Jessica Edstorp1, Yuxia Wei2, Emma Ahlqvist3, Lars Alfredsson2,4, Valdemar Grill5, Leif Groop3,6, Bahareh Rasouli2,7, Elin P Sørgjerd8,9, Per M Thorsby10,11, Tiinamaija Tuomi3,6,12,13,14, Bjørn O Åsvold8,9,15, Sofia Carlsson2. 1. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. jessica.edstorp@ki.se. 2. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 3. Department of Clinical Sciences in Malmö, Clinical Research Centre, Lund University, Malmö, Sweden. 4. Center for Occupational and Environmental Medicine, Region Stockholm, Stockholm, Sweden. 5. Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. 6. Institute for Molecular Medicine Finland, Helsinki University, Helsinki, Finland. 7. Department of Global Health and Population, Harvard TH Chan School of Public Health, Boston, MA, USA. 8. HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway. 9. Department of Endocrinology, Clinic of Medicine, St Olavs Hospital, Trondheim, Norway. 10. Hormone Laboratory, Department of Medical Biochemistry, Oslo University Hospital, Aker, Oslo, Norway. 11. Biochemical Endocrinology and Metabolism Research Group, Oslo University Hospital, Aker, Oslo, Norway. 12. Division of Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland. 13. Research Program for Diabetes and Obesity, University of Helsinki, Helsinki, Finland. 14. Folkhälsan Research Center, Helsinki, Finland. 15. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Abstract
AIMS/HYPOTHESES: Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. METHODS: Analyses were based on Swedish case-control data (collected 2010-2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984-2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case-control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. RESULTS: Smoking (RRpooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. CONCLUSIONS/ INTERPRETATION: Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA. DATA AVAILABILITY: Analysis codes are shared through GitHub ( https://github.com/jeseds/Smoking-use-of-smokeless-tobacco-HLA-genotypes-and-incidence-of-LADA ).
AIMS/HYPOTHESES: Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. METHODS: Analyses were based on Swedish case-control data (collected 2010-2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984-2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case-control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. RESULTS: Smoking (RRpooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. CONCLUSIONS/ INTERPRETATION: Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA. DATA AVAILABILITY: Analysis codes are shared through GitHub ( https://github.com/jeseds/Smoking-use-of-smokeless-tobacco-HLA-genotypes-and-incidence-of-LADA ).
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