CD226rs763361 Is Associated with the Susceptibility to Type 1 Diabetes and Greater Frequency of GAD65 Autoantibody in a Brazilian Cohort

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.

Association of CD226 polymorphisms with the susceptibility to type 1 diabetes in Chinese children

“…In our analysis, the minor T allele appeared to be aggressive, with 28.3% of children with T1D carrying the TT genotype compared with 11.2% of the healthy controls. These findings confirm previously published data from Brazilian cohorts published by Mattana et al (2014), which showed that the presence of the T allele might be one of the genetic risk factors for T1D.…”

“…In previous studies, the rs763361 SNP in the CD226 gene has been reported to be associated with susceptibility to autoimmune diseases Douroudis et al, 2010;Maiti et al, 2010), including T1D in a Brazilian population (Mattana et al, 2014). Moreover, Lofgren et al (2010) identified the potential interference of the rs727088 SNP on the regulation of CD226 transcription both in T cells and natural killer cells.…”

“…Therefore, the exact effect of polymorphisms in CD226 requires additional investigation. Mattana et al (2014) revealed that the gender of the subjects is a factor in T1D risk, as their study found that T1D risk associated with the rs763361 SNP was higher in females than males. This suggests an additive effect of female hormones with this SNP.…”

“…The association of the rs763361 or rs727088 SNPs with T1D risk was also investigated in several studies. In their study on a Brazilian population, Mattana et al (2014) reported that the rs763361 SNP in CD226 is associated with susceptibility to T1D. Moreover, two SNPs (rs763361 and rs727088) in the CD226 gene were associated with SLE and systemic sclerosis-related pulmonary fibrosis (Lofgren et al, 2010).…”

Critical roles of co‐activation receptor DNAX accessory molecule‐1 in natural killer cell immunity

“…A single nucleotide polymorphism in CD226 can result in the amino acid substitution Gly 307 Ser (rs763361). This correlates with the development of a wide range of immune‐related diseases, such as systemic lupus erythematosus, systemic sclerosis (SSc), type I diabetes and rheumatoid arthritis (RA) …”