Association of common type 1 and type 2 diabetes gene variants with latent autoimmune diabetes in adults: A meta‐analysis

Abstract

Background The aim of this meta‐analysis was to determine the association of common type 1 diabetes (T1D) and type 2 diabetes (T2D) gene variants (protein tyrosine phosphatase non‐receptor 22 [PTPN22] rs2476601C/T, insulin [INS] rs689A/T and transcription factor 7‐like 2 [TCF7L2] rs7903146C/T) with latent autoimmune diabetes in adults (LADA). Methods A systematic search of electronic databases was conducted up to 2017 and data from 16 independent case‐control studies for three gene variants were pooled. The pooled allele and genotype frequencies for each T1D and T2D gene variant were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Heterogeneity tests and evaluation of publication bias were performed for all studies. Results In all, 8869 cases and 20 829 controls pooled from 16 case‐control studies were included in the analysis. For rs2476601, a significant association was found for homozygote TT (OR 2.67; 95% CI 1.92‐3.70; P < 0.0001), heterozygote CT (OR 1.61; 95% CI 1.44‐1.79; P < 0.0001), and the T allele (OR 1.62; 95% CI 1.48‐1.78; P < 0.0001). Overall, a significant inverse association was observed for rs689 in the TT genotype (OR 0.43; 95% CI 0.30‐0.64; P < 0.0001), AT genotype (OR 0.53; 95% CI 0.45‐0.62; P < 0.0001), and T allele (OR 0.61; 95% CI 0.52‐0.71; P < 0.0001). For the rs7903146 polymorphism, the T allele (OR 1.19; 95% CI 1.00‐1.40; P = 0.04) may be associated with the risk of LADA. Conclusion The rs2476601C/T, rs689A/T, and rs7903146C/T polymorphisms were found to be associated with the risk of LADA, thereby indicating that, genetically, LADA could be an admixture of both T1D and T2D.

Type 2 Diabetes: How Much of an Autoimmune Disease?

“…The risk of LADA is substantially increased with family history of T1D disease but also, albeit significantly less so, of T2D disease (36). A meta-analysis from 16 independent case-control studies (8,869 cases and 20,829 controls total), aimed at determining the association of T1D and T2D gene variants, demonstrated that some of these polymorphisms are associated with the risk of LADA, further supporting the idea of LADA as a combination of both T1D and T2D and emphasizing its heterogeneity (37). The first genome-wide association study of LADA revealed how the leading genetic signals were principally shared with T1D, although positive genetic correlations genome-wide were registered also with T2D.…”

Genetics: Is LADA just late onset type 1 diabetes?

“…The T allele was associated with a reduced risk of T1DM, but was not associated with the risk of LADA. In their meta-analysis, Ramu et al ( 22 ) also showed an inverse association between LADA and the presence of the T allele in the codominant, dominant and recessive models.…”

“…Interestingly, there was a 30-year difference in the mean age of diagnosis between the groups. In their 2019 meta-analysis, Ramu et al ( 22 ) also compared subjects with LADA and healthy controls, and reported a significant association for the risk allele in rs2476601 with LADA in the codominant, dominant and recessive models.…”

Influence of Insulin Receptor Single Nucleotide Polymorphisms on Glycaemic Control and Formation of Anti-Insulin Antibodies in Diabetes Mellitus

“…These SNPs include the common rs3842752, located in the three prime untraslated region (3’ UTR) of the INS mRNA and potentially causing mRNA instability [ 17 ], and rs689 located in an intron splice-site [ 15 , 18 , 19 , 20 ]. In addition to T1D, rs689 has been shown to associate with T2D [ 21 , 22 ] and the relatively prevalent diabetes subtype, latent autoimmune diabetes of adulthood (LADA) [ 23 , 24 ], which resembles the autoimmune nature of T1D and the metabolic profile of T2D [ 25 , 26 ].…”