glomerular filtration rate &lt;60 mL/min/1.73 m 2. Arterial stiffness was defined as brachial-ankle pulse wave velocity &gt;1550 cm/s. Results Using the genetic risk score as the IV, we demonstrated causal relations of each 1-standard deviation increment in BMI with CKD (odds ratio [OR]: 2.36; 95% confidence interval [CI]: 1.11-5.00) and arterial stiffness (OR: 1.71; 95% CI: 1.22-2.39). Using the 14 single nucleotide polymorphisms individually as IVs, each 1-standard deviation increment in BMI casually associated with CKD (OR: 2.58; 95% CI: 1.39-4.79) and arterial stiffness (OR: 1.87; 95% CI: 1.24-2.81) in the inverse-variance weighted analysis, and MR-Egger regression revealed no evidence of horizontal pleiotropy (Both P for intercept≥0.34). The causality between obesity and CKD was validated in two-sample MR analysis among Europeans (681275 of Genetic Investigation of ANthropometric Traits and 133413 of CKD Genetics). Conclusions This study provided novel insights into causality of obesity with CKD and arterial stiffness, highlighting the importance of weight management for primary prevention and control of subclinical vascular diseases.

scholarly journals Coffee Consumption, Genetic Polymorphisms, and the Risk of Type 2 Diabetes Mellitus: A Pooled Analysis of Four Prospective Cohort Studies

2020 ◽  
Vol 17 (15) ◽  
pp. 5379
Author(s):  
An Na Kim ◽  
Hyun Jeong Cho ◽  
Jiyoung Youn ◽  
Taiyue Jin ◽  
Moonil Kang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Regression Models ◽  
Coffee Consumption ◽  
Pooled Analysis ◽  
Random Effects Model ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Logistic Regression Models

The association between coffee consumption and the risk of type 2 diabetes may vary by genetic variants. Our study addresses the question of whether the incidence of type 2 diabetes is related to the consumption of coffee and whether this relationship is modified by polymorphisms related to type 2 diabetes. We performed a pooled analysis of four Korean prospective studies that included 71,527 participants; median follow-up periods ranged between 2 and 13 years. All participants had completed a validated food-frequency questionnaire (FFQ) at baseline. The odds ratios (ORs) and 95% confidence intervals (CIs) for type 2 diabetes were calculated using logistic regression models. The ORs were combined using a fixed or random effects model depending on the heterogeneity across the studies. Compared with 0 to <0.5 cups/day of coffee consumption, the OR for type 2 diabetes was 0.89 (95% CI: 0.80–0.98, p for trend = 0.01) for ≥3 cups/day of coffee consumption. We did not observe significant interactions by five single nucleotide polymorphisms (SNPs) related to type 2 diabetes (CDKAL1 rs7756992, CDKN2A/B rs10811661, KCNJ11 rs5215, KCNQ1 rs163184, and PEPD rs3786897) in the association between coffee and the risk of type 2 diabetes. We found that coffee consumption was inversely associated with the risk of type 2 diabetes.

Genetic variations in semaphorin/neuropilin signaling to predict clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) receiving bevacizumab-based chemotherapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11608-11608
Author(s):  
Yuji Miyamoto ◽  
Fotios Loupakis ◽  
Wu Zhang ◽  
Shu Cao ◽  
Satoshi Okazaki ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Clinical Outcome ◽  
Clinical Outcomes ◽  
Phase Iii ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Ras Mutation ◽  
Mutation Status ◽  
Gtpase Activating Proteins

11608 Background: Neuropilin ( NRP) is known to be an important VEGF co-receptor that acts as a key mediator of angiogenesis. Its ligands, semaphorins ( SEMA), compete with VEGF for NRP binding and can themselves have angiogenic activity. Plexins are also receptors of SEMAs, and have the GTPase activating proteins (GAPs) domain for RAS. NRPs are shown to signal through RAS pathways. We aimed to evaluate whether single nucleotide polymorphisms (SNPs) of genes involved in the SEMA/NRPpathways predict clinical outcome in bevacizumab-treated mCRC pts. Methods: Associations between nine SNPs in 7 genes ( SEMA3A, SEMA3D, SEMA3F, NRP1, NRP2, PLXNA1 and PLXND1) and clinical outcomes were evaluated in mCRC patients receiving first-line FOLFIRI-bevacizumab in a phase III trial: TRIBE ( N= 228). Associations between genotype and RAS mutation status with clinical outcomes was also examined. Main characteristics were the following: male/female = 138/90; median age = 60; RAS-wildtype/mutant = 55/116; median PFS = 9.7 months; median OS = 26.1 months, median follow-up time = 49.3 months. Results: NRP1 rs2228638 Any A ( N= 40) showed a significantly longer PFS compared to G/G variant ( N= 188) in the univariate (11.6 months (M) vs. 9.5 M, HR = 0.64, 95%CI = 0.43-0.95, p = 0.022) and the multivariate analysis (HR = 0.59, 95%CI = 0.38-0.90, p = 0.016). SEMA3F rs12632110 A/A ( N= 20) showed a significantly shorter PFS compared to any G variant (N = 205) in the multivariate analysis (HR = 1.89, 95%CI = 1.02-3.49, p = 0.043). Among RAS-mutant pts, SEMA3F rs12632110, SEMA3F rs1046956, SEMA3D rs7800072, NRP1 rs228638, PLXNA1 rs4679323 and PLXND1 rs2255703 polymorphisms were significantly associated with PFS in the univariate and multivariate analysis. PLXNA1 rs4679323 was also significantly associated with OS in the univariate and multivariate analysis. There was no association between these polymorphisms and outcome in patients with RASwildtype tumors. Conclusions: Genetic variants within SEMA/NRP pathways may be prognostic markers in RAS mutant mCRC patients treated with bevacizumab-based chemotherapy.

scholarly journals Do genetic risk scores for body mass index predict risk of phobic anxiety? Evidence for a shared genetic risk factor

2014 ◽  
Vol 45 (1) ◽  
pp. 181-191 ◽  
Author(s):  
S. Walter ◽  
M. M. Glymour ◽  
K. Koenen ◽  
L. Liang ◽  
E. J. Tchetgen Tchetgen ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Conclusive Evidence ◽  
Anxiety Symptoms ◽  
Risk Scores ◽  
Health Study ◽  
Nucleotide Polymorphisms ◽  
Phobic Anxiety

BackgroundObesity and anxiety are often linked but the direction of effects is not clear.MethodUsing genetic instrumental variable (IV) analyses in 5911 female participants from the Nurses' Health Study (NHS, initiated 1976) and 3697 male participants from the Health Professional Follow-up Study (HPFS, initiated 1986), we aimed to determine whether obesity increases symptoms of phobic anxiety. As instrumental variables we used the fat mass and obesity-associated (FTO) gene, the melanocortin 4 receptor (MC4R) gene and a genetic risk score (GRS) based on 32 single nucleotide polymorphisms (SNPs) that significantly predict body mass index (BMI). ‘Functional’ GRSs corresponding with specific biological pathways that shape BMI (adipogenesis, appetite and cardiopulmonary) were considered. The main outcome was phobic anxiety measured by the Crown Crisp Index (CCI) in 2004 in the NHS and in 2000 in the HPFS.ResultsIn observational analysis, a 1-unit higher BMI was associated with higher phobic anxiety symptoms [women:β = 0.05, 95% confidence interval (CI) 0.030–0.068; men:β = 0.04, 95% CI 0.016–0.071). IV analyses showed that BMI was associated with higher phobic anxiety symptoms in theFTO-instrumented analysis (p = 0.005) but not in the GRS-instrumented analysis (p = 0.256). Functional GRSs showed heterogeneous, non-significant effects of BMI on phobic anxiety symptoms.ConclusionsOur findings do not provide conclusive evidence in favor of the hypothesis that higher BMI leads to higher levels of phobic anxiety, but rather suggest that genes that influence obesity, in particularFTO, may have direct effects on phobic anxiety, and hence that obesity and phobic anxiety may share common genetic determinants.

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