TY - JOUR
T1 - Autoimmunity plays a role in the onset of diabetes after 40 years of age
AU - Rolandsson, Olov
AU - Hampe, Christiane S.
AU - Sharp, Stephen J.
AU - Ardanaz, Eva
AU - Boeing, Heiner
AU - Fagherazzi, Guy
AU - Mancini, Francesca Romana
AU - Nilsson, Peter M.
AU - Overvad, Kim
AU - Chirlaque, Maria Dolores
AU - Dorronsoro, Miren
AU - Gunter, Marc J.
AU - Kaaks, Rudolf
AU - Key, Timothy J.
AU - Khaw, Kay Tee
AU - Krogh, Vittorio
AU - Kühn, Tilman
AU - Palli, Domenico
AU - Panico, Salvatore
AU - Sacerdote, Carlotta
AU - Sánchez, Maria José
AU - Severi, Gianluca
AU - Spijkerman, Annemieke M.W.
AU - Tumino, Rosario
AU - van der Schouw, Yvonne T.
AU - Riboli, Elio
AU - Forouhi, Nita G.
AU - Langenberg, Claudia
AU - Wareham, Nicholas J.
N1 - Funding Information:
O. Rolandsson: The Västerboten County Council; M. Dorronsoro: We thank the participants of the Spanish EPIC cohort for their contribution to the study as well as to the team of trained nurses who participated in the recruitment; R. Kaaks: German Cancer Aid, German Ministry of Research (BMBF); K. T. Khaw: Medical Research Council UK, Cancer Research UK; T. Kühn: German Cancer Aid, German Cancer Research Center (DKFZ), German Federal Ministry of Education and Research (BMBF); S. Panico: Compagnia di San Paolo; A. M. W. Spijkerman: EPIC Bilthoven and Utrecht acknowledge the Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), Statistics Netherlands (the Netherlands); EPIC Ragusa acknowledges for their participation blood donors of AVIS-Ragusa (local blood donors association); Y. T. van der Schouw: EPIC Bilthoven and Utrecht acknowledge the Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), Dutch ZON (Zorg Onderzoek Nederland), WCRF, Statistics Netherland; E. Riboli: Imperial College Biomedical Research Centre.
Funding Information:
Open access funding provided by Umea University. Funding for the InterAct project was provided by the EU FP6 Programme (grant number LSHM_CT_2006_037197). The autoantibody measurement was funded by Västerbotten County Council and Umeå University, Sweden (OR), the National Institutes of Health (DK26190) (CSH) and the Medical Research Council (MC_UU_12015/1) (NJW). OR: the Västerbotten County Council, Umeå University; MDC: Health Research Fund (FIS) of the Spanish Ministry of Health; Murcia Regional Government (N∫ 6236); EA: the Health Research Fund (FIS) of the Spanish Ministry of Health and Navarre Regional Government; RK: German Cancer Aid, the German Ministry of Research (BMBF); TJK: Cancer Research UK; KTK: the Medical Research Council UK, Cancer Research UK; PMN: the Swedish Research Council; KO: the Danish Cancer Society; SP: Compagnia di San Paolo; AMWS: the Dutch Ministry of Public Health, Welfare and Sports (VWS), the Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands; RT: AIRE-ONLUS Ragusa, AVIS-Ragusa, Sicilian Regional Government; AMWS: LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF); YTvdS: verification of diabetes cases was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the UMC Utrecht, LK Research Funds, Dutch Prevention Funds; NGF: MRC core support (MC_UU_12015/5); NIHR Cambridge Biomedical Research Centre (IS-BRC-1215-20014). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Acknowledgements
Funding Information:
We thank all EPIC participants and staff for their contribution to this study. We thank N. Kerrison (MRC Epidemiology Unit, Cambridge, UK) for managing the data and the laboratory team at the MRC Epidemiology Unit, Cambridge for managing the blood samples for the EPIC-InterAct project. We thank the participants of the Spanish EPIC cohort for their contribution to the study as well as the team of trained nurses who participated in the recruitment. O. Rolandsson: The V?sterboten County Council; M. Dorronsoro: We thank the participants of the Spanish EPIC cohort for their contribution to the study as well as to the team of trained nurses who participated in the recruitment; R. Kaaks: German Cancer Aid, German Ministry of Research (BMBF); K. T. Khaw: Medical Research Council UK, Cancer Research UK; T. K?hn: German Cancer Aid, German Cancer Research Center (DKFZ), German Federal Ministry of Education and Research (BMBF); S. Panico: Compagnia di San Paolo; A. M. W. Spijkerman: EPIC Bilthoven and Utrecht acknowledge the Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), Statistics Netherlands (the Netherlands); EPIC Ragusa acknowledges for their participation blood donors of AVIS-Ragusa (local blood donors association); Y. T. van der Schouw: EPIC Bilthoven and Utrecht acknowledge the Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), Dutch ZON (Zorg Onderzoek Nederland), WCRF, Statistics Netherland; E. Riboli: Imperial College Biomedical Research Centre. Some of the data were presented as an abstract at the 54th EASD Annual Meeting in 2018.
Publisher Copyright:
© 2019, The Author(s).
PY - 2020/2/1
Y1 - 2020/2/1
N2 - Aims/hypothesis: Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. Methods: GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results: GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation: Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.
AB - Aims/hypothesis: Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. Methods: GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results: GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation: Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.
KW - Autoantibody
KW - Autoimmunity
KW - Genetic risk score
KW - Incident diabetes
KW - Type 1 diabetes
KW - Type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85075181942&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/31713011
U2 - 10.1007/s00125-019-05016-3
DO - 10.1007/s00125-019-05016-3
M3 - Article
C2 - 31713011
AN - SCOPUS:85075181942
SN - 0012-186X
VL - 63
SP - 266
EP - 277
JO - Diabetologia
JF - Diabetologia
IS - 2
ER -