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

Mishra, Rajashree ; Åkerlund, Mikael LU ; Cousminer, Diana L. ; Ahlqvist, Emma LU ; Bradfield, Jonathan P. ; Chesi, Alessandra ; Hodge, Kenyaita M. ; Guy, Vanessa C. ; Brillon, David J. and Pratley, Richard E. , et al. (2020) In Diabetes Care 43(2). p.418-425
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... (More)

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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published
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Diabetes Care
volume
43
issue
2
pages
8 pages
publisher
American Diabetes Association
external identifiers
  • scopus:85078380035
  • pmid:31843946
ISSN
1935-5548
DOI
10.2337/dc19-0986
language
English
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yes
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e8e5d593-7bc6-4368-a332-aa380c99eadc
date added to LUP
2020-02-05 09:16:37
date last changed
2020-02-12 10:20:39
@article{e8e5d593-7bc6-4368-a332-aa380c99eadc,
  abstract     = {<p>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.</p>},
  author       = {Mishra, Rajashree and Åkerlund, Mikael and Cousminer, Diana L. and Ahlqvist, Emma and Bradfield, Jonathan P. and Chesi, Alessandra and Hodge, Kenyaita M. and Guy, Vanessa C. and Brillon, David J. and Pratley, Richard E. and Rickels, Michael R. and Vella, Adrian and Ovalle, Fernando and Harris, Ronald I. and Melander, Olle and Varvel, Stephen and Hakonarson, Hakon and Froguel, Phillippe and Lonsdale, John T. and Mauricio, Didac and Schloot, Nanette C. and Khunti, Kamlesh and Greenbaum, Carla J. and Yderstræde, Knud B. and Tuomi, Tiinamaija and Voight, Benjamin F. and Schwartz, Stanley and Boehm, Bernhard O. and Groop, Leif and Leslie, Richard David and Grant, Struan F.A.},
  issn         = {1935-5548},
  language     = {eng},
  number       = {2},
  pages        = {418--425},
  publisher    = {American Diabetes Association},
  series       = {Diabetes Care},
  title        = {Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC},
  url          = {http://dx.doi.org/10.2337/dc19-0986},
  doi          = {10.2337/dc19-0986},
  volume       = {43},
  year         = {2020},
}