TY - JOUR
T1 - Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes
AU - Bone Mineral Density in Childhood Study
AU - Mishra, Rajashree
AU - Chesi, Alessandra
AU - Cousminer, Diana L.
AU - Hawa, Mohammad I.
AU - Bradfield, Jonathan P.
AU - Hodge, Kenyaita M.
AU - Guy, Vanessa C.
AU - Hakonarson, Hakon
AU - Mauricio, Didac
AU - Schloot, Nanette C.
AU - Yderstræde, Knud B.
AU - Voight, Benjamin F.
AU - Schwartz, Stanley
AU - Boehm, Bernhard O.
AU - Leslie, Richard David
AU - Grant, Struan F.A.
AU - Kalkwarf, Heidi J.
AU - Lappe, Joan M.
AU - Gilsanz, Vicente
AU - Oberfield, Sharon E.
AU - Shepherd, John A.
AU - Kelly, Andrea
AU - Zemel, Babette S.
N1 - Funding Information:
SFAG is supported by the NIH (R01 DK085212) and the Daniel B. Burke Endowed Chair for Diabetes Research. DM is supported by CIBERDEM, Instituto de Salud Carlos III (Spain).
Funding Information:
We would like to thank the JDRF, German Research Council (DFG: SFB 518, A1), German Diabetes Foundation, and EUFP5 (Action LADA) for providing samples for this research. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/4/25
Y1 - 2017/4/25
N2 - 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.
AB - 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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U2 - 10.1186/s12916-017-0846-0
DO - 10.1186/s12916-017-0846-0
M3 - Article
C2 - 28438156
AN - SCOPUS:85018568040
VL - 15
SP - 1
JO - BMC Medicine
JF - BMC Medicine
SN - 1741-7015
IS - 1
M1 - 88
ER -