Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes
Mishra, Rajashree (Division of Human Genetics. The Children's Hospital of Philadelphia)
Chesi, Alessandra (Division of Human Genetics. The Children's Hospital of Philadelphia)
Cousminer, Diana L. (Department of Genetics, Perelman School of Medicine, University of Pennsylvania)
Hawa, Mohammad I. (Department of Immunobiology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London)
Bradfield, Jonathan P. (Center for Applied Genomics, The Children's Hospital of Philadelphia)
Hodge, Kenyaita M. (Division of Human Genetics. The Children's Hospital of Philadelphia)
Guy, Vanessa C. (Division of Human Genetics. The Children's Hospital of Philadelphia)
Hakonarson, Hakon (Division of Human Genetics. The Children's Hospital of Philadelphia)
Mauricio, Dídac (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Schloot, Nanette C. (German Diabetes Center, Düsseldorf)
Yderstræde, Knud B. (Odense University Hospital)
Voight, Benjamin F. (Department of Genetics, Perelman School of Medicine, University of Pennsylvania)
Schwartz, Stanley (Main Line Health System, Wynnewood, PA, USA.)
Boehm, Bernhard O. (Department of Internal Medicine I. Ulm University Medical Centre)
Leslie, Richard David (Department of Immunobiology. Barts and the London School of Medicine and Dentistry, Queen Mary University of London)
Grant, Struan F. A. (Division of Human Genetics. The Children's Hospital of Philadelphia)

Data: 2017
Resum: 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 nondiabetic 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.
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès.
Document: article ; recerca ; publishedVersion
Matèria: Latent autoimmune diabetes in adults ; Genetic risk scores
Publicat a: BMC Medicine, Vol. 15 Núm. 88 (2017) , p. 1-10



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