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BMC Medicine
Published in: BMC Medicine 1/2017

Open Access 01-12-2017 | Research article

Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes

Authors: Rajashree Mishra, Alessandra Chesi, Diana L. Cousminer, Mohammad I. Hawa, Jonathan P. Bradfield, Kenyaita M. Hodge, Vanessa C. Guy, Hakon Hakonarson, Didac Mauricio, Nanette C. Schloot, Knud B. Yderstræde, Benjamin F. Voight, Stanley Schwartz, Bernhard O. Boehm, Richard David Leslie, Struan F. A. Grant, Bone Mineral Density in Childhood Study

Published in: BMC Medicine | Issue 1/2017

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Abstract

Background

In adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as ‘latent autoimmune diabetes in adults’ (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes.

Methods

We tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 non-diabetic controls of European ancestry using a linear mixed model. We then compared the associations of T1D and T2D loci between LADA and T1D and T2D cases, respectively. We quantified the difference in genetic risk between each given disease at each locus, and also calculated genetic risk scores to quantify how genetic liability to T1D and T2D distinguished LADA cases from controls.

Results

Overall, our results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus. Several T1D loci were associated with LADA, including the major histocompatibility complex region, as well as at PTPN22, SH2B3, and INS. Contrary to previous studies, the key T2D risk allele at TCF7L2 (rs7903146-T) had a significantly lower frequency in LADA cases, suggesting that this locus does not play a role in LADA etiology. When constrained on antibody status, the similarity between LADA and T1D became more apparent; however, the HNF1A and TCF7L2 observations persisted.

Conclusion

LADA is genetically closer to T1D than T2D, although the genetic load of T1D risk alleles is less than childhood-onset T1D, particularly at the major histocompatibility complex region, potentially accounting for the later disease onset. Our results show that the genetic spectrum of T1D extends into adult-onset diabetes, where it can clinically masquerade as T2D. Furthermore, T2D genetic risk plays a small role in LADA, with a degree of evidence for the HNF1A locus, highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes.
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Metadata
Title
Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes
Authors
Rajashree Mishra
Alessandra Chesi
Diana L. Cousminer
Mohammad I. Hawa
Jonathan P. Bradfield
Kenyaita M. Hodge
Vanessa C. Guy
Hakon Hakonarson
Didac Mauricio
Nanette C. Schloot
Knud B. Yderstræde
Benjamin F. Voight
Stanley Schwartz
Bernhard O. Boehm
Richard David Leslie
Struan F. A. Grant
Bone Mineral Density in Childhood Study
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2017
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-017-0846-0

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