Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus.
Ontology highlight
ABSTRACT:
SUBMITTER: Pang H
PROVIDER: S-EPMC8086251 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
| S-EPMC4311266 | biostudies-literature
Project description:Despite thousands of genetic loci identified to date, a large proportion of genetic variation predisposing to complex disease and traits remains unaccounted for. Advances in sequencing technology enable focused explorations on the contribution of low-frequency and rare variants to human traits. Here we review experimental approaches and current knowledge on the contribution of these genetic variants in complex disease and discuss challenges and opportunities for personalised medicine.
| S-EPMC5408830 | biostudies-literature
Project description:SIRT1 has been demonstrated in nutrient-sensing and insulin-signaling pathways in in vivo and in vitro experiments, but there is minimal information concerning the association between gene polymorphisms of SIRT1 and type 2 diabetes mellitus (T2DM) in a Chinese Han population. Using case-control design, we recruited 310 unrelated T2DM patients from inpatients at Shanghai Jiao Tong University Affiliated Sixth People's Hospital, while 301 healthy controls were volunteers from the community for regular medical checkup. All participants were genotyped within the SIRT1 region. The following five SNPs rs10509291, rs12778366, rs10997870, rs10823112, and rs4746720 cover 100% of common genetic variations (minor allele frequency≥0.05) within the SIRT1 gene (r2≥0.8). The genotypes of SIRT1 gene polymorphisms were analyzed by the Snapshot assay and DNA sequencing. The resulting data show that there was significant genetic differentiation in rs10823112 [p=0.003; OR (95% CI)=1.515 (1.152-1.994) for genotype], rs4746720 [p=0.024; OR (95% CI)=1.37 (1.037-1.674) for genotype], and rs10509291 [p=0.002; OR (95% CI)=1.551 (1.179-2.04) for genotype] between T2DM and control subjects. However, the result of rs4746720 was no longer significant after correction for multiple testing (p after Bonferroni correction=0.12); the results of rs10509291and rs10823112 were still significantly different between the two groups (p after Bonferroni correction=0.01 and 0.015, respectively). Linear regression analyses adjusting for age, gender, and body mass index (BMI) showed that HbA1c and HOMA-IR in subjects with rs10509291 AA genotype were higher than those with TT genotype in T2DM group (p=0.045, p=0.035, respectively). Together, our data show that genetic variation of the SIRT1 gene is related to insulin resistance and increase risk of T2DM in Chinese Han population. The risk allele A at SIRT1 rs10509291 was closely associated with T2DM, and subjects who were homozygous of the A allele were more likely to develop T2DM.
| S-EPMC8750030 | biostudies-literature
Project description:BackgroundPPP1R3B has been suggested as a candidate gene for monogenic forms of diabetes as well as type 2 diabetes (T2D) due to its association with glycaemic trait and its biological role in glycogen synthesis.ObjectivesTo study if rare missense variants in PPP1R3B increase the risk of maturity onset diabetes of the young (MODY), T2D or affect measures of glucose metabolism.MethodTargeted resequencing of PPP1R3B was performed in 8,710 samples; MODY patients with unknown etiology (n = 54), newly diagnosed patients with T2D (n = 2,930) and population-based control individuals (n = 5,726, of whom n = 4,569 had normal glucose tolerance). All population-based sampled individuals were examined using an oral glucose tolerance test.ResultsAmong n = 396 carriers, we identified twenty-three PPP1R3B missense mutations, none of which segregated with MODY. The burden of likely deleterious PPP1R3B variants was significantly increased with a total of 17 carriers among patients with T2D (0.58% (95% CI: 0.36-0.93)) compared to 18 carriers among non-diabetic individuals (0.31% (95% CI: 0.20-0.49)), resulting in an increased risk of T2D (OR (95% CI) = 2.57 (1.14-5.79), p = 0.02 (age and sex adjusted)). Furthermore, carriers with diabetes had less abdominal fat and a higher serum concentration of LDL-cholesterol compared to patients with T2D without rare missense PPP1R3B variants. In addition, non-diabetic carriers had a higher birth weight compared to non-carriers.ConclusionRare missense PPP1R3B variants may predispose to T2D.
| S-EPMC6328241 | biostudies-literature
Project description:Next Generation Sequencing (NGS) has uncovered hundreds of common and rare genetic variants involved in complex and rare diseases including immune deficiencies in both an autosomal recessive and autosomal dominant pattern. These rare variants however, cannot be classified clinically, and common variants only marginally contribute to disease susceptibility. In this study, we evaluated the multi-gene panel results of Common Variable Immunodeficiency (CVID) patients and argue that rare variants located in different genes play a more prominent role in disease susceptibility and/or etiology. We performed NGS on DNA extracted from the peripheral blood leukocytes from 103 patients using a panel of 19 CVID-related genes: CARD11, CD19, CD81, ICOS, CTLA4, CXCR4, GATA2, CR2, IRF2BP2, MOGS, MS4A1, NFKB1, NFKB2, PLCG2, TNFRSF13B, TNFRSF13C, TNFSF12, TRNT1 and TTC37. Detected variants were evaluated and classified based on their impact, pathogenicity classification and population frequency as well as the frequency within our study group. NGS revealed 112 different (a total of 227) variants with under 10% population frequency in 103 patients of which 22(19.6%) were classified as benign, 29(25.9%) were classified as likely benign, 4(3.6%) were classified as likely pathogenic and 2(1.8%) were classified as pathogenic. Moreover, 55(49.1%) of the variants were classified as variants of uncertain significance. We also observed different variant frequencies when compared to population frequency databases. Case-control data is not sufficient to unravel the genetic etiology of immune deficiencies. Thus, it is important to understand the incidence of co-occurrence of two or more rare variants to aid in illuminating their potential roles in the pathogenesis of immune deficiencies.
| S-EPMC8050305 | biostudies-literature
Project description:Most replicated genetic determinants for type 1 diabetes are common (minor allele frequency [MAF] >5%). We aimed to identify novel rare or low-frequency (MAF <5%) single nucleotide polymorphisms with large effects on risk of type 1 diabetes. We undertook deep imputation of genotyped data followed by genome-wide association testing and meta-analysis of 9,358 type 1 diabetes case and 15,705 control subjects from 12 European cohorts. Candidate variants were replicated in a separate cohort of 4,329 case and 9,543 control subjects. Our meta-analysis identified 27 independent variants outside the MHC, among which 3 were novel and had MAF <5%. Three of these variants replicated with P replication < 0.05 and P combined < P discovery In silico analysis prioritized a rare variant at 2q24.3 (rs60587303 [C], MAF 0.5%) within the first intron of STK39, with an effect size comparable with those of common variants in the INS and PTPN22 loci (combined [from the discovery and replication cohorts] estimate of odds ratio [ORcombined] 1.97, 95% CI 1.58-2.47, P combined = 2.9 × 10-9). Pharmacological inhibition of Stk39 activity in primary murine T cells augmented effector responses through enhancement of interleukin 2 signaling. These findings provide insight into the genetic architecture of type 1 diabetes and have identified rare variants having a large effect on disease risk.
| S-EPMC7085253 | biostudies-literature
Project description:It has recently been suggested that the low-frequency c.136-14_136-13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136-14_136-13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136-14_136-13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease.
| S-EPMC3266400 | biostudies-literature
Project description:OBJECTIVES/SPECIFIC AIMS: This study aims to identify genetic biomarkers of GDM and facilitate the understanding of its molecular underpinnings. METHODS/STUDY POPULATION: We identified a cohort of mothers diagnosed with GDM in our longitudinal birth study by mining Electronic Health Records of participants utilizing PheCode map with ICD-9 and ICD-10 codes. We verified each case using ACOG’s GDM diagnosis criteria. RESULTS/ANTICIPATED RESULTS: Whole genome sequencing (WGS) data were available for 111 confirmed cases (out of 205) and 706 controls (out of 1,429) from different ancestries (412 EUR, 256 AMR, 56 EAS, 26 SAS and 18 AFR; 49 OTHER). SAS had the highest incidence of GDM at 38.46% and EUR had the lowest at 6.55%. We performed logistic regression using computed ancestry, age and BMI as covariates to determine if any variants are associated with GDM. The top variant (rs139014401) was found in an intron of DFFB gene, which is p53-bound and regulates DNA fragmentation during apoptosis. We will investigate the robustness of 49 identified variants and will separate the cohort by ancestry to detect population-specific differences in the top loci. DISCUSSION/SIGNIFICANCE OF IMPACT: Identification of molecular biomarkers in GDM across different ancestral backgrounds will address a gap in current GDM research. Findings may enhance screening and enable clinicians to identify those at risk for developing GDM earlier in the pregnancy. Early management of mothers at risk may lead to better health outcomes for mother and baby.
| S-EPMC6808337 | biostudies-literature
Project description:Type 1 diabetes (T1D) is a chronic metabolic disorder characterized by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically predisposed individuals. Genome-wide association studies (GWAS) have identified over 60 risk regions across the human genome, marked by single nucleotide polymorphisms (SNPs), which confer genetic predisposition to T1D. There is increasing evidence that disease-associated SNPs can alter gene expression through spatial interactions that involve distal loci, in a tissue- and development-specific manner. Here, we used three-dimensional (3D) genome organization data to identify genes that physically co-localized with DNA regions that contained T1D-associated SNPs in the nucleus. Analysis of these SNP-gene pairs using the Genotype-Tissue Expression database identified a subset of SNPs that significantly affected gene expression. We identified 246 spatially regulated genes including HLA-DRB1, LAT, MICA, BTN3A2, CTLA4, CD226, NOTCH1, TRIM26, PTEN, TYK2, CTSH, and FLRT3, which exhibit tissue-specific effects in multiple tissues. We observed that the T1D-associated variants interconnect through networks that form part of the immune regulatory pathways, including immune-cell activation, cytokine signaling, and programmed cell death protein-1 (PD-1). Our results implicate T1D-associated variants in tissue and cell-type specific regulatory networks that contribute to pancreatic beta cell inflammation and destruction, adaptive immune signaling, and immune-cell proliferation and activation. A number of other regulatory changes we identified are not typically considered to be central to the pathology of T1D. Collectively, our data represent a novel resource for the hypothesis-driven development of diagnostic, prognostic, and therapeutic interventions in T1D.
| S-EPMC6258722 | biostudies-literature
Project description:BackgroundSeveral studies have reported the association of PTPN2 gene with type 1 diabetes mellitus (T1DM) in many populations but not in the Chinese Han population. Therefore, the goal of our study was to replicate the reported association between 2 single-nucleotide polymorphisms (SNPs; rs478582 and rs2542151) in the PTPN2 gene and T1DM in Chinese Han children.Material and methodsThis case-control study included 141 Chinese Han children with T1DM and 282 healthy controls. Genetic variants of rs478582 and rs2542151 in PTPN2 gene were performed by PCR amplification followed by restriction fragment length polymorphism method.ResultsNo difference was observed in association of rs478582 in The PTPN2 gene and T1DM. The distribution of allele frequency of rs2542151 differed significantly between T1DM patients and healthy controls (OR, 0.6; 95%CI: 0.44 to 0.95; and P=0.024). Dominant model of rs254215 also was associated with T1DM (OR, 0.6; 95%CI: 0.40 to 0.96; and P=0.032). Younger age at onset in G carriers appeared to increase the risk for T1DM (P=0.030).ConclusionsThe findings suggested that rs2542151 SNP in The PTPN2 gene was associated with T1DM in Chinese Han children. Further studies with larger sample sizes involving gene-gene interactions are urgently needed.
| S-EPMC4566944 | biostudies-literature