Differences in F pocket impact on HLA I genetic associations with autoimmune diabetes.
Ontology highlight
ABSTRACT: Introduction
Human leukocyte antigen (HLA) I molecules present antigenic peptides to activate CD8+ T cells. Type 1 Diabetes (T1D) is an auto-immune disease caused by aberrant activation of the CD8+ T cells that destroy insulin-producing pancreatic β cells. Some HLA I alleles were shown to increase the risk of T1D (T1D-predisposing alleles), while some reduce this risk (T1D-protective alleles).Methods
Here, we compared the T1D-predisposing and T1D-protective allotypes concerning peptide binding, maturation, localization and surface expression and correlated it with their sequences and energetic profiles using experimental and computational methods.Results
T1D-predisposing allotypes had more peptide-bound forms and higher plasma membrane levels than T1D-protective allotypes. This was related to the fact that position 116 within the F pocket was more conserved and made more optimal contacts with the neighboring residues in T1D-predisposing allotypes than in protective allotypes.Conclusion
Our work uncovers that specific polymorphisms in HLA I molecules potentially influence their susceptibility to T1D.
SUBMITTER: Ren X
PROVIDER: S-EPMC11003304 | biostudies-literature | 2024
REPOSITORIES: biostudies-literature
Publications
Differences in F pocket impact on HLA I genetic associations with autoimmune diabetes.
Ren Xu X Amarajeewa A W Peshala AWP Jayasinghe M D Tharushika MDT Garstka Malgorzata A MA
Frontiers in immunology 20240325
<h4>Introduction</h4>Human leukocyte antigen (HLA) I molecules present antigenic peptides to activate CD8<sup>+</sup> T cells. Type 1 Diabetes (T1D) is an auto-immune disease caused by aberrant activation of the CD8<sup>+</sup> T cells that destroy insulin-producing pancreatic β cells. Some <i>HLA I</i> alleles were shown to increase the risk of T1D (T1D-predisposing alleles), while some reduce this risk (T1D-protective alleles).<h4>Methods</h4>Here, we compared the T1D-predisposing and T1D-prot ...[more]
Similar Datasets
Project description:There is strong genetic association between type 1A diabetes (T1D) and autoimmune thyroid disease (AITD). T1D and AITD frequently occur together in the same individual, a condition classified as a variant of the autoimmune polyglandular syndrome type 3 (APS3). Because T1D and AITD are individually strongly associated with different HLA class II sequences, we asked which HLA class II pocket sequence and structure confer joint susceptibility to both T1D and AITD in the same individual (APS3v). We sequenced the HLA-DR gene in 105 APS3v patients and 153 controls, and identified a pocket amino acid signature, DR?-Tyr-26, DR?-Leu-67, DR?-Lys-71, and DR?-Arg-74, that was strongly associated with APS3v (P = 5.4 × 10(-14), odds ratio = 8.38). Logistic regression analysis demonstrated that DR?-Leu-67 (P = 9.4 × 10(-13)) and DR?-Arg-74 (P = 1.21 × 10(-13)) gave strong independent effects on disease susceptibility. Structural modeling studies demonstrated that pocket 4 was critical for the development of T1D+AITD; all disease-associated amino acids were linked to areas of the pocket that interact directly with the peptide and, therefore, influence peptide binding. The disease-susceptible HLA-DR pocket was more positively charged (Lys-71, Arg-74) compared with the protective pocket (Ala-71, Gln-74). We conclude that a specific pocket amino acid signature confers joint susceptibility to T1D+AITD in the same individual by causing significant structural changes in the MHC II peptide binding pocket and influencing peptide binding and presentation. Moreover, Arg-74 is a major amino acid position for the development of several autoimmune diseases. These findings suggest that blocking the critical Arg-74 pocket might offer a method for treating certain autoimmune conditions.
| S-EPMC2947869 | biostudies-literature
Project description:ObjectivesTo examine human leukocyte antigen HLA DRB1-DQB1 haplotypes within a multi-ethnic cohort and assess their association with characteristics of diabetes onset.MethodsThe sample included 1662 participants from the SEARCH for Diabetes in Youth Study who tested positive for GADA and/or IA-2A autoantibodies. Blood drawn at the study visit was used to measure fasting C-peptide (FCP) and genotype HLA DRB1 and DQB1 loci. Diabetic ketoacidosis (DKA) at diagnosis was determined from medical records. Multivariable linear and logistic regression models stratified by race/ethnicity were used to assess associations with DRB1-DQB1 haplotypes.ResultsThe frequency of DRB1*03 susceptibility haplotypes ranged 27.5-28.9% in all racial/ethnic groups. The frequency of susceptibility DRB1*04-DQB1*0302 was higher in non-Hispanic White (NHW; 34.1%) and Hispanic (38.9%) compared to non-Hispanic Black (NHB; 20.8%) youth. Neutral and protective haplotypes were low frequency in all groups. DBR1*03 haplotypes were associated with younger age at diagnosis in NHW and positivity for multiple autoantibodies in Hispanics. DRB1*04-DQB1*0302 haplotypes were associated with multiple autoantibody positivity in NHW and Hispanics, and lower FCP and higher odds of DKA in Hispanics only. Although protective DRB1*04-DQB1*0301 haplotypes were associated with older age at diagnosis in NHW, they were also associated with multiple autoantibody positivity in these youth. Protective DRB1*13 haplotypes were associated with decreased odds of multiple autoantibody positivity in NHB youth.ConclusionsThe distribution of DRB1-DQB1 haplotypes and their association with onset-related characteristics of autoimmune diabetes varies across major racial/ethnic groups in the USA. This may contribute to variation in clinical presentation of autoimmune diabetes by race/ethnicity.
| S-EPMC3932799 | biostudies-literature
Project description:Background & aimsAssociation studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients.MethodsWe performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls.ResultsA total of 588 HLA variants were significantly associated with AIH, with HLA-B∗35:01 (p = 8.17 × 10-304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10-33; OR = 4.26) and rs7765379 (p = 5.08 × 10-18; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels.ConclusionsOur study reveals three novel and independent variants at HLA-B∗35:01, HLA-B∗08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH.Impact and implicationsThis study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.
| S-EPMC10711477 | biostudies-literature
Project description:The aim of this study was to assess the differences in correlation of PPARGC1A polymorphisms with type 2 diabetes (T2D) risk in adults of African origins: African Americans and Haitian Americans. The case-control study consisted of >30 years old, self-identified Haitian Americans (n = 110 cases and n = 116 controls) and African Americans (n = 124 cases and n = 122 controls) living in South Florida with and without T2D. Adjusted logistic regression indicated that both SNP rs7656250 (OR = 0.22, P = 0.005) and rs4235308 (OR = 0.42, P = 0.026) showed protective association with T2D in Haitian Americans. In African Americans, however, rs4235308 showed significant risk association with T2D (OR = 2.53, P = 0.028). After stratification with sex, in Haitian Americans, both rs4235308 (OR = 0.38, P = 0.026) and rs7656250 (OR = 0.23, P = 0.006) showed protective association with T2D in females whereas in African American males rs7656250 had statistically significant protective effect on T2D (OR = 0.37, P = 0.043). The trends observed for genetic association of PPARGC1A SNPs, rs4235308, and rs7656250 for T2D between Haitian Americans and African Americans point out differences in Black race and warrant replicative study with larger sample size.
| S-EPMC4419207 | biostudies-literature
Project description:Autoimmune polyglandular syndrome 3 variant (APS3v) refers to the co-occurrence of autoimmune thyroiditis (AITD) and type 1 diabetes (T1D) within the same individual. HLA class II confers the strongest susceptibility to APS3v. We previously identified a unique amino acid signature of the HLA-DR pocket (designated APS3v HLA-DR pocket) that predisposes to APS3v. We hypothesized that both thyroid and islet peptides can be presented by the unique APS3v HLA-DR pocket, triggering AITD + T1D together. To test this hypothesis we screened islet and thyroid peptides for their ability to bind to the APS3v HLA-DR pocket. Virtual screen of all possible thyroglobulin (Tg), thyroid-stimulating hormone receptor (TSHR), thyroid peroxidase (TPO), insulin (Ins), and glutamic acid decarboxylase 65 (GAD65) peptides identified 36 peptides that bound to this unique pocket. In vitro binding assays using baculovirus-produced recombinant APS3v HLA-DR identified 11 thyroid/islet peptides (of the 36 predicted binders) that bound with high affinity. By immunizing humanized HLA-DR3 mice carrying the APS3v HLA-DR pocket we identified 4 peptides (Tg.1571, GAD.492, TPO.758, TPO.338) that were presented by antigen presenting cells and elicited T-cell response. We conclude that both thyroid and islet peptides can bind to this flexible APS3v HLA-DR pocket and induce thyroid and islet specific T-cell responses. These findings set the stage to developing specific inhibitors of the APS3v HLA-DR pocket as a precision medicine approach to treating or preventing APS3v in patients that carry this genetic HLA-DR pocket variant.
| S-EPMC5752120 | biostudies-literature
Project description:Although the prevalence of autoimmune hepatitis in first-degree relatives is small, the relationship between genetic markers, especially human leucocyte antigens (HLA), and susceptibility to this disease, has been studied for over three decades. The genetic susceptibility to AIH is believed to be different in the two subtypes of the disease, AIH type 1 and AIH type 2. Type 1 AIH has anti-smooth muscle and anti-nuclear antibodies as its main markers, while those of type 2 AIH are the anti-liver/kidney microsome type 1 and anti-liver cytosol type 1 antibodies. The anti-soluble liver antigen/liver-pancreas antibodies, which, in addition to being present in both subtypes, mark an important number of patients without serological markers. Therefore, a third type of disease is questionable. The vast majority of immunogenetic studies compare the differences between the two main types and make no difference between which antibodies are present to define the subtype. This review seeks to analyze what was most important published in the AIH in this context, trying to relate the HLA alleles according to the AIH marker autoantibodies.
| S-EPMC9606223 | biostudies-literature
Project description:ObjectiveIn contrast with childhood-onset type 1 diabetes, the genetics of autoimmune diabetes in adults are not well understood. We have therefore investigated the genetics of diabetes diagnosed in adults positive for autoantibodies.Research design and methodsGAD autoantibodies (GADAs), insulinoma-associated antigen-2 antibodies (IA-2As), and islet cell autoantibodies were measured at time of diagnosis. Autoantibody-positive diabetic subjects (n = 1,384) and population-based control subjects (n = 2,235) were genotyped at 20 childhood-onset type 1 diabetes loci and FCRL3, GAD2, TCF7L2, and FTO.ResultsPTPN22 (1p13.2), STAT4 (2q32.2), CTLA4 (2q33.2), HLA (6p21), IL2RA (10p15.1), INS (11p15.5), ERBB3 (12q13.2), SH2B3 (12q24.12), and CLEC16A (16p13.13) were convincingly associated with autoimmune diabetes in adults (P ≤ 0.002), with consistent directions of effect as reported for pediatric type 1 diabetes. No evidence of an HLA-DRB1*03/HLA-DRB1*04 (DR3/4) genotype effect was obtained (P = 0.55), but it remained highly predisposing (odds ratio 26.22). DR3/4 was associated with a lower age at diagnosis of disease, as was DR4 (P = 4.67 × 10(-6)) but not DR3. DR3 was associated with GADA positivity (P = 6.03 × 10(-6)) but absence of IA-2A (P = 3.22 × 10(-7)). DR4 was associated with IA-2A positivity (P = 5.45 × 10(-6)).ConclusionsOur results are consistent with the hypothesis that the genetics of autoimmune diabetes in adults and children are differentiated by only relatively few age-dependent genetic effects. The slower progression toward autoimmune insulin deficiency in adults is probably due to a lower genetic load overall combined with subtle variation in the HLA class II gene associations and autoreactivity.
| S-EPMC3178303 | biostudies-literature
Project description:BackgroundRacial and ethnic minority groups have a higher prevalence of diabetes, increased risk for adverse complications, and worse health outcomes compared to Non-Hispanic Whites. Evidence suggests they also have higher healthcare expenses associated with diabetes care. Therefore, the objective of this study was to assess racial and ethnic differences in out-of-pocket (OOP) costs among a nationally representative sample of adults with diabetes.MethodsCross-sectional study of 17,702 adults (aged ≥18 years) with diabetes from years 2002-2011 in the Medical Expenditure Panel Survey Household Component. The outcome was OOP expenditures, and the primary predictor was race/ethnicity. Descriptive statistics summarized the sample population. Unadjusted mean values were computed to compare OOP expenses over time. A two-part model was used to estimate adjusted incremental OOP expenses.ResultsFor the overall sample, OOP expenditures decreased significantly over time. In addition, compared to NHWs, racial and ethnic minority groups had significantly lower OOP costs per year when adjusted for sociodemographic characteristics, comorbid conditions, and time. NHBs paid $481 less than NHWs; Hispanics paid $591 less than NHWs; and individuals in the 'Other' racial/ethnic category paid nearly $645 less compared to NHWs (p < 0.001).ConclusionsRacial/ethnic minority patients with diabetes had significantly less OOP expenses compared to NHWs, possibly due to differences in healthcare utilization. OOP expenses decreased significantly over time for all racial and ethnic groups. Additional research is needed to understand the factors associated with differences in OOP expenditures among racial groups.
| S-EPMC7995684 | biostudies-literature
Project description:ImportanceSex differences in genetic associations with human longevity remain largely unknown; investigations on this topic are important for individualized health care.ObjectiveTo explore sex differences in genetic associations with longevity.Design setting and participantsThis population-based case-control study used sex-specific genome-wide association study and polygenic risk score (PRS) analyses to examine sex differences in genetic associations with longevity. Five hundred sixty-four male and 1614 female participants older than 100 years were compared with a control group of 773 male and 1526 female individuals aged 40 to 64 years. All were Chinese Longitudinal Healthy Longevity Study participants with Han ethnicity who were recruited in 1998 and 2008 to 2014.Main outcomes and measuresSex-specific loci and pathways associated with longevity and PRS measures of joint effects of sex-specific loci.ResultsEleven male-specific and 11 female-specific longevity loci (P < 10-5) and 35 male-specific and 25 female-specific longevity loci (10-5 ≤ P < 10-4) were identified. Each of these loci's associations with longevity were replicated in north and south regions of China in one sex but were not significant in the other sex (P = .13-.97), and loci-sex interaction effects were significant (P < .05). The associations of loci rs60210535 of the LINC00871 gene with longevity were replicated in Chinese women (P = 9.0 × 10-5) and US women (P = 4.6 × 10-5) but not significant in Chinese and US men. The associations of the loci rs2622624 of the ABCG2 gene were replicated in Chinese women (P = 6.8 × 10-5) and European women (P = .003) but not significant in both Chinese and European men. Eleven male-specific pathways (inflammation and immunity genes) and 34 female-specific pathways (tryptophan metabolism and PGC-1α induced) were significantly associated with longevity (P < .005; false discovery rate < 0.05). The PRS analyses demonstrated that sex-specific associations with longevity of the 4 exclusive groups of 11 male-specific and 11 female-specific loci (P < 10-5) and 35 male-specific and 25 female-specific loci (10-5 ≤P < 10-4) were jointly replicated across north and south discovery and target samples. Analyses using the combined data set of north and south showed that these 4 groups of sex-specific loci were jointly and significantly associated with longevity in one sex (P = 2.9 × 10-70 to 1.3 × 10-39) but not jointly significant in the other sex (P = .11 to .70), while interaction effects between PRS and sex were significant (P = 4.8 × 10-50 to 1.2 × 10-16).Conclusion and relevanceThe sex differences in genetic associations with longevity are remarkable, but have been overlooked by previously published genome-wide association studies on longevity. This study contributes to filling this research gap and provides a scientific basis for further investigating effects of sex-specific genetic variants and their interactions with environment on healthy aging, which may substantially contribute to more effective and targeted individualized health care for male and female elderly individuals.
| S-EPMC6173523 | biostudies-literature
Project description:Large numbers of statistically significant associations between sentinel SNPs and case-control status have been replicated by genome-wide association studies (GWAS). Nevertheless, currently few underlying molecular mechanisms of complex disease are known. Our approach has been to investigate whether variation in binding of a transcription factor, the vitamin D receptor (VDR) whose activating ligand vitamin D has often been proposed as a modifiable factor in multiple disorders, could explain any of these associations. VDR modifies gene expression by binding DNA as a heterodimer with the Retinoid X receptor (RXR). We identified 43,332 genetic variants significantly associated with altered VDR binding affinity (VDR-BVs) using a high-resolution (ChIP-exo) genome-wide analysis of 27 HapMap lymphoblastoid cell lines (LCLs). The VDR-BVs are over-represented in well conserved consensus RXR:VDR binding motifs. However, most fell outside of recognisable RXR:VDR motifs, implying that genetic variation often affects RXR:VDR binding affinity only indirectly. Finally, we compared 341 VDR-BVs replicating by position in multiple individuals against background sets of variants lying within VDR-binding regions that had been matched in allele frequency and were independent with respect to linkage disequilibrium. In this stringent test, these replicated VDR-BVs were significantly (q < 0.1) and substantially (> 2-fold) enriched in GWAS intervals associated with autoimmune and other diseases, including inflammatory bowel disease, Crohn's disease and rheumatoid arthritis. Replicated VDR-BVs associated with these disorders could represent causal disease risk alleles whose effect is modifiable by vitamin D levels.
2017-03-17 | GSE73254 | GEO