Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Sciences in Malmö, Clinical Research Centre, Lund University, Malmö, Sweden.
J Clin Endocrinol Metab. 2019 Oct 1;104(10):4815-4826. doi: 10.1210/jc.2019-00183.
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.
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).
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.
Overweight interacts with HLA high-risk genotypes but also with genes associated with type 2 diabetes in the promotion of LADA.
我们研究了体重指数（BMI）与人类白细胞抗原（HLA）、TCF7L2-rs7903146 和 FTO-rs9939609 基因型之间的潜在相互作用，这些相互作用与成人隐匿性自身免疫性糖尿病（LADA）和 2 型糖尿病的风险有关。
我们汇总了两项基于人群的研究的数据：（i）一项瑞典研究，纳入了 LADA 的新发病例[谷氨酸脱羧酶自身抗体（GADA）阳性；n=394]和 2 型糖尿病（GADA 阴性；n=1290）以及匹配的无糖尿病对照者（n=2656）；（ii）一项前瞻性挪威研究，纳入了 LADA 的新发病例（n=131）和 2 型糖尿病（n=1901）以及 886120 人年的随访数据。分析调整了年龄、性别、体力活动和吸烟因素。通过归因比例（AP）评估超重（BMI≥25kg/m2）与 HLA/TCF7L2/FTO 高危基因型之间的交互作用。
超重与 HLA、TCF7L2 和 FTO 高危基因型的组合与 LADA 的汇总相对风险（RRpooled）分别为 7.59（95% CI，5.27 至 10.93）、2.65（95% CI，1.97 至 3.56）和 2.21（95% CI，1.60 至 3.07）相关，与低/中遗传风险的正常体重个体相比。超重与 HLA（AP，0.29；95%CI，0.10 至 0.47）、TCF7L2（AP，0.31；95%CI，0.09 至 0.52）和 FTO（AP，0.38；95%CI，0.15 至 0.61）之间存在显著的交互作用。在 DR4 基因型纯合子的超重个体中，LADA 的风险最高[RR，26.76（95% CI，15.42 至 46.43）；AP，0.58（95% CI，0.32 至 0.83）（瑞典数据）]。超重与 TCF7L2 也与 2 型糖尿病显著交互（AP，0.26；95%CI，0.19 至 0.33），但与 HLA 高危基因型或 FTO 无交互作用。
超重与 HLA 高危基因型相互作用，也与与 2 型糖尿病相关的基因相互作用，促进了 LADA 的发生。
