Genetic variants near the IRS1 gene, physical activity and type 2 diabetes in US men and women.
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ABSTRACT:
SUBMITTER: He MA
PROVIDER: S-EPMC4433538 | biostudies-literature | 2011 Jun
REPOSITORIES: biostudies-literature
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Genetic variants near the IRS1 gene, physical activity and type 2 diabetes in US men and women.
He M A MA Workalemahu T T Cornelis M C MC Hu F B FB Qi L L
Diabetologia 20110326 6
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Project description:Background and aimsA recent genome-wide association study identified rs2943641C > T, 500 kb from the insulin receptor substrate-1 gene (IRS1), as a type-2 diabetes (T2D) susceptibility locus. We aimed to replicate this association by meta-analysis and examine whether common variants within IRS1, present on the HumanCVD BeadChip, were associated with T2D risk.Methods and resultsWe genotyped rs2943641 in 2389 prevalent or incident T2D patients and 6494 controls from two prospective and three case studies based in UK and in the European Atherosclerosis Research Study-II (EARSII; n = 714). Thirty-three IRS1 variants had been genotyped in the prospective Whitehall-II study (n = 4752) using the HumanCVD BeadChip. In a fixed-effects meta-analysis of the UK study cohorts rs2943641T allele was associated with 6% lower risk of T2D (p = 0.18), with T-allele carriers having an odds ratio (OR) of 0.89 (95% confidence interval [CI]: 0.80-1.00, p = 0.056) compared to CC subjects. The T-allele was also associated with lower fasting insulin and homeostasis model assessment index of insulin resistance in Whitehall-II and with lower post-load insulin after an oral glucose tolerance test in EARSII (all p < 0.05). None of the IRS1 variants on the chip showed linkage disequilibrium with rs2943641. In silico analysis with follow-up genotyping (total n = 9313) identified that the rare allele of the IRS1 promoter variant rs6725556A > G showed association with reduced T2D risk (OR per G-allele: 0.82, 95%CI: 0.69-0.96, p = 0.015).ConclusionsWe confirm the association of rs2943641T with T2D protection. There is a possible independent effect on risk of a putative IRS1 promoter variant.
| S-EPMC3657179 | biostudies-literature
Project description:BackgroundGenome-wide association studies have identified novel type 2 diabetes loci, each of which has a modest impact on risk.ObjectiveTo examine the joint effects of several type 2 diabetes risk variants and their combination with conventional risk factors on type 2 diabetes risk in 2 prospective cohorts.DesignNested case-control study.SettingUnited States.Participants2809 patients with type 2 diabetes and 3501 healthy control participants of European ancestry from the Health Professionals Follow-up Study and Nurses' Health Study.MeasurementsA genetic risk score (GRS) was calculated on the basis of 10 polymorphisms in 9 loci.ResultsAfter adjustment for age and body mass index (BMI), the odds ratio for type 2 diabetes with each point of GRS, corresponding to 1 risk allele, was 1.19 (95% CI, 1.14 to 1.24) and 1.16 (CI, 1.12 to 1.20) for men and women, respectively. Persons with a BMI of 30 kg/m(2) or greater and a GRS in the highest quintile had an odds ratio of 14.06 (CI, 8.90 to 22.18) compared with persons with a BMI less than 25 kg/m(2) and a GRS in the lowest quintile after adjustment for age and sex. Persons with a positive family history of diabetes and a GRS in the highest quintile had an odds ratio of 9.20 (CI, 5.50 to 15.40) compared with persons without a family history of diabetes and with a GRS in the lowest quintile. The addition of the GRS to a model of conventional risk factors improved discrimination by 1% (P < 0.001).LimitationThe study focused only on persons of European ancestry; whether GRS is associated with type 2 diabetes in other ethnic groups remains unknown.ConclusionAlthough its discriminatory value is currently limited, a GRS that combines information from multiple genetic variants might be useful for identifying subgroups with a particularly high risk for type 2 diabetes.Primary funding sourceNational Institutes of Health.
| S-EPMC3825275 | biostudies-literature
Project description:IntroductionThe ability to perform bodily movement varies in ageing men and women. We investigated whether physical fitness may explain sex differences in daily physical activity energy expenditure (PAEE) among older people.MethodsIn this cross-sectional study, a population-based cohort of 75, 80, and 85-year-old men and women (n = 409, 62% women) underwent laboratory-based assessment of walking speed, maximal knee extension strength, and body fat percentage. Free-living physical activity was assessed as total PAEE, and light (LPA) and moderate-to-vigorous physical activity (MVPA) using individually calibrated combined accelerometry and heart rate sensing. Path modelling was used to examine indirect associations between sex, physical fitness, and physical activity.ResultsMen had better physical fitness and higher overall PAEE (mean 34.0 (SD 10.8) kJ/kg/day) than women (28.3 (8.4) kJ/kg/day, p<0.001). The path model for PAEE explained 33% of the variance. The direct association between sex and PAEE was non-significant, whereas the association between sex and PAEE mediated by body fat (β = 0.20, p<0.001) and walking speed (β = 0.05, p = 0.001) were statistically significant. Similarly, associations between sex and MVPA mediated by body fat (β = 0.11, p = 0.002) and walking speed (β = 0.05, p = 0.001) were significant, as were the associations between sex and LPA mediated by body fat (β = 0.24, p<0.001) and walking speed (β = 0.03, p = 0.019).ConclusionDifferences in physical activity between men and women may reflect underlying differences in cardiorespiratory fitness and adiposity. These results highlight the importance of maintaining physical fitness to support active living in older adults.
| S-EPMC11790164 | biostudies-literature
Project description:Physical activity (PA) and hypertension (HTN) are important influences on the development of type 2 diabetes (T2D). However, the joint impact of PA and HTN on T2D development is unknown.Two community-based prospective cohort studies, with the same protocols, instruments and questionnaires, were conducted among adults in urban areas of Nanjing, China, during 2004-2007 and 2007-2010. T2D was defined using World Health Organization criteria based on physicians' diagnosis and fasting blood glucose concentration. PA level (sufficient/insufficient) and blood pressure status (hypertensive/normotensive) were assessed at baseline and the third year of follow-up. We pooled and analyzed data from these two studies.Among 4550 participants aged 35 years or older, the three-year cumulative incidence of T2D was 5.1%. After adjusting for potential confounders, participants with sufficient PA were less likely to develop T2D than those with insufficient PA (OR = 0.43, 95%CI = 0.27, 0.68) and those who were normotensive were less likely to develop T2D than those who were hypertensive (OR = 0.39, 95%CI = 0.29, 0.51). Compared to participants with insufficient PA and who were hypertensive, those with sufficient PA and hypertension were at lower risk of developing T2D (OR = 0.36, 95%CI = 0.19, 0.69), as were those with insufficient PA who were normotensive (OR = 0.37, 95%CI = 0.28, 0.50) and those with sufficient PA who were normotensive (OR = 0.19, 95%CI = 0.10, 0.37).Insufficient PA was found to be associated with the development of T2D among adults with and without hypertension. These findings support a role for promoting higher physical activity levels to lower T2D risk in both hypertensive and non-hypertensive individuals.
| S-EPMC3923808 | biostudies-other
Project description:Large population-based studies investigating the association of physical activity (PA) with the metabolite signature contribute significantly to the understanding of the effects of PA on metabolic pathways associated with the risk of type2 diabetes. Our study included 8749 Finnish men without diabetes at baseline recruited from the Metabolic Syndrome in Men (METSIM) cohort. We used a questionnaire to measure leisure-time PA. Metabolites were measured in 7271 men as a part of Metabolon's untargeted Discovery HD4 platform using ultrahigh-performance liquid chromatography-tandem mass spectrometry. We found 198 metabolites significantly associated with PA. Several of these metabolites were novel including especially steroids, amino acids, imidazoles, carboxylic acids, and hydroxy acids. Increased PA was significantly associated with high levels of choline plasmalogens, lysophosphatidylcholines, polyunsaturated fatty acids, carotenoids, long chain acylcarnitines, imidazoles, bilirubins, aryl sulfates, hydroxy acids, indolepropionate, and indolelactate. Several of these metabolites have been previously associated with a decreased risk of type 2 diabetes and with a healthy diet. Our population-based study shows that the metabolite signature of increased PA includes multiple metabolic pathways and is associated with better adherence to a healthy lifestyle.
| S-EPMC8779070 | biostudies-literature
Project description:ObjectiveTo evaluate whether the genetic susceptibility of T2D was associated with overall survival (OS) and disease-free survival (DFS) outcomes for breast cancer (BC).MethodsIncluded in the study were 6346 BC patients who participated in three population-based epidemiological studies of BC and were genotyped with either GWAS or Exome-chip. We constructed a genetic risk score (GRS) for diabetes using risk variants identified from the GWAS catalog (http://genome.gov/gwastudies) that were associated with T2D risk at a minimum significance level of P ≤ 5.0E-8 among Asian population and evaluated its associations with BC outcomes with Cox proportional hazards models.ResultsDuring a median follow-up of 8.08 years (range, 0.01-16.95 years), 1208 deaths were documented in 6346 BC patients. Overall, the diabetes GRS was not associated with OS and DFS. Analyses stratified by estrogen receptor status (ER) showed that the diabetes GRS was inversely associated with OS among women with ER- but not in women with ER+ breast cancer; the multivariable adjusted HR was 1.38 (95% CI: 1.05-1.82) when comparing the highest to the lowest GRS quartiles. The association of diabetes GRS with OS varied by diabetes status (P for interaction <0.01). In women with history of diabetes, higher diabetes GRS was significantly associated with worse OS, with HR of 2.22 (95% CI: 1.28-3.88) for the highest vs. lowest quartile, particularly among women with an ER- breast cancer, with corresponding HR being 4.59 (95% CI: 1.04-20.28). No significant association between the diabetes GRS and OS was observed across different BMI and PR groups.ConclusionsOur study suggested that genetic susceptibility of T2D was positively associated with total mortality among women with ER- breast cancer, particularly among subjects with a history of diabetes. Additional studies are warranted to verify the associations and elucidate the underlying biological mechanism.
| S-EPMC4332504 | biostudies-literature
Project description:High body iron store has been associated with an increased risk of type 2 diabetes (T2D); it remains unknown whether the genetic variants related to body iron status affect T2D risk. We aimed at comprehensively investigating the associations between the genetic variants related to body iron status and the T2D risk.Six common SNPs related to body iron status from recent genome-wide association (GWA) studies were determined in the Nurses' Health Study (NHS; 1,467 diabetic cases and 1,754 controls) and the Health Professionals Follow-up Study (HPFS; 1,124, diabetic cases and 1,298 controls). Plasma levels of ferritin, soluble transferrin receptor (sTfR), and transferrin were measured in NHS. Significant associations were observed for loci in TPMRSS6 with sTfR (P?=?3.47×10(-6)), TF with transferrin (P?=?0.0002 to 1.72×10(-10)); and HFE with ferritin (P?=?0.017 to 1.6×10(-8)), sTfR (P?=?0.007 to 7.9×10(-6)), and transferrin (P?=?0.006 to 0.0007). The six SNPs together explained 5.7%, 2.7%, and 13.3% of the variation in plasma levels of ferritin, sTfR, and transferrin. After adjustment for the conventional risk factors, the T allele of SNP rs855791 in the TPMRSS6 gene was significantly associated with a 19% decreased risk of T2D (OR?=?0.81; 95% CI?=?0.66-0.98; P?=?0.03) in men. Multiple tests attenuated this significant association to null. No associations were observed in women. SNPs at HFE and TF were not associated with diabetes risk in either sex. Dietary iron intake did not modify the associations of the newly identified loci with diabetes risk.The newly identified iron-related SNP rs855791 in TPMRSS6 was nominally associated with a decreased risk of T2D in men but not in women. The apparent differences by gender warrant further study.
| S-EPMC3397952 | biostudies-literature
Project description:ImportancePolygenic risk scores (PRS) for type 2 diabetes (T2D) can improve risk prediction for gestational diabetes (GD), yet the strength of the association between genetic and lifestyle risk factors has not been quantified.ObjectiveTo assess the association of PRS and physical activity in existing GD risk models and identify patient subgroups who may receive the most benefits from a PRS or physical activity intervention.Design, settings, and participantsThe Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort was established to study individuals without previous pregnancy lasting at least 20 weeks (nulliparous) and to elucidate factors associated with adverse pregnancy outcomes. A subcohort of 3533 participants with European ancestry was used for risk assessment and performance evaluation. Participants were enrolled from October 5, 2010, to December 3, 2013, and underwent genotyping between February 19, 2019, and February 28, 2020. Data were analyzed from September 15, 2020, to November 10, 2021.ExposuresSelf-reported total physical activity in early pregnancy was quantified as metabolic equivalents of task (METs). Polygenic risk scores were calculated for T2D using contributions of 84 single nucleotide variants, weighted by their association in the Diabetes Genetics Replication and Meta-analysis Consortium data.Main outcomes and measuresEstimation of the development of GD from clinical, genetic, and environmental variables collected in early pregnancy, assessed using measures of model discrimination. Odds ratios and positive likelihood ratios were used to evaluate the association of PRS and physical activity with GD risk.ResultsA total of 3533 women were included in this analysis (mean [SD] age, 28.6 [4.9] years). In high-risk population subgroups (body mass index ≥25 or aged ≥35 years), individuals with high PRS (top 25th percentile) or low activity levels (METs <450) had increased odds of a GD diagnosis of 25% to 75%. Compared with the general population, participants with both high PRS and low activity levels had higher odds of a GD diagnosis (odds ratio, 3.4 [95% CI, 2.3-5.3]), whereas participants with low PRS and high METs had significantly reduced risk of a GD diagnosis (odds ratio, 0.5 [95% CI, 0.3-0.9]; P = .01).Conclusions and relevanceIn this cohort study, the addition of PRS was associated with the stratified risk of GD diagnosis among high-risk patient subgroups, suggesting the benefits of targeted PRS ascertainment to encourage early intervention.
| S-EPMC9428742 | biostudies-literature
Project description:Aims/hypothesisWe examined the independent and combined associations of physical activity and obesity with incident type 2 diabetes in men and women.MethodsThe InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a randomly selected subcohort of 16,154 individuals, drawn from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. Physical activity was assessed by a four-category index. Obesity was measured by BMI and waist circumference (WC). Associations between physical activity, obesity and case-ascertained incident type 2 diabetes were analysed by Cox regression after adjusting for educational level, smoking status, alcohol consumption and energy intake. In combined analyses, individuals were stratified according to physical activity level, BMI and WC.ResultsA one-category difference in physical activity (equivalent to approximately 460 and 365 kJ/day in men and women, respectively) was independently associated with a 13% (HR 0.87, 95% CI 0.80, 0.94) and 7% (HR 0.93, 95% CI 0.89, 0.98) relative reduction in the risk of type 2 diabetes in men and women, respectively. Lower levels of physical activity were associated with an increased risk of diabetes across all strata of BMI. Comparing inactive with active individuals, the HRs were 1.44 (95% CI 1.11, 1.87) and 1.38 (95% CI 1.17, 1.62) in abdominally lean and obese inactive men, respectively, and 1.57 (95% CI 1.19, 2.07) and 1.19 (95% CI 1.01, 1.39) in abdominally lean and obese inactive women, respectively.Conclusions/interpretationPhysical activity is associated with a reduction in the risk of developing type 2 diabetes across BMI categories in men and women, as well as in abdominally lean and obese men and women.
| S-EPMC3369127 | biostudies-literature
Project description:Physical activity (PA) has been linked to a reduced risk of type 2 diabetes by reducing weight and improving insulin sensitivity. We investigated whether PA is associated with a lower incidence of latent autoimmune diabetes in adults (LADA) and whether the association is modified by genotypes of human leukocyte antigen (HLA), transcription factor 7-like 2 (TCF7L2)-rs7903146, or the fat mass and obesity-associated gene, FTO-rs9939609. We combined data from a Swedish case-control study and a Norwegian prospective study including 621 incident cases of LADA and 3596 cases of type 2 diabetes. We estimated adjusted pooled relative risks (RRs) and 95% CI of diabetes in relation to high (≥ 30 minutes of moderate activity 3 times/week) self-reported leisure time PA, compared to sedentariness. High PA was associated with a reduced risk of LADA (RR 0.61; CI, 0.43-0.86), which was attenuated after adjustment for body mass index (BMI) (RR 0.90; CI, 0.63-1.29). The reduced risk applied only to noncarriers of HLA-DQB1 and -DRB1 (RR 0.49; CI, 0.33-0.72), TCF7L2 (RR 0.62; CI, 0.45-0.87), and FTO (RR 0.51; CI, 0.32-0.79) risk genotypes. Adjustment for BMI attenuated but did not eliminate these associations. For type 2 diabetes, there was an inverse association with PA (RR 0.49; CI, 0.42-0.56), irrespective of genotype. Our findings indicate that high PA is associated with a reduced risk of LADA in individuals without genetic susceptibility.
| S-EPMC7947966 | biostudies-literature