Cytotoxic T-lymphocyte-associated protein 4 +49A/G polymorphisms contribute to the risk of type 1 diabetes in children: An updated systematic review and meta-analysis with trial sequential analysis

Abstract

Type 1 diabetes (T1D) is a heritable disease associated with multiple genetic variants. This systematic review and meta-analysis assessed the correlation between cytotoxic T-lymphocyte-associated protein 4(CTLA-4) +49A/G polymorphisms and the risk of T1D in children. The random effects model was used to estimate the related odds ratios (ORs) and 95% confidence intervals (CIs). Trial sequential analysis (TSA) was used to determine whether the currently available evidence was sufficient and conclusive. Our results indicated that CTLA-4 gene polymorphisms significantly increased the risk of childhood T1D in an allelic model (G vs. A: OR=1.33, 95%CI=1.19-1.48; I2=44.0% and P=0.001for heterogeneity) and a codominant model (GG vs. AA: OR=1.75, 95%CI=1.37-2.24; I2=57.5% and P=0.001for heterogeneity; GA vs. AA: OR=1.26, 95%CI=1.09-1.46; I2=40.4% and P=0.036for heterogeneity). Subgroup analysis results indicated that the ORs were higher in the Asian population (ORallelic model=1.60, ORGG vs. AA=2.46 and ORGA vs. AA=1.58) than the Caucasian population (ORallelic model==1.24, ORGG vs. AA=1.55 and ORGA vs. AA=1.19). The TSA results indicated that the evidence of the effect was sufficient. In conclusion, CTLA4 +49A/G polymorphisms increased the risk of T1D in children, and CTLA4 +49A/G can be considered to be a genetic marker for T1D in children.

Fulminant type 1 diabetes associated with Isolated ACTH deficiency induced by anti-programmed cell death 1 antibody—insight into the pathogenesis of autoimmune endocrinopathy—

“…Our case, however, presented HLA-DR4(-) and the risk allele reported in the pediatric and general population [24]; suggesting the existence of another mechanism of CTLA4 polymorphism involvement. Regarding the interaction of these molecules, although the working site on T cells differed, one report suggested regulating the soluble CTLA-4 concentration alongside the "G" code of CTLA-4 in patients with T1D [26].…”

“…Although the CTLA4 blockade induces the disease only in neonates, PD-1-PD-L1 interaction regulates the induction and progression of autoimmune diabetes in the NOD mouse at all ages, suggesting that PD-1 is involved both in inhibiting naïve T cells and the effector function of activated autoreactive T cells [23]. Regarding the role of CTLA4 in the development of autoimmune diabetes, polymorphisms of the allele reportedly exacerbate the risk of disease onset in pediatric and general population studies [24]. However, the risk allele of CTLA4 polymorphism for T1D or fulminant diabetes remains controversial.…”

Autoimmune thyroid disease and type 1 diabetes mellitus: same pathogenesis; new perspective?

“… 135 – 137 Therefore, meta-analyses support the findings that CTLA-4 polymorphism is a risk factor for T1DM susceptibility. 121 , 132 , 138 – 142 …”

Association of variants inPTPN22,CTLA‐4,IL2‐RA, andINSgenes with type 1 diabetes in Emiratis

“…This association of CTLA‐4 with T1D was first identified in European‐derived populations (Nisticò et al., 1996). The G allele of CTLA‐4 rs231775 has been shown to be associated with increased risk for T1D in different populations from Tunisia (Benmansour et al., 2010), Egypt (Saleh, Rohowsky, & Leski, 2008), Iran (Ahmadi et al., 2013), North America (Qu et al., 2009), and Asia (Wang, Du, Jia, Zhang, & Ma, 2017). This is in agreement with our findings.…”