|(A;A)||1||no increased risk of autoimmune thyroid disease|
|(A;G)||1.5||1.5x risk of autoimmune thyroiditis|
|(G;G)||2.3||2.3x risk of Hashimoto's thyroiditis, 1.47x risk of Graves' disease|
|Disease||Hashimoto thyroiditis Thyroid-associated orbitopathy Systemic lupus erythematosus Diabetes mellitus Celiac disease 3 not specified|
|CLNDBN||Hashimoto thyroiditis, susceptibility to Thyroid-associated orbitopathy, susceptibility to Systemic lupus erythematosus, susceptibility to Diabetes mellitus, insulin-dependent, susceptibility to Celiac disease 3 not specified|
|CLNSRC||OMIM Allelic Variant UniProtKB (protein)|
|CLNACC||RCV000018423.2, RCV000018424.2, RCV000018425.2, RCV000018426.2, RCV000018427.2, RCV000455037.1,|
|qualified_impact||Insufficiently evaluated pharmacogenetic|
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.
[PMID 27638540] 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."
[PMID 27111218] 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)."
[PMID 26963610] 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.
[PMID 25005490] 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."
[PMID 26823853] 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)."
[PMID 26221222] 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).
[PMID 18776148] Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: from epidemiology to mechanisms. 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.
[PMID 22718509] Association between CTLA-4 exon-1 +49A/G polymorphism and systemic lupus erythematosus: an updated analysis. 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)
[PMID 19438904] Clinical associations of the genetic variants of CTLA-4, Tg, TSHR, PTPN22, PTPN12 and FCRL3 in patients with Graves' disease
[PMID 19175525]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.
[PMID 19778566] +49G>A polymorphism in the CTLA-4 gene increases susceptibility to HBV-related HCC in male Chinese population
[PMID 19780033] Association of a functional polymorphism of PTPN22 encoding a lymphoid protein phosphatase in bilateral Meniere's disease
[PMID 19386687] CTLA4 gene polymorphisms are associated with chronic bronchitis
[PMID 20538028] CTLA-4 gene polymorphism +49 A/G is contributed to genetic susceptibility to two infection related cancers: hepatocellular carcinoma and cervical cancer
[PMID 20940051] Polymorphisms of the CTLA4 gene and kidney transplant rejection in Korean patients
[PMID 21040781] CTLA-4 confers a risk of recurrent schizophrenia, major depressive disorder and bipolar disorder in the Chinese Han population
[PMID 21513760] Association of CTLA4 gene polymorphisms with lymphatic filariasis in an East Malaysian population
[PMID 22011251] Cytotoxic T-Lymphocyte Antigen-4 +49G/A Polymorphism and Susceptibility to Pancreatic Cancer
[PMID 15452244] Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection.
[PMID 15726497] Gene-environment interaction effects on the development of immune responses in the 1st year of life.
[PMID 16380915] Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4.
[PMID 16449530] Cytokine polymorphisms in the Th1/Th2 pathway and susceptibility to non-Hodgkin lymphoma.
[PMID 16872485] Three allele combinations associated with multiple sclerosis.
[PMID 17327408] Prognostic significance of host immune gene polymorphisms in follicular lymphoma survival.
[PMID 17683561] The TCF7L2 locus and type 1 diabetes.
[PMID 17825114] Association of CTLA-4 gene polymorphisms with sporadic breast cancer in Chinese Han population.
[PMID 18200060] PTPN22 is genetically associated with risk of generalized vitiligo, but CTLA4 is not.
[PMID 18456185] Genetics and genomics of primary biliary cirrhosis.
[PMID 18528295] Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade.
[PMID 18556337] Impact of diabetes susceptibility loci on progression from pre-diabetes to diabetes in at-risk individuals of the diabetes prevention trial-type 1 (DPT-1).
[PMID 18576317] Lack of association of functional CTLA4 polymorphisms with juvenile idiopathic arthritis.
[PMID 18633131] Host immune gene polymorphisms in combination with clinical and demographic factors predict late survival in diffuse large B-cell lymphoma patients in the pre-rituximab era.
[PMID 18687755] Genetic variants in T helper cell type 1, 2 and 3 pathways and gastric cancer risk in a Polish population.
[PMID 18773895] The genetic basis of primary biliary cirrhosis: premises, not promises.
[PMID 18778710] Primary biliary cirrhosis is associated with a genetic variant in the 3' flanking region of the CTLA4 gene.
[PMID 18805939] Functional genetic polymorphisms and female reproductive disorders: part II--endometriosis.
[PMID 19014504] Lack of association between sCTLA-4 levels in human plasma and common CTLA-4 polymorphisms.
[PMID 19066394] Organochlorine exposure, immune gene variation, and risk of non-Hodgkin lymphoma.
[PMID 19131662] A meta-analysis of candidate gene polymorphisms and ischemic stroke in 6 study populations: association of lymphotoxin-alpha in nonhypertensive patients.
[PMID 19141582] Autoimmune thyroiditis and diabetes: dissecting the joint genetic susceptibility in a large cohort of multiplex families.
[PMID 19147066] Genomic and proteomic analysis of allogeneic hematopoietic cell transplant outcome. Seeking greater understanding the pathogenesis of GVHD and mortality.
[PMID 19173720] Low frequency of CD4+CD25+ Treg in SLE patients: a heritable trait associated with CTLA4 and TGFbeta gene variants.
[PMID 19180256] Genotype analysis of polymorphisms in autoimmune susceptibility genes, CTLA-4 and PTPN22, in an acute anterior uveitis cohort.
[PMID 19188433] Do non-HLA genes influence development of persistent islet autoimmunity and type 1 diabetes in children with high-risk HLA-DR,DQ genotypes?
[PMID 19263529] Genetic risk factors in recurrent venous thromboembolism: A multilocus, population-based, prospective approach.
[PMID 19300490] An African ancestry-specific allele of CTLA4 confers protection against rheumatoid arthritis in African Americans.
[PMID 19330901] Association of 77 polymorphisms in 52 candidate genes with blood pressure progression and incident hypertension: the Women's Genome Health Study.
[PMID 19379518] Development of a fingerprinting panel using medically relevant polymorphisms.
[PMID 19559392] A candidate gene association study of 77 polymorphisms in migraine.
[PMID 19609446] CTLA4 autoimmunity-associated genotype contributes to severe pulmonary tuberculosis in an African population.
[PMID 19622768] CTLA4 variants, UV-induced tolerance, and risk of non-melanoma skin cancer.
[PMID 19672595] Polymorphisms in the CD28/CTLA4/ICOS genes: role in malignant melanoma susceptibility and prognosis?
[PMID 19740340] The CTLA-4 gene polymorphisms are associated with CTLA-4 protein expression levels in multiple sclerosis patients and with susceptibility to disease.
[PMID 19956097] Remapping the type I diabetes association of the CTLA4 locus.
[PMID 19956109] The Type I Diabetes Genetics Consortium 'Rapid Response' family-based candidate gene study: strategy, genes selection, and main outcome.
[PMID 20352109] Association of the CTLA4 gene with Graves' disease in the Chinese Han population.
[PMID 20444755] Investigation of rheumatoid arthritis susceptibility genes identifies association of AFF3 and CD226 variants with response to anti-tumour necrosis factor treatment.
[PMID 20537165] The CTLA4 variants may interact with the IL23R- and NOD2-conferred risk in development of Crohn's disease.
[PMID 20557968] Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients.
[PMID 20565774] Population based allele frequencies of disease associated polymorphisms in the Personalized Medicine Research Project.
[PMID 20610662] Association of single nucleotide polymorphisms in cytotoxic T-lymphocyte antigen 4 and susceptibility to autoimmune type 1 diabetes in Tunisians.
[PMID 20732370] CTLA4 and CD86 gene polymorphisms and susceptibility to chronic obstructive pulmonary disease.
[PMID 21085187] Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP.
[PMID 21453059] Cytotoxic T-lymphocyte antigen-4 +49G/A polymorphism is associated with increased risk of osteosarcoma.
[PMID 21669243] CTLA-4, CD28, and ICOS gene polymorphism associations with non-small-cell lung cancer.
[PMID 21952918] Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus.
[PMID 22076708] Validation of genetic sequence variants as prognostic factors in early-stage head and neck squamous cell cancer survival.
[PMID 22288822] A pilot study on cytotoxic T lymphocyte-4 gene polymorphisms in urinary schistosomiasis.
[PMID 22376040] Gene-gene interactions between candidate gene polymorphisms are associated with total IgE levels in Korean children with asthma.
[PMID 22414241] Cytotoxic T-lymphocyte associated antigen-4 gene polymorphisms and primary biliary cirrhosis: A systematic review.
[PMID 22418270] Polymorphisms in cytotoxic T lymphocyte associated antigen-4 influence the rate of acute rejection after renal transplantation in 167 Chinese recipients.
[PMID 23018253] The impact of rs231775 (+49AG) CTLA4 gene polymorphism on transplanted kidney function
[PMID 23432218] Association between cytotoxic T-lymphocyte antigen 4 gene polymorphisms and primary biliary cirrhosis in Chinese population: data from a multicenter study
[PMID 23480667] Cytotoxic T-Lymphocyte Antigen-4 Genetic Variants and Risk of Ewing's Sarcoma
[PMID 23567921] Cytotoxic T-lymphocyte antigen 4 (CTLA4) +49AG and CT60 gene polymorphisms in Alopecia Areata: a case-control association study in the Italian population
[PMID 23597029] The associations between the polymorphisms in the CTLA-4 gene and the risk of Graves' disease in the Chinese population
[PMID 23661460] CTLA-4 and CD86 genetic variants and haplotypes in patients with rheumatoid arthritis in southeastern China
[PMID 23703660] The -319C/+49G/CT60G Haplotype of CTLA-4 Gene Confers Susceptibility to Rheumatoid Arthritis in Mexican Population
[PMID 23830732] CTLA-4 gene polymorphism at position +49 A>G in exon 1: a risk factor for cervical cancer in Indian women
[PMID 23944755] The impact of CTLA4 and PTPN22 genes polymorphisms on long-term renal allograft function and transplant outcomes
[PMID 23961418] Association of the HLA locus and TNF with type I autoimmune hepatitis susceptibility in New Zealand Caucasians
[PMID 24015180] CTLA4 Gene Polymorphisms Influence the Incidence of Infection after Renal Transplantation in Chinese Recipients
[PMID 24270470] Influence of cytotoxic T lymphocyte-associated antigen 4 polymorphisms on the outcomes of hepatitis B virus infection
[PMID 24298899] Investigation of CTLA-4 and CD86 gene polymorphisms in a group of Iranian patients with brucellosis infection
[PMID 24313821] Association of CTLA-4 Gene Polymorphism with End-Stage Renal Disease and Renal Allograft Outcome
[PMID 24385694] Effect of cytotoxic T-lymphocyte antigen-4, TNF-alpha polymorphisms on osteosarcoma: evidences from a meta-analysis
[PMID 22328738] Comprehensive assessment of rheumatoid arthritis susceptibility loci in a large psoriatic arthritis cohort.
[PMID 22905924] Cytotoxic T-lymphocyte antigen-4 polymorphisms and susceptibility to Ewing's sarcoma.
[PMID 23010350] Lack of association between CTLA-4 +49A/G and -318C/T polymorphisms and Behcet's disease risk: a meta-analysis.
[PMID 23133602] Pharmacogenetics of efficacy and safety of HCV treatment in HCV-HIV coinfected patients: significant associations with IL28B and SOCS3 gene variants.
[PMID 23261825] Association between cytotoxic T lymphocyte antigen-4 polymorphism and type 1 diabetes: a meta-analysis.
[PMID 25005490] The association of PTPN22 rs2476601 polymorphism and CTLA-4 rs231775 polymorphism with LADA risks: a systematic review and meta-analysis
[PMID 25785040] Association between CTLA-4 rs231775 polymorphism and risk of colorectal cancer: a meta analysis
[PMID 25940108] A CT60G>A polymorphism in the CTLA-4 gene of the recipient may confer susceptibility to acute graft versus host disease after allogeneic hematopoietic stem cell transplantation
[PMID 26079279] HCV F protein amplifies the predictions of IL-28B and CTLA-4 polymorphisms about the susceptibility and outcomes of HCV infection in Southeast China
[PMID 26403483] CTLA-4 and CD28 genes' polymorphisms and renal cell carcinoma susceptibility in the Polish population - a prospective study
[PMID 26546236] CTLA-4+49 A/G polymorphism and antiglutamic acid decarboxylase antibody-associated encephalopathy in Taiwanese children
[PMID 26582004] Association of CTLA4 exon-1 polymorphism with the tumor necrosis factor-α in the risk of systemic lupus erythematosus among South Indians
[PMID 28052683] Cytotoxic T Lymphocyte-Associated Antigen 4 rs231775 polymorphism and Osteosarcoma: an updated systematic review and meta-analysis.
[PMID 28384040] CTLA-4 +49 G/A Polymorphism Confers Autoimmune Disease Risk: An Updated Meta-Analysis.