Cervin Camilla, Lyssenko Valeriya, Bakhtadze Ekaterine, Lindholm Eero, Nilsson Peter, Tuomi Tiinamaija, Cilio Corrado M, Groop Leif
Department of Clinical Sciences-Diabetes & Endocrinology, Clinical Research Center, Malmö University Hospital, Lund University, S-205 02 Malmö, Sweden.
Diabetes. 2008 May;57(5):1433-7. doi: 10.2337/db07-0299. Epub 2008 Feb 29.
Latent autoimmune diabetes in adults (LADA) is often considered a slowly progressing subtype of type 1 diabetes, although the clinical picture more resembles type 2 diabetes. One way to improve classification is to study whether LADA shares genetic features with type 1 and/or type 2 diabetes.
To accomplish this, we studied whether LADA shares variation in the HLA locus or INS VNTR and PTPN22 genes with type 1 diabetes or the TCF7L2 gene with type 2 diabetes in 361 LADA, 718 type 1 diabetic, and 1,676 type 2 diabetic patients, as well as 1,704 healthy control subjects from Sweden and Finland.
LADA subjects showed, compared with type 2 diabetic patients, increased frequency of risk for the HLA-DQB1 *0201/*0302 genotype (27 vs. 6.9%; P < 1 x 10(-6)), with similar frequency as with type 1 diabetes (36%). In addition, LADA subjects showed higher frequencies of protective HLA-DQB1 *0602(3)/X than type 1 diabetic patients (8.1 vs. 3.2%, P = 0.003). The AA genotype of rs689, referring to the class I allele in the INS VNTR, as well as the CT/TT genotypes of rs2476601 in the PTPN22 gene, were increased both in type 1 diabetic (P = 3 x 10(-14) and P = 1 x 10(-10), respectively) and LADA (P = 0.001 and P = 0.002) subjects compared with control subjects. Notably, the frequency of the type 2 diabetes-associated CT/TT genotypes of rs7903146 in the TCF7L2 were increased in LADA subjects (52.8%; P = 0.03), to the same extent as in type 2 diabetic subjects (54.1%, P = 3 x 10(-7)), compared with control subjects (44.8%) and type 1 diabetic subjects (43.3%).
LADA shares genetic features with both type 1 (HLA, INS VNTR, and PTPN22) and type 2 (TCF7L2) diabetes, which justifies considering LADA as an admixture of the two major types of diabetes.
成人隐匿性自身免疫性糖尿病（LADA）通常被认为是1型糖尿病的一种进展缓慢的亚型，尽管其临床表现更类似于2型糖尿病。改善分类的一种方法是研究LADA是否与1型和/或2型糖尿病具有共同的遗传特征。
为实现这一目的，我们在361例LADA患者、718例1型糖尿病患者、1676例2型糖尿病患者以及来自瑞典和芬兰的1704名健康对照者中，研究了LADA与1型糖尿病在HLA基因座、胰岛素可变数目串联重复序列（INS VNTR）和蛋白酪氨酸磷酸酶非受体型22（PTPN22）基因上的变异情况，以及LADA与2型糖尿病在TCF7L2基因上的变异情况。
与2型糖尿病患者相比，LADA患者中HLA-DQB1 *0201/*0302基因型的风险频率增加（27%对6.9%；P < 1×10⁻⁶），与1型糖尿病患者的频率相似（36%）。此外，LADA患者中具有保护作用的HLA-DQB1 *0602(3)/X的频率高于1型糖尿病患者（8.1%对3.2%，P = 0.003）。在INS VNTR中，rs689的AA基因型以及PTPN22基因中rs2476601的CT/TT基因型，在1型糖尿病患者（分别为P = 3×10⁻¹⁴和P = 1×10⁻¹⁰）和LADA患者（P = 0.001和P = 0.002）中与对照者相比均增加。值得注意的是，LADA患者中与2型糖尿病相关的TCF7L2基因rs7903146的CT/TT基因型频率增加（52.8%；P = 0.03），与2型糖尿病患者（54.1%，P = 3×10⁻⁷）的增加程度相同，而对照者为44.8%，1型糖尿病患者为43.3%。
LADA与1型糖尿病（HLA、INS VNTR和PTPN22）及2型糖尿病（TCF7L2）均具有共同的遗传特征，这证明将LADA视为两种主要类型糖尿病的混合体是合理的。
