Autoimmunity plays a role in the onset of diabetes after 40 years of age

Olov Rolandsson, Christiane S. Hampe, Stephen J. Sharp, Eva Ardanaz, Heiner Boeing, Guy Fagherazzi, Francesca Romana Mancini, Peter M. Nilsson, Kim Overvad, Maria Dolores Chirlaque, Miren Dorronsoro, Marc J. Gunter, Rudolf Kaaks, Timothy J. Key, Kay Tee Khaw, Vittorio Krogh, Tilman Kühn, Domenico Palli, Salvatore Panico, Carlotta SacerdoteMaria José Sánchez, Gianluca Severi, Annemieke M.W. Spijkerman, Rosario Tumino, Yvonne T. van der Schouw, Elio Riboli, Nita G. Forouhi, Claudia Langenberg, Nicholas J. Wareham

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)266-277
Number of pages12
JournalDiabetologia
Volume63
Issue number2
DOIs
StatePublished - Feb 1 2020

Fingerprint

Autoimmunity
Type 2 Diabetes Mellitus
Antibodies
Type 1 Diabetes Mellitus
Neoplasms
Radioligand Assay
Insulin Resistance
Protein Isoforms
Cohort Studies
Smoking
Prospective Studies
Education

Keywords

  • Autoantibody
  • Autoimmunity
  • Genetic risk score
  • Incident diabetes
  • Type 1 diabetes
  • Type 2 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Rolandsson, O., Hampe, C. S., Sharp, S. J., Ardanaz, E., Boeing, H., Fagherazzi, G., ... Wareham, N. J. (2020). Autoimmunity plays a role in the onset of diabetes after 40 years of age. Diabetologia, 63(2), 266-277. https://doi.org/10.1007/s00125-019-05016-3

Autoimmunity plays a role in the onset of diabetes after 40 years of age. / Rolandsson, Olov; Hampe, Christiane S.; Sharp, Stephen J.; Ardanaz, Eva; Boeing, Heiner; Fagherazzi, Guy; Mancini, Francesca Romana; Nilsson, Peter M.; Overvad, Kim; Chirlaque, Maria Dolores; Dorronsoro, Miren; Gunter, Marc J.; Kaaks, Rudolf; Key, Timothy J.; Khaw, Kay Tee; Krogh, Vittorio; Kühn, Tilman; Palli, Domenico; Panico, Salvatore; Sacerdote, Carlotta; Sánchez, Maria José; Severi, Gianluca; Spijkerman, Annemieke M.W.; Tumino, Rosario; van der Schouw, Yvonne T.; Riboli, Elio; Forouhi, Nita G.; Langenberg, Claudia; Wareham, Nicholas J.

In: Diabetologia, Vol. 63, No. 2, 01.02.2020, p. 266-277.

Research output: Contribution to journalArticle

Rolandsson, O, Hampe, CS, Sharp, SJ, Ardanaz, E, Boeing, H, Fagherazzi, G, Mancini, FR, Nilsson, PM, Overvad, K, Chirlaque, MD, Dorronsoro, M, Gunter, MJ, Kaaks, R, Key, TJ, Khaw, KT, Krogh, V, Kühn, T, Palli, D, Panico, S, Sacerdote, C, Sánchez, MJ, Severi, G, Spijkerman, AMW, Tumino, R, van der Schouw, YT, Riboli, E, Forouhi, NG, Langenberg, C & Wareham, NJ 2020, 'Autoimmunity plays a role in the onset of diabetes after 40 years of age', Diabetologia, vol. 63, no. 2, pp. 266-277. https://doi.org/10.1007/s00125-019-05016-3
Rolandsson O, Hampe CS, Sharp SJ, Ardanaz E, Boeing H, Fagherazzi G et al. Autoimmunity plays a role in the onset of diabetes after 40 years of age. Diabetologia. 2020 Feb 1;63(2):266-277. https://doi.org/10.1007/s00125-019-05016-3
Rolandsson, Olov ; Hampe, Christiane S. ; Sharp, Stephen J. ; Ardanaz, Eva ; Boeing, Heiner ; Fagherazzi, Guy ; Mancini, Francesca Romana ; Nilsson, Peter M. ; Overvad, Kim ; Chirlaque, Maria Dolores ; Dorronsoro, Miren ; Gunter, Marc J. ; Kaaks, Rudolf ; Key, Timothy J. ; Khaw, Kay Tee ; Krogh, Vittorio ; Kühn, Tilman ; Palli, Domenico ; Panico, Salvatore ; Sacerdote, Carlotta ; Sánchez, Maria José ; Severi, Gianluca ; Spijkerman, Annemieke M.W. ; Tumino, Rosario ; van der Schouw, Yvonne T. ; Riboli, Elio ; Forouhi, Nita G. ; Langenberg, Claudia ; Wareham, Nicholas J. / Autoimmunity plays a role in the onset of diabetes after 40 years of age. In: Diabetologia. 2020 ; Vol. 63, No. 2. pp. 266-277.
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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.

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

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