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Abstract Objective We investigated potential interactions between body mass index (BMI) and genotypes of human leukocyte antigen (HLA), TCF7L2-rs7903146, and FTO-rs9939609 in relation to the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes. Methods We pooled data from two population-based studies: (i) a Swedish study with incident cases of LADA [positive for glutamic acid decarboxylase autoantibodies (GADA); n = 394) and type 2 diabetes (negative for GADA; n = 1290) and matched controls without diabetes (n = 2656) and (ii) a prospective Norwegian study that included incident cases of LADA (n = 131) and type 2 diabetes (n = 1901) and 886,120 person-years of follow-up. Analyses were adjusted for age, sex, physical activity, and smoking. Interaction between overweight (BMI ≥ 25 kg/m2) and HLA/TCF7L2/FTO high-risk genotypes was assessed by attributable proportion due to interaction (AP). Results The combination of overweight and high-risk genotypes of HLA, TCF7L2, and FTO was associated with pooled relative risk (RRpooled) of 7.59 (95% CI, 5.27 to 10.93), 2.65 (95% CI, 1.97 to 3.56), and 2.21 (95% CI, 1.60 to 3.07), respectively, for LADA, compared with normal-weight individuals with low/intermediate genetic risk. There was a significant interaction between overweight and HLA (AP, 0.29; 95% CI, 0.10 to 0.47), TCF7L2 (AP, 0.31; 95% CI, 0.09 to 0.52), and FTO (AP, 0.38; 95% CI, 0.15 to 0.61). The highest risk of LADA was seen in overweight individuals homozygous for the DR4 genotype [RR, 26.76 (95% CI, 15.42 to 46.43); AP, 0.58 (95% CI, 0.32 to 0.83) (Swedish data)]. Overweight and TCF7L2 also significantly interacted in relation to type 2 diabetes (AP, 0.26; 95% CI, 0.19 to 0.33), but no interaction was observed with high-risk genotypes of HLA or FTO. Conclusions Overweight interacts with HLA high-risk genotypes but also with genes associated with type 2 diabetes in the promotion of LADA.

Aims/hypothesis Some studies find an increased risk of type 1 diabetes in children exposed to antibiotics. We investigated if exposure to antibiotics increases the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes. Methods We used data from a Swedish case–control study (Epidemiological Study of Risk Factors for LADA and Type 2 Diabetes [ESTRID]: LADA, n =597; type 2 diabetes, n =2065; control participants matched on participation time, n =2386) and a case–control study nested within the Norwegian Trøndelag Health Study (HUNT) ( n =82/1279/2050). Anatomical Therapeutic Chemical (ATC) codes indicating antibiotic dispensations were retrieved from the Swedish National Prescribed Drug Register and Norwegian Prescription Database. Multivariable adjusted ORs with 95% CIs were estimated by conditional logistic regression and pooled using fixed-effects inverse-variance weighting. Results We observed no increased risk of LADA with exposure to antibiotics up to 1 year (OR pooled 1.15, 95% CI 0.93, 1.41) or 1–5 years (OR pooled 0.98, 95% CI 0.80, 1.20) prior to diagnosis/matching for one or more vs no dispensation of any type of antibiotic. An increased risk was observed for one or more vs no dispensations of narrow-spectrum antibiotics, but not broad-spectrum antibiotics, 6–10 years prior to LADA diagnosis (OR pooled 1.39, 95% CI 1.01, 1.91), which was driven by the Swedish data. There was little evidence of an increased risk of type 2 diabetes associated with antibiotic exposure 1–10 years prior to diagnosis. Conclusions/interpretation We found no evidence that exposure to broad-spectrum antibiotics up to 10 years prior to diagnosis increases the risk of LADA. There was some indication of increased LADA risk with exposure to narrow-spectrum antibiotics, which warrants further investigation. Graphical 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 (RR pooled 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 ). Graphical abstract

Abstract Purpose Physical activity (PA) has been linked to a reduced risk of type 2 diabetes by reducing weight and improving insulin sensitivity. We investigated whether PA is associated with a lower incidence of latent autoimmune diabetes in adults (LADA) and whether the association is modified by genotypes of human leukocyte antigen (HLA), transcription factor 7-like 2 (TCF7L2)-rs7903146, or the fat mass and obesity-associated gene, FTO-rs9939609. Methods We combined data from a Swedish case-control study and a Norwegian prospective study including 621 incident cases of LADA and 3596 cases of type 2 diabetes. We estimated adjusted pooled relative risks (RRs) and 95% CI of diabetes in relation to high (≥ 30 minutes of moderate activity 3 times/week) self-reported leisure time PA, compared to sedentariness. Results High PA was associated with a reduced risk of LADA (RR 0.61; CI, 0.43-0.86), which was attenuated after adjustment for body mass index (BMI) (RR 0.90; CI, 0.63-1.29). The reduced risk applied only to noncarriers of HLA-DQB1 and -DRB1 (RR 0.49; CI, 0.33-0.72), TCF7L2 (RR 0.62; CI, 0.45-0.87), and FTO (RR 0.51; CI, 0.32-0.79) risk genotypes. Adjustment for BMI attenuated but did not eliminate these associations. For type 2 diabetes, there was an inverse association with PA (RR 0.49; CI, 0.42-0.56), irrespective of genotype. Main Conclusions Our findings indicate that high PA is associated with a reduced risk of LADA in individuals without genetic susceptibility.

IntroductionCluster analysis has previously revealed five reproducible subgroups of diabetes, differing in risks of diabetic complications. We aimed to examine the clusters’ predictive ability for vascular complications as compared with established risk factors in a general adult diabetes population.Research design and methodsParticipants from the second (HUNT2, 1995–1997) and third (HUNT3, 2006–2008) surveys of the Norwegian population-based Trøndelag Health Study (HUNT Study) with adult-onset diabetes were included (n=1899). To identify diabetes subgroups, we used the same variables (age at diagnosis, body mass index, HbA1c, homeostasis model assessment estimates of beta cell function and insulin resistance, and glutamic acid decarboxylase antibodies) and the same data-driven clustering technique as in previous studies. We used Cox proportional hazards models to investigate associations between clusters and risks of vascular complications and mortality. We estimated the C-index and R2 to compare predictive abilities of the clusters to those of established risk factors as continuous variables. All models included adjustment for age, sex, diabetes duration and time of inclusion.ResultsWe reproduced five subgroups with similar key characteristics as identified in previous studies. During median follow-up of 9–13 years (differing between outcomes), the clusters were associated with different risks of vascular complications and all-cause mortality. However, in prediction models, individual established risk factors were at least as good predictors as cluster assignment for all outcomes. For example, for retinopathy, the C-index for the model including clusters (0.65 (95% CI 0.63 to 0.68)) was similar to that of HbA1c (0.65 (95% CI 0.63 to 0.68)) or fasting C-peptide (0.66 (95% CI 0.63 to 0.68)) alone. For chronic kidney disease, the C-index for clusters (0.74 (95% CI 0.72 to 0.76)) was similar to that of triglyceride/high-density lipoprotein ratio (0.74 (95% CI 0.71 to 0.76)) or fasting C-peptide (0.74 (95% CI 0.72 to 0.76)), and baseline estimated glomerular filtration rate yielded a C-index of 0.76 (95% CI 0.74 to 0.78).ConclusionsCluster assignment did not provide better prediction of vascular complications or all-cause mortality compared with established risk factors.