Rare Genetic Variants of Large Effect Influence Risk of Type 1 Diabetes.
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ABSTRACT:
SUBMITTER: Forgetta V
PROVIDER: S-EPMC7085253 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:While recently performed genome-wide association studies have advanced the identification of genetic variants predisposing to type 2 diabetes (T2D), the potential application of these novel findings for disease prediction and prevention has not been well studied. Diabetes prediction and prevention have become urgent issues owing to the rapidly increasing prevalence of diabetes and its associated mortality, morbidity, and health care cost. New prediction approaches using genetic markers could facilitate early identification of high risk sub-groups of the population so that appropriate prevention methods could be effectively applied to delay, or even prevent, disease onset.This paper assessed 18 recently identified T2D loci for their potential role in diabetes prediction. We built a new predictive genetic test for T2D using the Framingham Heart Study dataset. Using logistic regression and 15 additional loci, the new test was slightly improved over the existing test using just three loci. A formal comparison between the two tests suggests no significant improvement. We further formed a predictive genetic test for identifying early onset T2D and found higher classification accuracy for this test, not only indicating that these 18 loci have great potential for predicting early onset T2D, but also suggesting that they may play important roles in causing early-onset T2D.To further improve the test's accuracy, we applied a newly developed nonparametric method capable of capturing high order interactions to the data, but it did not outperform a logistic regression that only considers single-locus effects. This could be explained by the absence of gene-gene interactions among the 18 loci.
| S-EPMC2795948 | biostudies-literature
Project description:The conceptual basis for a genetic predisposition underlying the risk for developing type 1 diabetes (T1D) predates modern human molecular genetics. Over half of the genetic risk has been attributed to the human leukocyte antigen (HLA) class II gene region and to the insulin (INS) gene locus - both thought to confer direction of autoreactivity and tissue specificity. Notwithstanding, questions still remain regarding the functional contributions of a vast array of minor polygenic risk variants scattered throughout the genome that likely influence disease heterogeneity and clinical outcomes. Herein, we summarize the available literature related to the T1D-associated coding variants defined at the time of this review, for the genes PTPN22, IFIH1, SH2B3, CD226, TYK2, FUT2, SIRPG, CTLA4, CTSH and UBASH3A. Data from genotype-selected human cohorts are summarized, and studies from the non-obese diabetic (NOD) mouse are presented to describe the functional impact of these variants in relation to innate and adaptive immunity as well as to β-cell fragility, with expression profiles in tissues and peripheral blood highlighted. The contribution of each variant to progression through T1D staging, including environmental interactions, are discussed with consideration of how their respective protein products may serve as attractive targets for precision medicine-based therapeutics to prevent or suspend the development of T1D.
| S-EPMC8119379 | biostudies-literature
Project description:Although more than 20 genetic susceptibility loci have been reported for type 2 diabetes (T2D), most reported variants have small to moderate effects and account for only a small proportion of the heritability of T2D, suggesting that the majority of inter-person genetic variation in this disease remains to be determined. We conducted a multistage, genome-wide association study (GWAS) within the Asian Consortium of Diabetes to search for T2D susceptibility markers. From 590,887 SNPs genotyped in 1,019 T2D cases and 1,710 controls selected from Chinese women in Shanghai, we selected the top 2,100 SNPs that were not in linkage disequilibrium (r(2)<0.2) with known T2D loci for in silico replication in three T2D GWAS conducted among European Americans, Koreans, and Singapore Chinese. The 5 most promising SNPs were genotyped in an independent set of 1,645 cases and 1,649 controls from Shanghai, and 4 of them were further genotyped in 1,487 cases and 3,316 controls from 2 additional Chinese studies. Consistent associations across all studies were found for rs1359790 (13q31.1), rs10906115 (10p13), and rs1436955 (15q22.2) with P-values (per allele OR, 95%CI) of 6.49 × 10(-9) (1.15, 1.10-1.20), 1.45 × 10(-8) (1.13, 1.08-1.18), and 7.14 × 10(-7) (1.13, 1.08-1.19), respectively, in combined analyses of 9,794 cases and 14,615 controls. Our study provides strong evidence for a novel T2D susceptibility locus at 13q31.1 and the presence of new independent risk variants near regions (10p13 and 15q22.2) reported by previous GWAS.
| S-EPMC2940731 | biostudies-literature
Project description:We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10(-20)) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10(-13)). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10(-10)) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.
| S-EPMC4074058 | biostudies-literature
Project description:Type 1 diabetes mellitus (T1DM) is defined as an autoimmune disorder and has enormous complexity and heterogeneity. Although its precise pathogenic mechanisms are obscure, this disease is widely acknowledged to be precipitated by environmental factors in individuals with genetic susceptibility. To date, the known susceptibility loci, which have mostly been identified by genome-wide association studies, can explain 80%-85% of the heritability of T1DM. Researchers believe that at least a part of its missing genetic component is caused by undetected rare and low-frequency variants. Most common variants have only small to modest effect sizes, which increases the difficulty of dissecting their functions and restricts their potential clinical application. Intriguingly, many studies have indicated that rare and low-frequency variants have larger effect sizes and play more significant roles in susceptibility to common diseases, including T1DM, than common variants do. Therefore, better recognition of rare and low-frequency variants is beneficial for revealing the genetic architecture of T1DM and for providing new and potent therapeutic targets for this disease. Here, we will discuss existing challenges as well as the great significance of this field and review current knowledge of the contributions of rare and low-frequency variants to T1DM.
| S-EPMC8086251 | biostudies-literature
Project description:Although prostate cancer is known to have a strong genetic basis and is influenced by both common and rare variants, the ability to investigate the combined effect of such genetic risk factors has been limited to date. We conducted an investigation of 81 094 men from the UK Biobank, including 3568 prostate cancer cases, to examine the combined effect of rare pathogenic/likely pathogenic/deleterious (P/LP/D) germline variants and common prostate cancer risk variants, measured using a polygenic risk score (PRS), on prostate cancer risk. The absolute risk of prostate cancer for HOXB13, BRCA2, ATM, and CHEK2 P/LP/D carriers ranged from 9% to 56%, and the absolute risk in noncarriers ranged from 2% to 31%, by age 85 yr, for men in the lowest and highest PRS decile, respectively. The high-penetrant HOXB13 G84E prostate cancer risk variant was most common in cases in the lowest PRS quintile (4.4%) and least common in cases in the highest PRS quintile (0.5%; p = 0.005), whereas there was no statistically significant difference in frequencies by PRS in controls. While rare and common variants strongly and distinctly influence prostate cancer onset, consideration of rare and common variants in conjunction will lead to more precise estimates of a man's lifetime risk of prostate cancer. PATIENT SUMMARY: We found that the risk of prostate cancer conveyed by rare variants could vary depending on an individual's genetic profile of common risk variants. This implies that in order to comprehensively assess genetic risk of prostate cancer, it is important to consider both rare and common variants.
| S-EPMC8286329 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have boosted our knowledge of genetic risk variants in autoimmune diseases (AIDs). Most of the risk variants are located within or near genes with immunological functions, and the majority is found to be non-coding, pointing towards a regulatory role. We have performed a cis expression quantitative trait locus (eQTL) screen to investigate whether single nucleotide polymorphisms (SNPs) associated with AIDs influence gene expression in thymus. Genotyping was performed using the Immunochip and 353 AID associated SNPs were tested against expression of surrounding genes (+/- 1 Mb) from human thymic tissue (N=42). We identified eight genes where the expression was associated with AID risk SNPs at a study-wide level of significance (P < 2.57x10-5). Five genes (FCRL3, RNASET2, C2orf74, SIRPG and SYS1) displayed cis eQTL signals also in other tissues, while for two loci (NPIPB8 and LOC388814), the eQTL signal appear to be thymus-specific. Since many AID risk variants from GWAS have been subsequently fine-mapped in recent Immunochip projects, we explored the overlap between these novel AID risk variants and the thymic eQTL regions. Moreover, we examined the functional annotation of the seven expression altering SNPs (eSNPs). Our study reveals autoimmune risk variants that act as eQTLs in thymus. We have highlighted functional variants within these genetic regions that potentially can represent causal autoimmune risk variants. Total RNA from 42 human thymic samples were obtained from children undergoing cardiac surgery.
2016-01-21 | E-GEOD-77052 | biostudies-arrayexpress
Project description:Type 2 diabetes mellitus incidence is increased in HIV-infected persons. We examined the associations of diabetes mellitus with known diabetes mellitus-risk alleles from the general population in the context of HIV infection, and explored effect modification by combination antiretroviral therapy (cART).The Women's Interagency HIV Study is a prospective cohort of HIV-infected women. Seventeen European-derived diabetes mellitus-risk polymorphisms were genotyped in the eligible participants of the Women's Interagency HIV Study. Analyses were run separately for non-African Americans (Whites, Hispanics, Asians, and other; n?=?378, 49 with incident diabetes mellitus) and African Americans (n?=?591, 49 with incident diabetes mellitus). Cox proportional-hazards models were fit to estimate hazard ratios for diabetes mellitus overall and within strata of cART.In non-African Americans, heterogeneity across cART regimen was observed for nine of the 14 polymorphisms (phet?<?0.05). One polymorphism was statistically significantly inversely associated with diabetes mellitus risk among women taking two nucleotide reverse transcriptase inhibitors (NRTIs) + non-nucleotide reverse transcriptase inhibitor (NNRTI). Five polymorphisms were statistically significantly associated with diabetes mellitus among women treated with at least two NRTIs?+?at least one protease inhibitor and one polymorphism was associated with diabetes mellitus among those treated with at least three NRTIs?±?NNRTI. The hazard ratio per risk allele for IGF2BP2 rs1470579 was 2.67 (95% confidence interval 1.67-4.31) for women taking cART with at least two NRTIs?+?at least one protease inhibitor and 2.45 (95% confidence interval 1.08-5.53) in women taking at least three NRTIs?±?NNRTI (phet?=?2.50?×?10?³). No such associations were observed in the African Americans.Genetic susceptibility to diabetes mellitus, based on the variants studied, is substantially elevated among HIV-infected women using cART containing three or more NRTI/protease inhibitor components. A personalized medicine approach to cART selection may be indicated for HIV-infected persons carrying these diabetes mellitus-risk variants.
| S-EPMC4269472 | biostudies-literature
Project description:OBJECTIVES:Genome-wide association studies have dramatically increased the number of common genetic variants that are robustly associated with type 2 diabetes. A possible clinical use of this information is to identify individuals at high risk of developing the disease, so that preventative measures may be more effectively targeted. Here, we assess the ability of 18 confirmed type 2 diabetes variants to differentiate between type 2 diabetic case and control subjects. RESEARCH DESIGN AND METHODS:We assessed index single nucleotide polymorphisms (SNPs) for the 18 independent loci in 2,598 control subjects and 2,309 case subjects from the Genetics of Diabetes Audit and Research Tayside Study. The discriminatory ability of the combined SNP information was assessed by grouping individuals based on number of risk alleles carried and determining relative odds of type 2 diabetes and by calculating the area under the receiver-operator characteristic curve (AUC). RESULTS:Individuals carrying more risk alleles had a higher risk of type 2 diabetes. For example, 1.2% of individuals with >24 risk alleles had an odds ratio of 4.2 (95% CI 2.11-8.56) against the 1.8% with 10-12 risk alleles. The AUC (a measure of discriminative accuracy) for these variants was 0.60. The AUC for age, BMI, and sex was 0.78, and adding the genetic risk variants only marginally increased this to 0.80. CONCLUSIONS:Currently, common risk variants for type 2 diabetes do not provide strong predictive value at a population level. However, the joint effect of risk variants identified subgroups of the population at substantially different risk of disease. Further studies are needed to assess whether individuals with extreme numbers of risk alleles may benefit from genetic testing.
| S-EPMC2570411 | biostudies-literature
Project description:Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives.
| S-EPMC5935235 | biostudies-literature