Abstract
CD226 rs763361 variant increases susceptibility to type 1 diabetes (T1D) in Caucasians. There is no data about CD226 variants in the very heterogeneous Brazilian population bearing a wide degree of admixture. We investigated its association with T1D susceptibility, clinical phenotypes, and autoimmune manifestations (islet and extrapancreatic autoantibodies). Casuistry. 532 T1D patients and 594 controls in a case-control study. Initially, CD226 coding regions and boundaries were sequenced in a subset of 106 T1D patients and 102 controls. In a second step, two CD226 variants, rs763361 (exon 7) and rs727088 (3′ UTR region), involved with CD226 regulation, were genotyped in the entire cohort. C-peptide and autoantibody levels were determined. No new polymorphic variant was found. The variants rs763361 and rs727088 were in strong linkage disequilibrium. The TT genotype of rs763361 was associated with TID risk (OR = 1.503; 95% CI = 1.135–1.991; P = 0.0044), mainly in females (P = 0.0012), greater frequency of anti-GAD autoantibody (31.9% × 24.5%; OR = 1.57; CI = 1.136–2.194; P = 0.0081), and lower C-peptide levels when compared to those with TC + CC genotypes (0.41 ± 0.30 ng/dL versus 0.70 ± 0.53 ng/dL P = 0.0218). Conclusions. The rs763361 variant of CD226 gene (TT genotype) was associated with susceptibility to T1D and with the degree of aggressiveness of the disease in T1D patients from Brazil. Ancestry had no effect.
Highlights
Type 1 diabetes is a heterogeneous autoimmune disorder characterized by severe pancreatic β-cell loss [1,2,3,4]
The TT genotype of rs763361 was associated with TID risk (OR = 1.503; 95% CI = 1.135–1.991; P = 0.0044), mainly in females (P = 0.0012), greater frequency of anti-GAD autoantibody (31.9% × 24.5%; OR = 1.57; CI = 1.136–2.194; P = 0.0081), and lower C-peptide levels when compared to those with TC + CC genotypes (0.41 ± 0.30 ng/dL versus 0.70 ± 0.53 ng/dL P = 0.0218)
We found that rs763361 in CD226 is associated with type 1 diabetes risk, mainly in females, and with greater frequency of GAD autoantibody and lower C-peptide levels, probably reflecting a more aggressive pattern of autoimmune aggression
Summary
Type 1 diabetes is a heterogeneous autoimmune disorder characterized by severe pancreatic β-cell loss [1,2,3,4]. The major histocompatibility complex (MHC) contributes to the main risk, followed by the insulin and the protein tyrosine phosphatase nonreceptor 22 (PTPN22) genes (2-4), including in the Brazilian population [5,6,7]. Genetic and environmental factors contribute to the different incidence of T1D among populations. Genetic risk differ among different populations and sometimes even among groups with the same ethnicity [2, 3]. The Brazilian population is one of the most heterogeneous in the world with a wide degree and diverse patterns of admixture. Major contributions come from European ancestry (0.771), followed by African (0.143) and Amerindian ancestries (0.085) [8]. The incidence of T1D seems to be increasing in Mediators of Inflammation
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