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Cited by 46Diabetes and associated disordersGenetic Associations and EpidemiologyMultiple Sclerosis Research Studies

Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC

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Mishra, Rajashree, Åkerlund, Mikael, Cousminer, Diana L., Ahlqvist, Emma, Bradfield, Jonathan P., Chesi, Alessandra, Hodge, Kenyaita M., Guy, Vanessa C. +23 more·2020·Diabetes Care
DOI 10.2337/dc19-0986PMC PMC6971787
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Abstract

OBJECTIVE: The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS: Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS: The strongest associations in the MHC class II region (rs3957146, β [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (β [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, β [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS: In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.

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  • Compared with childhood-onset type 1 diabetes mellitus, adult-onset disease has a lower frequency of high-risk HLA types, lower concordance rates in twins, more protective genotypes, lower genetic risk scores and lower overall genetic load.

    “Evidence suggests that, compared with childhood-onset T1DM, adult-onset (ages ≥18 years) disease has a lower frequency of high-risk HLA types54, lower concordance rates in twins55, more protective genotypes56, lower genetic risk scores57 and lower overall genetic load (with minor differences in HLA class II gene associations)56.”

    From The epidemiology of type 1 diabetes mellitus in older adults (2025) · cites this paper as [56]

    The Conclusion (page unavailable) says that protective type 1 diabetes HLA haplotypes are more frequent in LADA than in childhood-onset type 1 diabetes and describes LADA as genetically attenuated. It does not establish a lower overall genetic load for all adult-onset T1DM (ages ≥18); its comparison is specifically with LADA. The other comparisons in the citing sentence have separate citations and are not assessed against this source. (LLM, conf=0.82)

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Research works printed but not linked: 29

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  4. Cousminer DL, Ahlqvist E, Mishra R, Andersen MK, Chesi A, Hawa MI, et al. First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes. Diabetes Care [Internet]. 2018;41(November):dc181032. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30254083
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  7. Kalkwarf HJ, Zemel BS, Gilsanz V, Lappe JM, Horlick M, Oberfield S, et al. The bone mineral density in childhood study: bone mineral content and density according to age, sex, and race. J Clin Endocrinol Metab [Internet]. 2007;92(6):2087-99. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17311856
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  14. Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, Nilsson A, et al. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes [Internet]. 1999;48(1):150-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9892237
  15. Hawa MI, Kolb H, Schloot N, Beyan H, Paschou SA, Buzzetti R, et al. Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: Action LADA 7. Diabetes Care [Internet]. 2013;36(4):908-13. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23248199
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  17. Ahlqvist E, Storm P, Karajamaki A, Martinell M, Dorkhan M, Carlsson A, et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol [Internet]. 2018; Available from: https://www.ncbi.nlm.nih.gov/pubmed/29503172
  18. Cousminer DL, Ahlqvist E, Mishra R, Andersen MK, Chesi A, Hawa MI, et al. First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes. Diabetes Care [Internet]. 2018;41(November):dc181032. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30254083
  19. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med [Internet]. 1998;15(7):539-53. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9686693
  20. Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF, Stevens HE, et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA- A. Nature [Internet]. 2007;450(7171):887-92. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18004301
  21. Kalkwarf HJ, Zemel BS, Gilsanz V, Lappe JM, Horlick M, Oberfield S, et al. The bone mineral density in childhood study: bone mineral content and density according to age, sex, and race. J Clin Endocrinol Metab [Internet]. 2007;92(6):2087-99. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17311856
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  24. Jia X, Han B, Onengut-Gumuscu S, Chen WM, Concannon PJ, Rich SS, et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS One [Internet]. 2013;8(6):e64683. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23762245
  25. Marchini J, Howie B, Myers S, McVean G, Donnelly P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet [Internet]. 2007;39(7):906-13. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17572673
  26. Desai M, Zeggini E, Horton VA, Owen KR, Hattersley AT, Levy JC, et al. An association analysis of the HLA gene region in latent autoimmune diabetes in adults. Diabetologia [Internet]. 2007;50(1):68-73. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17143607
  27. Sharp SA, Rich SS, Wood AR, Jones SE, Beaumont RN, Harrison JW, et al. Development and standardization of an improved type 1 diabetes genetic risk score for use in newborn screening and incident diagnosis. Diabetes Care -Press. 2019;42(February):200-7.
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Cited by

Sorted by citations

  • The epidemiology of type 1 diabetes mellitus in older adults

    Tomic, D., Harding, J. L., Jenkins, A. J., Shaw, J. E., & Magliano, D. J. (2025) · Nature Reviews Endocrinology · doi:10.1038/s41574-024-01046-z · Cited by 58 · see citing works

    “…T1DM, adult-onset (ages ≥18 years) disease has a lower frequency of high-risk HLA types 54 , lower concordance rates in twins 55 , more protective genotypes 56 , lower genetic risk scores 57 and lower overall genetic load (with minor differences in HLA class II gene associations) 56 .”

Authors
Mishra, R., Åkerlund, M., Cousminer, D. L., Ahlqvist, E., Bradfield, J. P., Chesi, A., Hodge, K. M., Guy, V. C., Brillon, D. J., Pratley, R. E., Rickels, M. R., Vella, A., Ovalle, F., Harris, R. I., Melander, O., Varvel, S., Hakonarson, H., Froguel, P., Lonsdale, J. T., Mauricio, D., Schloot, N. C., Khunti, K., Greenbaum, C. J., Yderstræde, K. B., Tuomi, T., Voight, B. F., Schwartz, S., Boehm, B. O., Groop, L., Leslie, R. D., & Grant, S. F. A.
Affiliations
  • Children's Hospital of Philadelphia (US)
  • Lund University (SE)
  • Weill Cornell Medicine (US)
  • Translational Research Institute for Metabolism and Diabetes (US)
  • University of Pennsylvania (US)
  • Mayo Clinic (US)
  • University of Alabama at Birmingham (US)
  • Geisinger Health System (US)
  • Health Diagnostic Laboratory, Inc., Richmond, VA
  • CNRS 8199, Université Lille Nord de France, Pasteur Institute, Lille, France
  • National Disease Research Interchange (US)
  • Hospital de la Santa Creu i Sant Pau, CIBERDEM, Barcelona, Spain
  • Deutsches Diabetes-Zentrum e.V. (DE)
  • University of Leicester (GB)
  • Benaroya Research Institute (US)
  • Odense University Hospital (DK)
  • University of Helsinki (FI)
  • Main Line Health (US)
  • Nanyang Technological University (SG)
  • Queen Mary University of London (GB)
Corresponding author
Grant, Struan F.A.
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2019-12-16
Volume
43
Issue
2
Pages
418-425
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc19-0986
PMC
PMC6971787
OpenAlex
W2996735054
Cited by
46
References
3
Citations by year
2026: 6 · 2025: 6 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 7 · 2020: 7
FWCI
3.00
Type
journal article
Language
en
Open access
Licence
www.diabetesjournals.org/content/license (vor, 35 d)
Locations
  • Diabetes Care (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion, other-oa)
  • HAL (submittedVersion)
  • DR-NTU (Nanyang Technological University) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Työväentutkimus Vuosikirja (submittedVersion, other-oa)
  • Lund University Publications (Lund University) (submittedVersion)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
Funders
  • National Institutes of Health (1K99HD099330-1)
  • CIBERDEM, Instituto de Salud Carlos III
  • German Research Council (SFB, R01-DK-085212)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
latent autoimmune diabetes in adults, childhood-onset type 1 diabetes, major histocompatibility complex, MHC class I, MHC class II, HLA-B39, type 1 diabetes risk
MeSH terms
Latent Autoimmune Diabetes in Adults, Adolescent, Adult, Alleles, Child, Child, Preschool, Chromosomes, Human, Pair 6, Diabetes Mellitus, Type 1, Diagnosis, Differential, Female, Genes, MHC Class II, Genes, MHC Class I, Genetic Testing, Humans, Male, Cohort Studies, Case-Control Studies, Age of Onset, Polymorphism, Single Nucleotide, Young Adult, Genetic Association Studies

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