期刊
PLOS MEDICINE
卷 11, 期 5, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pmed.1001647
关键词
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资金
- EU FP6 programme [LSHM_CT_2006_037197]
- Swedish Research Council
- Novo Nordisk
- Swedish Diabetes Association
- Swedish Heart-Lung Foundation
- Wellcome Trust [WT098017, WT090532, 098051, 083270/Z/07/Z]
- Spanish Ministry of Health
- Murcia Regional Government [6236]
- Spanish Ministry of Health - ISCII RETICC [RD06/0020]
- German Cancer Aid, German Ministry of Research (BMBF)
- Cancer Research UK
- Medical Research Council UK
- Danish Cancer Society
- Compagnia di San Paolo
- Asturias Regional Government
- Vasterboten County Council
- Dutch Ministry of Public Health, Welfare and Sports
- Netherlands Cancer Registry
- LK Research Funds
- Dutch Prevention Funds
- Dutch ZON (Zorg Onderzoek Nederland)
- World Cancer Research Fund (WCRF)
- Statistics Netherlands
- AIRE-ONLUS Ragusa
- AVIS-Ragusa
- Sicilian Regional Government
- NL Agency [IGE05012]
- Board of the UMC Utrecht
- United Kingdom NIHR Cambridge Biomedical Research Centre
- MRC [G0601261]
- Imperial College Biomedical Research Centre
- Wellcome Trust [083270/Z/07/Z] Funding Source: Wellcome Trust
- Cancer Research UK [16491, 14136] Funding Source: researchfish
- Medical Research Council [G0401527, MC_UP_A100_1003, MC_U106179471, G1002084, MC_UU_12015/5, MC_UU_12015/1, G0601261, G1000143] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10114, NF-SI-0512-10135, CL-2011-18-004, NF-SI-0611-10099] Funding Source: researchfish
- Novo Nordisk Fonden [NNF13OC0005781] Funding Source: researchfish
- MRC [MC_UU_12015/1, G1002084, MC_UP_A100_1003, G0601261, MC_UU_12015/5] Funding Source: UKRI
Background: Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention. Methods and Findings: The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction = 1.20x10(-4)). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction = 1.50x10(-3)) and waist circumference (p for interaction = 7.49x10(-9)). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score. Conclusions: The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this subgroup is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.
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