Dataset Information

Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose.

ABSTRACT: Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D.

SUBMITTER: Wu P

PROVIDER: S-EPMC7205201 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose.

Wu Peitao P Rybin Denis D Bielak Lawrence F LF Feitosa Mary F MF Franceschini Nora N Li Yize Y Lu Yingchang Y Marten Jonathan J Musani Solomon K SK Noordam Raymond R Raghavan Sridharan S Rose Lynda M LM Schwander Karen K Smith Albert V AV Tajuddin Salman M SM Vojinovic Dina D Amin Najaf N Arnett Donna K DK Bottinger Erwin P EP Demirkan Ayse A Florez Jose C JC Ghanbari Mohsen M Harris Tamara B TB Launer Lenore J LJ Liu Jingmin J Liu Jun J Mook-Kanamori Dennis O DO Murray Alison D AD Nalls Mike A MA Peyser Patricia A PA Uitterlinden André G AG Voortman Trudy T Bouchard Claude C Chasman Daniel D Correa Adolfo A de Mutsert Renée R Evans Michele K MK Gudnason Vilmundur V Hayward Caroline C Kao Linda L Kardia Sharon L R SLR Kooperberg Charles C Loos Ruth J F RJF Province Michael M MM Rankinen Tuomo T Redline Susan S Ridker Paul M PM Rotter Jerome I JI Siscovick David D Smith Blair H BH van Duijn Cornelia C Zonderman Alan B AB Rao D C DC Wilson James G JG Dupuis Josée J Meigs James B JB Liu Ching-Ti CT Vassy Jason L JL

PloS one 20200507 5

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were ...[more]

PMID: 32379818

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Project description:BACKGROUND:The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain. METHODS:We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies. RESULTS:After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths. CONCLUSIONS:In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).

Dataset Information

Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose.

Publications

Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose.

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