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

• Published in: The journal of clinical endocrinology and metabolism 2019-10, Vol.104 (10), p.4815-4826
• Main Authors: Hjort, Rebecka, Löfvenborg, Josefin E, Ahlqvist, Emma, Alfredsson, Lars, Andersson, Tomas, Grill, Valdemar, Groop, Leif, Sørgjerd, Elin P, Tuomi, Tiinamaija, Åsvold, Bjørn Olav, Carlsson, Sofia
• Format: Article
• Language: English
• Subjects: Adult; Aged; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics; ANDIS; Autoantibodies; Autoimmune diseases; Autoimmunity; Biotechnology industry; Body mass index; Body weight; Case-Control Studies; Clinical Medicine; Clinical s; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - genetics; Diabetes therapy; diabetics; Endocrinology and Diabetes; Endokrinologi och diabetes; Exercise; Female; Genetic aspects; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Genotypes; Glutamate; Glutamate decarboxylase; Glutamic acid; Histocompatibility antigen HLA; Histocompatibility antigens; HLA Antigens - genetics; HLA histocompatibility antigens; Humans; Incidence; Klinisk medicin; Latent Autoimmune Diabetes in Adults - complications; Latent Autoimmune Diabetes in Adults - epidemiology; Latent Autoimmune Diabetes in Adults - genetics; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Middle Aged; Norway - epidemiology; Overweight; Overweight - complications; Overweight - epidemiology; Overweight - genetics; Physical activity; Polymorphism, Single Nucleotide; Population studies; Risk Factors; Sweden - epidemiology; Transcription Factor 7-Like 2 Protein - genetics; Type 2 diabetes
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2019-00183

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.