Maria J. Redondo, David Cuthbertson, Andrea K. Steck, Kevan C. Herold, Richard Oram, Mark Atkinson, Todd M. Brusko, Hemang M. Parikh, Jeffrey P. Krischer, Suna Onengut-Gumuscu, Stephen S. Rich, Jay M. Sosenko
{"title":"无高危HLA-DR4-DQ8或HLA-DR3-DQ2单倍型的自身抗体阳性个体的特征","authors":"Maria J. Redondo, David Cuthbertson, Andrea K. Steck, Kevan C. Herold, Richard Oram, Mark Atkinson, Todd M. Brusko, Hemang M. Parikh, Jeffrey P. Krischer, Suna Onengut-Gumuscu, Stephen S. Rich, Jay M. Sosenko","doi":"10.1007/s00125-024-06338-7","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Many studies of type 1 diabetes pathogenesis focus on individuals with high-risk HLA haplotypes. We tested the hypothesis that, among islet autoantibody-positive individuals, lacking <i>HLA-DRB1*04-DQA1*03-DQB1*0302</i> (HLA-DR4-DQ8) and/or <i>HLA-DRB1*0301-DQA1*0501-DQB1*0201</i> (HLA-DR3-DQ2) is associated with phenotypic differences, compared with those who have these high-risk HLA haplotypes.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We classified autoantibody-positive relatives of individuals with type 1 diabetes into four groups based on having both HLA-DR4-DQ8 and HLA-DR3-DQ2 (DR3/DR4; <i>n</i>=1263), HLA-DR4-DQ8 but not HLA-DR3-DQ2 (DR4/non-DR3; <i>n</i>=2340), HLA-DR3-DQ2 but not HLA-DR4-DQ8 (DR3/non-DR4; <i>n</i>=1607) and neither HLA-DR3-DQ2 nor HLA-DR4-DQ8 (DRX/DRX; <i>n</i>=1294). Group comparisons included demographics, metabolic markers and the prevalence of autoantibodies against GAD65 (GADA%), IA-2 (IA-2A%) or insulin (IAA%) at enrolment. A <i>p</i> value <0.01 was considered statistically significant.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>IA-2A% was lower in the DRX/DRX group (20.9%) than in the DR4/non-DR3 (38.5%, <i>p</i><0.001) and DR3/DR4 (44.8%, <i>p</i><0.001) groups, but similar to the DR3/non-DR4 group (20.0%). Conversely, IAA% was similar in the DRX/DRX (43.4%), DR4/non-DR3 (41.1%) and DR3/DR4 (41.0%) groups, but lower in the DR3/non-DR4 group (30.1%, <i>p</i><0.001). Participants in the DRX/DRX group were older, with a lower prevalence of White participants and a higher prevalence of overweight/obesity, and higher preserved C-peptide (as measured by a lower Index60) than those in the DR3/DR4 group (all comparisons, <i>p</i><0.005), a lower prevalence of White or non-Hispanic participants and a lower Index60 than those in the DR4/non-DR3 group, and younger age, a higher prevalence of Hispanic participants and a lower Index60 than those in the DR3/non-DR4 group (all comparisons, <i>p</i><0.005). Among the 1292 participants who progressed to clinical type 1 diabetes, those in the DR3/non-DR4 group had higher GADA%, lower IA-2A% and lower IAA% than the other groups (all comparisons, <i>p</i><0.01), and those in the DR3/DR4 group had the youngest age at diagnosis (all comparisons, <i>p</i><0.001).</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Autoantibody-positive individuals who lack both high-risk HLA haplotypes (DRX/DRX) or have HLA-DR3-DQ2 but lack HLA-DR4-DQ8 (DR3/non-DR4) have phenotypic differences compared with DR3/DR4 and DR4/non-DR3 individuals, suggesting that there is aetiological heterogeneity in type 1 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\n","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"5 1","pages":""},"PeriodicalIF":8.4000,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Characteristics of autoantibody-positive individuals without high-risk HLA-DR4-DQ8 or HLA-DR3-DQ2 haplotypes\",\"authors\":\"Maria J. Redondo, David Cuthbertson, Andrea K. Steck, Kevan C. Herold, Richard Oram, Mark Atkinson, Todd M. Brusko, Hemang M. Parikh, Jeffrey P. Krischer, Suna Onengut-Gumuscu, Stephen S. Rich, Jay M. Sosenko\",\"doi\":\"10.1007/s00125-024-06338-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3 data-test=\\\"abstract-sub-heading\\\">Aims/hypothesis</h3><p>Many studies of type 1 diabetes pathogenesis focus on individuals with high-risk HLA haplotypes. We tested the hypothesis that, among islet autoantibody-positive individuals, lacking <i>HLA-DRB1*04-DQA1*03-DQB1*0302</i> (HLA-DR4-DQ8) and/or <i>HLA-DRB1*0301-DQA1*0501-DQB1*0201</i> (HLA-DR3-DQ2) is associated with phenotypic differences, compared with those who have these high-risk HLA haplotypes.</p><h3 data-test=\\\"abstract-sub-heading\\\">Methods</h3><p>We classified autoantibody-positive relatives of individuals with type 1 diabetes into four groups based on having both HLA-DR4-DQ8 and HLA-DR3-DQ2 (DR3/DR4; <i>n</i>=1263), HLA-DR4-DQ8 but not HLA-DR3-DQ2 (DR4/non-DR3; <i>n</i>=2340), HLA-DR3-DQ2 but not HLA-DR4-DQ8 (DR3/non-DR4; <i>n</i>=1607) and neither HLA-DR3-DQ2 nor HLA-DR4-DQ8 (DRX/DRX; <i>n</i>=1294). Group comparisons included demographics, metabolic markers and the prevalence of autoantibodies against GAD65 (GADA%), IA-2 (IA-2A%) or insulin (IAA%) at enrolment. A <i>p</i> value <0.01 was considered statistically significant.</p><h3 data-test=\\\"abstract-sub-heading\\\">Results</h3><p>IA-2A% was lower in the DRX/DRX group (20.9%) than in the DR4/non-DR3 (38.5%, <i>p</i><0.001) and DR3/DR4 (44.8%, <i>p</i><0.001) groups, but similar to the DR3/non-DR4 group (20.0%). Conversely, IAA% was similar in the DRX/DRX (43.4%), DR4/non-DR3 (41.1%) and DR3/DR4 (41.0%) groups, but lower in the DR3/non-DR4 group (30.1%, <i>p</i><0.001). Participants in the DRX/DRX group were older, with a lower prevalence of White participants and a higher prevalence of overweight/obesity, and higher preserved C-peptide (as measured by a lower Index60) than those in the DR3/DR4 group (all comparisons, <i>p</i><0.005), a lower prevalence of White or non-Hispanic participants and a lower Index60 than those in the DR4/non-DR3 group, and younger age, a higher prevalence of Hispanic participants and a lower Index60 than those in the DR3/non-DR4 group (all comparisons, <i>p</i><0.005). Among the 1292 participants who progressed to clinical type 1 diabetes, those in the DR3/non-DR4 group had higher GADA%, lower IA-2A% and lower IAA% than the other groups (all comparisons, <i>p</i><0.01), and those in the DR3/DR4 group had the youngest age at diagnosis (all comparisons, <i>p</i><0.001).</p><h3 data-test=\\\"abstract-sub-heading\\\">Conclusions/interpretation</h3><p>Autoantibody-positive individuals who lack both high-risk HLA haplotypes (DRX/DRX) or have HLA-DR3-DQ2 but lack HLA-DR4-DQ8 (DR3/non-DR4) have phenotypic differences compared with DR3/DR4 and DR4/non-DR3 individuals, suggesting that there is aetiological heterogeneity in type 1 diabetes.</p><h3 data-test=\\\"abstract-sub-heading\\\">Graphical Abstract</h3>\\n\",\"PeriodicalId\":11164,\"journal\":{\"name\":\"Diabetologia\",\"volume\":\"5 1\",\"pages\":\"\"},\"PeriodicalIF\":8.4000,\"publicationDate\":\"2024-12-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Diabetologia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00125-024-06338-7\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Diabetologia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00125-024-06338-7","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Characteristics of autoantibody-positive individuals without high-risk HLA-DR4-DQ8 or HLA-DR3-DQ2 haplotypes
Aims/hypothesis
Many studies of type 1 diabetes pathogenesis focus on individuals with high-risk HLA haplotypes. We tested the hypothesis that, among islet autoantibody-positive individuals, lacking HLA-DRB1*04-DQA1*03-DQB1*0302 (HLA-DR4-DQ8) and/or HLA-DRB1*0301-DQA1*0501-DQB1*0201 (HLA-DR3-DQ2) is associated with phenotypic differences, compared with those who have these high-risk HLA haplotypes.
Methods
We classified autoantibody-positive relatives of individuals with type 1 diabetes into four groups based on having both HLA-DR4-DQ8 and HLA-DR3-DQ2 (DR3/DR4; n=1263), HLA-DR4-DQ8 but not HLA-DR3-DQ2 (DR4/non-DR3; n=2340), HLA-DR3-DQ2 but not HLA-DR4-DQ8 (DR3/non-DR4; n=1607) and neither HLA-DR3-DQ2 nor HLA-DR4-DQ8 (DRX/DRX; n=1294). Group comparisons included demographics, metabolic markers and the prevalence of autoantibodies against GAD65 (GADA%), IA-2 (IA-2A%) or insulin (IAA%) at enrolment. A p value <0.01 was considered statistically significant.
Results
IA-2A% was lower in the DRX/DRX group (20.9%) than in the DR4/non-DR3 (38.5%, p<0.001) and DR3/DR4 (44.8%, p<0.001) groups, but similar to the DR3/non-DR4 group (20.0%). Conversely, IAA% was similar in the DRX/DRX (43.4%), DR4/non-DR3 (41.1%) and DR3/DR4 (41.0%) groups, but lower in the DR3/non-DR4 group (30.1%, p<0.001). Participants in the DRX/DRX group were older, with a lower prevalence of White participants and a higher prevalence of overweight/obesity, and higher preserved C-peptide (as measured by a lower Index60) than those in the DR3/DR4 group (all comparisons, p<0.005), a lower prevalence of White or non-Hispanic participants and a lower Index60 than those in the DR4/non-DR3 group, and younger age, a higher prevalence of Hispanic participants and a lower Index60 than those in the DR3/non-DR4 group (all comparisons, p<0.005). Among the 1292 participants who progressed to clinical type 1 diabetes, those in the DR3/non-DR4 group had higher GADA%, lower IA-2A% and lower IAA% than the other groups (all comparisons, p<0.01), and those in the DR3/DR4 group had the youngest age at diagnosis (all comparisons, p<0.001).
Conclusions/interpretation
Autoantibody-positive individuals who lack both high-risk HLA haplotypes (DRX/DRX) or have HLA-DR3-DQ2 but lack HLA-DR4-DQ8 (DR3/non-DR4) have phenotypic differences compared with DR3/DR4 and DR4/non-DR3 individuals, suggesting that there is aetiological heterogeneity in type 1 diabetes.
期刊介绍：
Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.
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