Genetic susceptibility, obesity and lifetime risk of type 2 diabetes: The ARIC study and Rotterdam Study

Symen Ligthart, Natalie R. Hasbani, Fariba Ahmadizar, Thijs T.W. van Herpt, Maarten J.G. Leening, André G. Uitterlinden, Eric J.G. Sijbrands, Alanna C. Morrison, Eric Boerwinkle, James S. Pankow, Elizabeth Selvin, M. Arfan Ikram, Maryam Kavousi, Paul S. de Vries, Abbas Dehghan

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Aims: Both lifestyle factors and genetic background contribute to the development of type 2 diabetes. Estimation of the lifetime risk of diabetes based on genetic information has not been presented, and the extent to which a normal body weight can offset a high lifetime genetic risk is unknown. Methods: We used data from 15,671 diabetes-free participants of European ancestry aged 45 years and older from the prospective population-based ARIC study and Rotterdam Study (RS). We quantified the remaining lifetime risk of diabetes stratified by genetic risk and quantified the effect of normal weight in terms of relative and lifetime risks in low, intermediate and high genetic risk. Results: At age 45 years, the lifetime risk of type 2 diabetes in ARIC in the low, intermediate and high genetic risk category was 33.2%, 41.3% and 47.2%, and in RS 22.8%, 30.6% and 35.5% respectively. The absolute lifetime risk for individuals with normal weight compared to individuals with obesity was 24% lower in ARIC and 8.6% lower in RS in the low genetic risk group, 36.3% lower in ARIC and 31.3% lower in RS in the intermediate genetic risk group, and 25.0% lower in ARIC and 29.4% lower in RS in the high genetic risk group. Conclusions: Genetic variants for type 2 diabetes have value in estimating the lifetime risk of type 2 diabetes. Normal weight mitigates partly the deleterious effect of high genetic risk.

Original languageEnglish (US)
Article numbere14639
JournalDiabetic Medicine
Issue number10
StatePublished - Oct 2021

Bibliographical note

Funding Information:
The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Rotterdam Study is supported by Erasmus MC and Erasmus University Rotterdam; Netherlands Organisation for Scientific Research (NWO); Netherlands Organisation for Health Research and Development (ZonMW); Research Institute for Diseases in the Elderly (RIDE); Netherlands Genomics Initiative; Ministry of Education, Culture and Science; Ministry of Health, Welfa re and Sports; European Commission (DG XII); and Municipality of Rotterdam. None of the funders had any role in study design, study conduct; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript. The dedication, commitment and contribution of inhabitants, general practitioners and pharmacists of the Ommoord district to the Rotterdam Study are gratefully acknowledged. PSdV and NRH were additionally supported by the American Heart Association grant number 18CDA34110116.

Publisher Copyright:
© 2021 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.


  • BMI
  • lifetime risk
  • obesity
  • polygenic score
  • type 2 diabetes


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