rs231775

rs231775, also known as +49A>G (or CTLA-4 A49G), is a polymorphism of the CTLA4 gene. Polymorphisms are associated with several autoimmune diseases, especially autoimmune thyroiditis, as well as several other disorders. A 2017 study titled "CD28/CTLA-4/ICOS haplotypes confers susceptibility to Graves’ disease and modulates clinical phenotype of disease" found that rs5742909 CC and rs231775 G allele "were associated with the family burden of GD" (Graves' disease, a form of Autoimmune thyroiditis). The G allele at rs231775 did not affect risk for Graves' Orbitopathy (GO), but favored severe disease outcome for GO. The presence of the A allele "was significantly associated with sporadic GD." A 2016 study titled "Association of Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) Gene Polymorphisms with Autoimmune Thyroid Disease in Children and Adults: Case-Control Study" found that in a Han Chinese population, rs231775 "Genotype G/G conferred a risk of 1.55 (95% CI, 1.20–2.02; Pc = 0.002) for GD (Graves' disease) in adults and of 1.56 (95% CI, 1.19–2.05; Pc = 0.002) in children. Allele G was significantly associated with GD (Graves' disease) in adults (OR, 1.50; 95% CI, 1.21–1.84; Pc < 0.001) and in children (OR, 1.42; 95% CI, 1.15–1.77; Pc = 0.002)." A 2016 study titled "Association of Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Thyroglobulin (TG) Genetic Variants with Autoimmune Hypothyroidism" sampled 84 hypothyroidism patients and 62 controls from Gujarat, India. Researchers found that CTLA4 Exon1 (+49A/G) rs231775 polymorphisms increased the odds of autoimmune hypothyroidism in their sample: Odds ratios were * for AA, 1.0 (Genotypes were similar between patients and controls) * for AG, 5.333 (95%CI 2.043 to 13.92, p=0.0004) compared to AA * for GG, 5.778 (95%CI 1.829 to 18.25, p=0.0004) compared to AA They also discovered that polymorphisms of rs231775 were associated with significantly decreased mRNA expression of both full length (flCTLA4) and soluble (sCTLA4) transcripts. * AA genotypes were similar between patients and controls. * AG decreased expression of both significantly (by p = 0.0141 for flCTLA4, and by p = 0.0358 for sCTLA4) in patients compared to controls * GG decreased expression levels slightly (by p = 0.0007 for flCTLA4, and by p = 0.0102 for sCTLA4) in patients compared to controls They also found significant differences in patients vs. controls when analyzing the TG exon 33 SNP rs2076740. A 2014 study titled "The association of PTPN22 rs2476601 polymorphism and CTLA-4 rs231775 polymorphism with LADA risks: a systematic review and meta-analysis" examined Latent Autoimmune Diabetes in Adults (LADA) and found that "The minor T allele at rs2476601 and the minor G at rs231775 carried estimated relative risks (odds ratio) of 1.52 (95 % CI 1.29–1.79) and 1.39 (95 % CI 1.11–1.74), respectively. These alleles contributed to an absolute lowering of the risk of all LADA (latent autoimmune diabetes in adults) by 4.88 and 14.93 % when individuals do not carry these alleles." Researchers stated that "LADA accounts for 2–12 % of all cases of diabetes" but "The progression to insulin dependence in LADA patients is believed more rapidly than classic type 2 diabetes patients" and "8–10 % of patients diagnosed with T2D are in fact misdiagnosed LADA." A 2015 study titled "Association between CTLA-4 rs231775 polymorphism and hepatocellular carcinoma susceptibility" revealed that "The frequencies of genotype AA and allele A in CTLA-4 rs231775 polymorphism were significantly higher in cases" of liver cancer than the control group (AA vs. GG: OR=2.81, P=0.043; A vs. G: OR=1.63, P=0.022). Meanwhile, the genetic expression level of CTLA-4 was remarkably higher in cases compared with the controls. The association analysis indicated that AA genotype carriers exhibited highest level of CTLA-4 (P<0.01)." A 2015 study titled "Associations between CTLA-4 +49 A/G (rs231775) polymorphism and cancer risk: a meta-analysis based on 52 case-control studies" stated "This meta-analysis suggests that the CTLA-4 +49 A/G polymorphism may be a protective factor for cancer." The minor G allele decreased cancer risk overall and for a large number of cancer types, "especially for breast cancer, lung cancer, and other cancers, epithelial tumor, respiratory system cancer, reproductive and breast cancer, malignant bone tumor," "but not digestive system cancer, hematopoietic malignancy and skin cancer." Most of the decreased cancer risk was in Asian populations. Table 3 data demonstrated "association between the risk of cancer and the CTLA-4 +49 A/G polymorphism (GG+AG vs. AA)." Although most of the Asian data showed "decreased risk," a few studies showed extreme increased risk, and these data skewed the average OD. On average, the data showed 0.85 OD of decreased cancer risk overall (0.98 for Caucasians and 0.76 for Asians). In this 2008 article, researchers reported that "One of the best demonstrations of the power of subset analysis is the CTLA-4 gene in T1D. Although CTLA-4 showed very weak association with T1D, when analyzed in the subset of patients with both T1D and AITD, the genetic effect of CTLA-4 was significantly stronger." Note: rs231775 is one SNP within the CTLA-4 gene. . Published 2012. From abstract: "The combined results showed that there were significant differences in genotype distribution between SLE cases and control on the basis of all studies, GG versus AA (OR = 1.53, 95 % CI: 1.12-2.10), GG versus GA/AA (OR = 1.30, 95 % CI: 1.04-1.64), GG versus GA (OR = 1.27, 95 % CI: 1.03-1.55). When stratifying for the race, the phenomenon was found that SLE cases had a significantly higher frequency of GG/GA versus AA (OR = 1.58, 95 % CI: 1.23-2.03), GG versus AA (OR = 1.89, 95 % CI: 1.23-2.91), GG versus GA/AA(OR = 1.39, 95 % CI: 1.03-1.89), GA versus AA(OR = 1.38, 95 % CI: 1.06-1.80) and G versus A(OR = 1.34, 95 % CI: 1.07-1.67) than control in Asians." (Abstract) rs231775 (CTLA4_+49_G/A P=0.0219) and rs733618 (CTLA4_-1722_T/C P=0.0096) susceptibility to Graves' disease associated with the development of placental abruption and preeclampsia, with women having the G allele being at risk rs231775 was not associated with type-1 diabetes in a study of 207 Portuguese patients. In a meta-analysis of CTLA4 gene SNPs, rs231775 was most associated with vitiligo; however, the association seems to hold only in the subgroup of patients with other autoimmune diseases.

A;A

see text at rs231775

A;G

see text at rs231775

G;G

see text at rs231775