Structural basis of ethnic-specific variants of PAX4 associated with type 2 diabetes.
Ontology highlight
ABSTRACT:
SUBMITTER: Hosoe J
PROVIDER: S-EPMC8257626 | biostudies-literature | 2021 Jul
REPOSITORIES: biostudies-literature
Publications
Structural basis of ethnic-specific variants of PAX4 associated with type 2 diabetes.
Hosoe Jun J Suzuki Ken K Miya Fuyuki F Kato Takashi T Tsunoda Tatsuhiko T Okada Yukinori Y Horikoshi Momoko M Shojima Nobuhiro N Yamauchi Toshimasa T Kadowaki Takashi T
Human genome variation 20210705 1
Recently, we conducted genome-wide association studies of type 2 diabetes (T2D) in a Japanese population, which identified 20 novel T2D loci that were not associated with T2D in Europeans. Moreover, nine novel missense risk variants, such as those of PAX4, were not rare in the Japanese population, but rare in Europeans. We report in silico structural analysis of ethnic-specific variants of PAX4, which suggests the pathogenic effect of these variants. ...[more]
Similar Datasets
Project description:IntroductionEast Asians are more susceptible to early-onset diabetes than Europeans and exhibit reduced insulin secretion at earlier stages. PAX4 plays a critical role in the development of β-cells. The dysfunction-missense variants PAX4 R192H and PAX4 R192S are common in East Asians but rare in Europeans. Therefore, we aim to investigate the diabetes-associated genes, including PAX4 R192H/S, in East Asians with early-onset diabetes.MethodsExome variants of 80 Chinese early-onset diabetes patients (onset age < 35 years) after the exclusion of type 1 diabetes (T1D) were detected by a customized gene panel covering 32 known diabetes-associated genes. Then, 229 subjects with early-onset diabetes (T1D excluded) and 1679 controls from the Chinese population were genotyped to validate the association of PAX4 R192H/S with early-onset diabetes and related phenotypes.ResultsThe gene panel detected 11 monogenic diabetes patients with five novel mutations among the 80 early-onset diabetes patients. Asian-specifically enriched PAX4 R192H and R192S were associated with early-onset diabetes (R192H: OR 1.88, 95% CI 1.37-2.60, P = 8.41 × 10-5; R192S: OR 1.71, 95% CI 1.17-2.51, P = 0.005). In early-onset diabetes patients, PAX4 R192H carriers had higher haemoglobin A1c (HbA1c) levels (P = 0.030) and lower 2 h C-peptide levels in the oral glucose tolerance test (OGTT) (P = 0.040); R192S carriers had lower fasting C-peptide (FCP) (P = 0.011) and 2 h C-peptide levels (P = 0.033) in OGTT than non-variant carriers.ConclusionsThe ethnic-specific enrichment of PAX4 R192H/S predisposing East Asians to early-onset diabetes with decreased C-peptide levels may be one explanation of the discrepancy of diabetes between East Asians and Europeans.Clinical trial registrationClinicalTrials.gov (NCT01938365).
| S-EPMC7843779 | biostudies-literature
Project description:Paired box 4 (Pax4) is a key transcription factor involved in the embryonic development of the pancreatic islets of Langerhans. Consisting of a conserved paired box domain and a homeodomain, this transcription factor plays an essential role in early endocrine progenitor cells, where it is necessary for cell-fate commitment towards the insulin-secreting β cell lineage. Knockout of Pax4 in animal models leads to the absence of β cells, which is accompanied by a significant increase in glucagon-producing α cells, and typically results in lethality within days after birth. Mutations in Pax4 that cause an impaired Pax4 function are associated with diabetes pathogenesis in humans. In adulthood, Pax4 expression is limited to a distinct subset of β cells that possess the ability to proliferate in response to heightened metabolic needs. Upregulation of Pax4 expression is known to promote β cell survival and proliferation. Additionally, ectopic expression of Pax4 in pancreatic islet α cells or δ cells has been found to generate functional β-like cells that can improve blood glucose regulation in experimental diabetes models. Therefore, Pax4 represents a promising therapeutic target for the protection and regeneration of β cells in the treatment of diabetes. The purpose of this review is to provide a thorough and up-to-date overview of the role of Pax4 in pancreatic β cells and its potential as a therapeutic target for diabetes.
| S-EPMC10179455 | biostudies-literature
Project description:To reassess earlier suggested type I diabetes (T1D) associations of the insulin receptor substrate 1 (IRS1) and the paired domain 4 gene (PAX4) genes, the Type I Diabetes Genetics Consortium (T1DGC) evaluated single-nucleotide polymorphisms (SNPs) covering the two genomic regions. Sixteen SNPs were evaluated for IRS1 and 10 for PAX4. Both genes are biological candidate genes for T1D. Genotyping was performed in 2300 T1D families on both Illumina and Sequenom genotyping platforms. Data quality and concordance between the platforms were assessed for each SNP. Transmission disequilibrium testing neither show T1D association of SNPs in the two genes, nor did haplotype analysis. In conclusion, the earlier suggested associations of IRS1 and PAX4 to T1D were not supported, suggesting that they may have been false positive results. This highlights the importance of thorough quality control, selection of tagging SNPs, more than one genotyping platform in high throughput studies, and sufficient power to draw solid conclusions in genetic studies of human complex diseases.
| S-EPMC2804261 | biostudies-literature
Project description:The decrease of antibody efficacy to mutated SARS-CoV-2 spike RBD explains the breakthrough infections and reinfections by Omicron variants. Here, we analyzed broadly neutralizing antibodies isolated from long-term hospitalized convalescent patients of early SARS-CoV-2 strains. One of the antibodies named NCV2SG48 is highly potent to broad SARS-CoV-2 variants including Omicron BA.1, BA.2, and BA.4/5. To reveal the mode of action, we determined the sequence and crystal structure of the Fab fragment of NCV2SG48 in a complex with spike RBD from the original, Delta, and Omicron BA.1. NCV2SG48 is from a minor VH but the multiple somatic hypermutations contribute to a markedly extended binding interface and hydrogen bonds to interact with conserved residues at the core receptor-binding motif of RBD, which efficiently neutralizes a broad spectrum of variants. Thus, eliciting the RBD-specific B cells to the longitudinal germinal center reaction confers potent immunity to broad SARS-CoV-2 variants emerging one after another.
| S-EPMC10088672 | biostudies-literature
Project description:ObjectiveTo evaluate the Type 2 Diabetes (T2D) risk variants in the Pashtun ethnic population of Khyber Pakhtunkhwa using nascent whole-exome sequencing (WES) to better understand the pathogenesis of this complex polygenic disorder.MethodologyA total of 100 confirmed patients with T2D of Pashtun ethnicity were included in the study, DNA was extracted from whole blood samples, and paired-end libraries were prepared using the Illumina Nextera XT DNA library kit carefully following the manufacturer's instructions. Illumina HiSeq 2000 was used to obtain sequences of the prepared libraries followed by bioinformatics data analysis.ResultsA total of n=11 pathogenic/likely pathogenic variants were reported in the CAP10, PAX4, IRS-2, NEUROD1, CDKL1 and WFS1. Among the reported variants CAP10/rs55878652 (c.1990-7T>C; p.Leu446Pro) and CAP10/rs2975766 (c.1996A>G; p.Ile666Val) identified were novel, and have not yet been reported for any disease in the database.The variants CAP10/rs7607759 (c.1510A>G, p.Thr504Ala), PAX4/rs712701 (c.962A>C; p.His321Pro), PAX4/rs772936097 (c.748-3delT; p.Arg325Trp), IRS-2/rs1805097 (c.3170G>A; p.Gly1057Asp), NEUROD1/rs1801262 (c.133A>G; p.Thr45Ala), CDKL1/rs77152992 (c.1226C>T; p.Pro409Leu), WFS1/rs1801212 (c.997G>A; p.Val333Ile), WFS1/rs1801208 (c.1367G>A; p.Arg456His), and WFS1/rs734312 (c.1832G>A; p.Arg611His) are previously identified in other ethnic populations. Our study reconfirms the associations of these variants with T2D in the Pakistani Pashtun population.ConclusionIn-silico analysis of exome sequencing data suggests a statistically substantial association of all (n=11) identified variants with T2D in the Pashtun ethnic population. This study may serve as a foundation for performing future molecular studies aimed at unraveling T2D associated genes.
| S-EPMC10207872 | biostudies-literature
Project description:Type 2 diabetes (T2D) is a chronic systemic disease with a complex etiology, characterized by insulin resistance and mitochondrial dysfunction in various cell tissues. To explore this relationship, we conducted a secondary analysis of complete mtDNA sequences from 1261 T2D patients and 1105 control individuals. Our findings revealed significant associations between certain single-nucleotide polymorphisms (SNPs) and T2D. Notably, the variants m.1438A>G (rs2001030) (controls: 32 [27.6%], T2D: 84 [72.4%]; OR: 2.46; 95%CI: 1.64-3.78; p < 0.001), m.14766C>T (rs193302980) (controls: 498 [36.9%], T2D: 853 [63.1%]; OR: 2.57, 95%CI: 2.18-3.04, p < 0.001), and m.16519T>C (rs3937033) (controls: 363 [43.4%], T2D: 474 [56.6%]; OR: 1.24, 95%CI: 1.05-1.47, p = 0.012) were significantly associated with the likelihood of developing diabetes. The variant m.16189T>C (rs28693675), which has been previously documented in several studies across diverse populations, showed no association with T2D in our analysis (controls: 148 [13.39] T2D: 171 [13.56%]; OR: 1.03; 95%CI: 0.815-1.31; p = 0.83). These results provide evidence suggesting a link between specific mtDNA polymorphisms and T2D, possibly related to association rules, topological patterns, and three-dimensional conformations associated with regions where changes occur, rather than specific point mutations in the sequence.
| S-EPMC10670651 | biostudies-literature
Project description:AimsTo examine candidate insulin resistance single nucleotide polymorphisms (SNPs) for associations with glycemic control, insulin resistance, BMI, and complications in an observational type 1 diabetes (T1D) cohort: the Pittsburgh Epidemiology of Diabetes Complications (EDC) study.MethodsIn 422 European-ancestry participants, we assessed associations using additive models between 15 candidate SNPs and 25-year mortality, cardiovascular disease, microalbuminuria, overt nephropathy and proliferative retinopathy, and 25-year mean HbA1c, estimated glucose disposal rate (eGDR, inverse measure of insulin resistance), and BMI.ResultsThe A allele of rs12970134 was associated with higher mean HbA1c (β = +0.34 ± 0.09, p = 0.00009) and nominally associated with worse eGDR (p = 0.02). Further analyses suggest the HbA1c association may be modified by diabetes therapy regimen: rs12970134 AA genotype was associated with higher HbA1c under non-intensive therapy conditions (<3 insulin injections/day or monitoring blood glucose<3 times/day [p = 0.004]), but not under intensive therapy (≥3 injections/day or insulin pump and monitoring glucose≥3 times/day [p = 0.71]). There were no significant associations between any SNPs and BMI or complications.Conclusionsrs12970134, near MC4R, is strongly associated with HbA1c in this cohort. Further exploration of this genomic region is warranted, as it may hold promise for discovering new therapeutic targets to improve glycemic control in T1D.
| S-EPMC7936951 | biostudies-literature
Project description:The recent expansion of human genomics repositories has facilitated the discovery of novel TP53 variants in populations of different ethnic origins. Interpreting TP53 variants is a major clinical challenge because they are functionally diverse, confer highly variable predisposition to cancer (including elusive low-penetrance alleles), and interact with genetic modifiers that alter tumor susceptibility. Here, we discuss how a cancer risk continuum may relate to germline TP53 mutations on the basis of our current review of genotype-phenotype studies and an integrative analysis combining functional and sequencing datasets. Our study reveals that each ancestry contains a distinct TP53 variant landscape defined by enriched ethnic-specific alleles. In particular, the discovery and characterization of suspected low-penetrance ethnic-specific variants with unique functional consequences, including P47S (African), G334R (Ashkenazi Jewish), and rs78378222 (Icelandic), may provide new insights in terms of managing cancer risk and the efficacy of therapy. Additionally, our analysis highlights infrequent variants linked to milder cancer phenotypes in various published reports that may be underdiagnosed and require further investigation, including D49H in East Asians and R181H in Europeans. Overall, the sequencing and projected functions of TP53 variants arising within ethnic populations and their interplay with modifiers, as well as the emergence of CRISPR screens and AI tools, are now rapidly improving our understanding of the cancer susceptibility spectrum, leading toward more accurate and personalized cancer risk assessments.
| S-EPMC10560603 | biostudies-literature
Project description:Type 2 diabetes mellitus leads to debilitating complications that affect the quality of life of many Filipinos. Genetic variability contributes to 30% to 70% of T2DM risk. Determining genomic variants related to type 2 diabetes mellitus susceptibility can lead to early detection to prevent complications. However, interethnic variability in risk and genetic susceptibility exists. This study aimed to identify variants associated with type 2 diabetes mellitus among Filipinos using a case-control design frequency matched for age and sex. A comparison was made between 66 unrelated Filipino adults with type 2 diabetes mellitus and 121 without. Genotyping was done using a candidate gene approach on genetic variants of type 2 diabetes mellitus and its complications involving allelic association and genotypic association studies with correction for multiple testing. Nine (9) significant variants, mostly involved in glucose and energy metabolism, associated with type 2 diabetes mellitus in Filipinos were found. Notably, a CDKAL1 variant (rs7766070) confers the highest level of risk while rs7119 (HMG20A) and rs708272 (CETP) have high risk allele frequencies in this population at 0.77 and 0.66, respectively, making them potentially good markers for type 2 diabetes mellitus screening. The data generated can be valuable in developing genetic risk prediction models for type 2 diabetes mellitus to diagnose and prevent the condition among Filipinos.
| S-EPMC11575783 | biostudies-literature
Project description:It has been recently hypothesized that many of the signals detected in genome-wide association studies (GWAS) to T2D and other diseases, despite being observed to common variants, might in fact result from causal mutations that are rare. One prediction of this hypothesis is that the allelic associations should be population-specific, as the causal mutations arose after the migrations that established different populations around the world. We selected 19 common variants found to be reproducibly associated to T2D risk in European populations and studied them in a large multiethnic case-control study (6,142 cases and 7,403 controls) among men and women from 5 racial/ethnic groups (European Americans, African Americans, Latinos, Japanese Americans, and Native Hawaiians). In analysis pooled across ethnic groups, the allelic associations were in the same direction as the original report for all 19 variants, and 14 of the 19 were significantly associated with risk. In summing the number of risk alleles for each individual, the per-allele associations were highly statistically significant (P<10(-4)) and similar in all populations (odds ratios 1.09-1.12) except in Japanese Americans the estimated effect per allele was larger than in the other populations (1.20; P(het)?= 3.8×10(-4)). We did not observe ethnic differences in the distribution of risk that would explain the increased prevalence of type 2 diabetes in these groups as compared to European Americans. The consistency of allelic associations in diverse racial/ethnic groups is not predicted under the hypothesis of Goldstein regarding "synthetic associations" of rare mutations in T2D.
| S-EPMC2928808 | biostudies-literature