Interaction Between Overweight and Genotypes of HLA, TCF7L2, and FTO in Relation to the Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes

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/m(2)) 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.Peer reviewe

Validity of the FINDRISC as a prediction tool for diabetes in a contemporary Norwegian population : a 10-year follow-up of the HUNT study

Objective The Finnish Diabetes Risk Score (FINDRISC) is a recommended tool for type 2 diabetes prediction. There is a lack of studies examining the performance of the current 0-26 point FINDRISC scale. We examined the validity of FINDRISC in a contemporary Norwegian risk environment. Research design and methods We followed 47 804 participants without known diabetes and aged >= 20 years in the HUNT3 survey (2006-2008) by linkage to information on glucose-lowering drug dispensing in the Norwegian Prescription Database (2004-2016). We estimated the C-statistic, sensitivity and specificity of FINDRISC as predictor of incident diabetes, as indicated by incident use of glucose-lowering drugs. We estimated the 10-year cumulative diabetes incidence by categories of FINDRISC. Results The C-statistic (95% CI) of FINDRISC in predicting future diabetes was 0.77 (0.76 to 0.78). FINDRISC >= 15 (the conventional cut-off value) had a sensitivity of 38% and a specificity of 90%. The 10-year cumulative diabetes incidence (95% CI) was 4.0% (3.8% to 4.2%) in the entire study population, 13.5% (12.5% to 14.5%) for people with FINDRISC >= 15 and 2.8% (2.6% to 3.0%) for people with FINDRISC = 15 had a positive predictive value of 13.5% and a negative predictive value of 97.2% for diabetes within the next 10 years. To approach a similar sensitivity as in the study in which FINDRISC was developed, we would have to lower the cut-off value for elevated FINDRISC to >= 11. This would yield a sensitivity of 73%, specificity of 67%, positive predictive value of 7.7% and negative predictive value of 98.5%. Conclusions The validity of FINDRISC and the risk of diabetes among people with FINDRISC >= 15 is substantially lower in the contemporary Norwegian population than assumed in official guidelines. To identify similar to 3/4 of those developing diabetes within the next 10 years, we would have to lower the threshold for elevated FINDRISC to >= 11, which would label similar to 1/3 of the entire adult population as having an elevated FINDRISC necessitating a glycemia assessment.Peer reviewe