Coronary Heart Disease in Type 2 Diabetes Mellitus: Genetic Factors and Their Mechanisms, Gene-Gene, and Gene-Environment Interactions in the Asian Populations.
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ABSTRACT:
SUBMITTER: Zarkasi KA
PROVIDER: S-EPMC8775550 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Fifteen SNPs from nine different genes were genotyped on 1379 individuals, 758 T2DM patients and 621 controls, from the city of Hyderabad, India, using Sequenom Massarray platform. These data were analyzed to examine the role of gene-gene and gene-environment interactions in the manifestation of T2DM. The multivariate analysis suggests that TCF7L2, CDKAL1, IGF2BP2, HHEX and PPARG genes are significantly associated with T2DM, albeit only the first two of the above 5 were associated in the univariate analysis. Significant gene-gene and gene-environment interactions were also observed with reference to TCF7L2, CAPN10 and CDKAL1 genes, highlighting their importance in the pathophysiology of T2DM. In the analysis for cumulative effect of risk alleles, SLC30A8 steps in as significant contributor to the disease by its presence in all combinations of risk alleles. A striking difference between risk allele categories, 1-4 and 5-6, was evident in showing protective and susceptible roles, respectively, while the latter was characterized by the presence of TCF7L2 and CDKAL1 variants. Overall, these two genes TCF7L2 and CDKAL1 showed strong association with T2DM, either individually or in interaction with the other genes. However, we need further studies on gene-gene and gene-environment interactions among heterogeneous Indian populations to obtain unequivocal conclusions that are applicable for the Indian population as a whole.
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Project description:Uncovering the interaction between genomes and the environment is a principal challenge of modern genomics and preventive medicine. While theoretical models are well defined, little is known of the G?×?E interactions in humans. We used an integrative approach to comprehensively assess the interactions between 1.6 million data points, encompassing a range of environmental exposures, health, and gene expression levels, coupled with whole-genome genetic variation. From ?1000 individuals of a founder population in Quebec, we reveal a substantial impact of the environment on the transcriptome and clinical endophenotypes, overpowering that of genetic ancestry. Air pollution impacts gene expression and pathways affecting cardio-metabolic and respiratory traits, when controlling for genetic ancestry. Finally, we capture four expression quantitative trait loci that interact with the environment (air pollution). Our findings demonstrate how the local environment directly affects disease risk phenotypes and that genetic variation, including less common variants, can modulate individual's response to environmental challenges.
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Project description:ObjectiveAmong northeast Asians, the variant aldehyde dehydrogenase allele, ALDH2*2 (rs671, A/G, minor/major), has been inversely associated with alcohol dependence. The strength of the associations between ALDH2*2 and drinking behaviors depends on the developmental stage, the phenotype studied, and other moderating variables. This study examined ALDH2 gene status as a moderator of the associations between parental drinking, peer drinking, and acculturation with alcohol use among 222 Chinese American and Korean American college freshmen.MethodNegative binomial regressions were used to test the main and interactive effects of ALDH2 with contextual factors on alcohol frequency (drinking days) and quantity (drinks per drinking day) in the past 3 months.ResultsALDH2*2 was associated with more subjective flushing symptoms and longer length of flushing but was unrelated to both alcohol frequency and quantity. Peer drinking was positively associated with both alcohol frequency and quantity, but neither was moderated by ALDH2. We observed a nonsignificant trend for the interaction between parental drinking and ALDH2 on alcohol frequency, where parental drinking was positively associated with alcohol frequency only among participants with ALDH2*2. We found a significant interaction between acculturation and ALDH2 on alcohol frequency, where acculturation was positively associated with alcohol frequency only among those with ALDH2*2. Exploratory analyses stratified by Asian ethnic subgroup indicated that this interaction was driven primarily by the Korean subsample.ConclusionsParental drinking and acculturation may facilitate more frequent drinking among those who have more intense reactions to alcohol (i.e., those with ALDH2*2) during the transition from high school to college.
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Project description:GWAS and eQTL studies identified thousands of genetic variants associated with complex traits and gene expression. Despite the important role of environmental exposures in complex traits, only a limited number of environmental factors were measured in these studies. Measuring molecular phenotypes in tightly controlled cellular environments provides a more tractable setting to study gene-environment interactions in the absence of other confounding variables. We performed RNA-seq and ATAC-seq in endothelial cells exposed to retinoic acid, dexamethasone, caffeine, and selenium to model genetic and environmental effects on gene regulation in the vascular endothelium-a common site of pathology in cardiovascular disease. We found that genes near regions of differentially accessible chromatin were more likely to be differentially expressed [OR = (3.41, 6.52), [Formula: see text]]. Furthermore, we confirmed that environment-specific changes in transcription factor binding are a key mechanism for cellular response to environmental stimuli. Single nucleotide polymorphisms (SNPs) in these transcription response factor footprints for dexamethasone, caffeine, and retinoic acid were enriched in GTEx eQTLs from artery tissues, indicating that these environmental conditions are latently present in GTEx samples. Additionally, SNPs in footprints for response factors in caffeine are enriched in colocalized eQTLs for coronary artery disease (CAD), suggesting a role for caffeine in CAD risk. By combining GWAS, eQTLs, and response genes, we annotated environmental components that can increase or decrease disease risk through changes in gene expression in 43 genes. Interestingly, each treatment may amplify or buffer genetic risk for CAD, depending on the particular SNP or gene considered.
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Project description:ObjectiveTo investigate whether women with congenital heart defect (CHD)-affected pregnancies were more likely to have functional single-nucleotide polymorphisms in genes encoding enzymes in folate-dependent pathways.MethodsA population-based case-control study of 572 women with CHD-affected pregnancies and 363 women in the control group was conducted. DNA samples were genotyped for single-nucleotide polymorphisms in three genes encoding for folate pathway enzymes. Maternal lifestyle factor information was obtained using standardized interviews.ResultsWomen in the case group were 1.5 times more likely to be obese (body mass index of 30 or higher) compared with those in the control group. Obese women carrying the MTHFR TT genotype were 4.6 times more likely to have an affected pregnancy compared with normal-weight women carrying a CC genotype. Obese women carrying one or two copies of the A allele in the BHMT polymorphism were 1.8 times more likely to have a CHD-affected pregnancy than were normal-weight women carrying a BHMT GG genotype. Among women who smoked, those carrying a TCII CG or GG genotype were 1.8 times more likely to have an affected fetus than were women who smoked and carried a CC genotype. Among women who drank alcohol, those carrying a TCII CG or GG genotype were 1.7 times more likely to have an affected fetus than were women who drank and carried a CC genotype.ConclusionResults indicate that functional polymorphisms in folate-related genes increase the risk of having a fetus with CHD when maternal lifestyle factors that alter folate metabolism are present.Level of evidenceII.
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Project description:Diabetes mellitus and heart failure are two multifaceted entities characterised by high morbidity and mortality. Early epidemiological and prospective studies have observed the frequent co-existence of both conditions. Importantly, diabetes mellitus can precipitate or worsen heart failure due to the accumulation of advanced glycation end products, oxidative stress, inflammatory status impairment, decay of intracellular calcium, changes in microRNAs expression, not to mention atherosclerosis progression and coronary artery disease. Heart failure also impairs glucose metabolism through less well-known mechanisms. Attention must especially be given in the treatment as there are frequently adverse interactions between the two diseases and novel agents against diabetic cardiomyopathy are under investigation. As several missing links still exist in the connection between heart failure and diabetes mellitus we will review, in this article, the most recent data underlying the interaction of them and provide an overview of the most important clinical perspectives.
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Project description:Coronary artery disease (CAD) is a common complication of Type 2 diabetes mellitus (T2DM). Understanding the pathogenesis of this complication is essential in both diagnosis and management. Thus, this study aimed to characterize the presence of CAD in T2DM using molecular markers and pathway analyses. Total RNA from peripheral blood mononuclear cells (PBMCs) underwent whole transcriptomic profiling using the Illumina HumanHT-12 v4.0 expression beadchip. Differential gene expression with gene ontogeny analyses was performed, with supporting correlational analyses using weighted correlation network analysis (WGCNA)
2024-03-01 | GSE250283 | GEO
Project description:BACKGROUND:Type 2 Diabetes Mellitus (T2DM) and Gestational Diabetes Mellitus (GDM) are part of a heterogeneous and complex metabolic group of disorders that share common pathophysiological circumstances, including ?-cell dysfunction and insulin resistance. The protein Calpain 10 (CAPN10) plays a role in glucose metabolism, pancreatic ?-cell insulin secretion, and thermogenesis. OBJECTIVE:Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) based genotyping of CAPN10 (rs2975760) polymorphism was carried out in T2DM and GDM with suitable controls for each of the pathologies from the same population. Genomic DNA was isolated from 787 participants, including 250 cases of T2DM, 287 pregnant women, of which 137 were identified as having GDM and the remaining 150 were confirmed as non-GDM, and 250 healthy control volunteers, and association analysis was carried out for genotypes and alleles. RESULTS:In the present study, T2DM was compared with healthy controls and was not found to be associated with the CAPN10 C allele (odds ratio, OR: 1.09; 95% CI = 0.8011-1.484; p = 0.5821). GDM also did not show any association when compared with non-GDM (OR: 1.124; 95% CI = 0.7585-1.667; p = 0.5606) respectively. CONCLUSION:Our study suggests that the CAPN10 (rs2975760) polymorphism scrutinized in this study is not associated with T2DM and GDM.
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Project description:Aims/hypothesisSleep duration is a risk factor for incident diabetes mellitus and CHD. The primary aim of the present study was to investigate, in sex-specific analyses, the role of incident diabetes as the possible biological mechanism for the reported association between short/long sleep duration and incident CHD. Considering that diabetes is a major risk factor for CHD, we hypothesised that any association with sleep duration would not hold for cases of incident CHD occurring before incident diabetes ('non-diabetes CHD') but would hold true for cases of incident CHD following incident diabetes ('diabetes-CHD').MethodsA total of 6966 men and 9378 women aged 45-73 years from the Malmö Diet Cancer Study, a population-based, prospective cohort, who had answered questions on habitual sleep duration and did not have a history of prevalent diabetes or CHD were included in the analyses. Incident cases of diabetes and CHD were identified using national registers. Sex-specific Cox proportional hazards regression models were stratified by BMI and adjusted for known covariates of diabetes and CHD.ResultsMean follow-up times for incident diabetes (n = 1137/1016 [men/women]), incident CHD (n = 1170/578), non-diabetes CHD (n = 1016/501) and diabetes-CHD (n = 154/77) were 14.2-15.2 years for men, and 15.8-16.5 years for women. In men, short sleep duration (< 6 h) was associated with incident diabetes (HR 1.35, 95% CI 1.01, 1.80), CHD (HR 1.41, 95% CI 1.06, 1.89) and diabetes-CHD (HR 2.34, 95% CI 1.20, 4.55). Short sleep duration was not associated with incident non-diabetes CHD (HR 1.35, 95% CI 0.98, 1.87). Long sleep duration (≥ 9 h) was associated with incident diabetes (HR 1.37, 95% CI 1.03, 1.83), CHD (HR 1.33, 95% CI 1.01, 1.75) and diabetes-CHD (HR 2.10, 95% CI 1.11, 4.00). Long sleep duration was not associated with incident non-diabetes CHD (HR 1.33, 95% CI 0.98, 1.80). In women, short sleep duration was associated with incident diabetes (HR 1.53, 95% CI 1.16, 2.01), CHD (HR 1.46, 95% CI 1.03, 2.07) and diabetes-CHD (HR 2.88, 95% CI 1.37, 6.08). Short sleep duration was not associated with incident non-diabetes CHD (HR 1.29, 95% CI 0.86, 1.93).Conclusions/interpretationThe associations between sleep duration and incident CHD directly reflect the associations between sleep duration and incident diabetes. Incident diabetes may thus be the explanatory mechanism for the association between short and long sleep duration and incident CHD.
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