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Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade.

ABSTRACT: Blockade of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a down-regulator of T-cell activation, can cause cancer regression in patients with metastatic melanoma. However, not all patients respond well to the therapy and some develop severe autoimmune reactions. We hypothesized that common genetic variation in the CTLA4 gene could contribute to response to CTLA-4 blockade and the occurrence of autoimmune reactions. We investigated 7 common single nucleotide polymorphisms, SNPs, (rs733618, rs4553808, rs11571317, rs5742909, rs231775, rs3087243, and rs7565213) in 152 white melanoma patients who received CTLA-4 blockade. Three SNPs were associated with response to therapy: proximal promoter SNPs, rs4553808 [P=0.002; odds ratio (OR) 3.39; 95% confidence interval (CI), 1.62-7.10] and rs11571327 (P=0.02; OR 2.89; 95% CI, 1.23-6.83) and the nonsynonymous SNP rs231775 (Thr17Ala, P=0.009; OR 0.39; 95% CI, 0.18-0.82). A haplotype analysis including the 7 SNPs suggested that the common haplotype, TACCGGG could be associated with no response (P=0.02) whereas the haplotype TGCCAGG (P=0.06; OR 4.13; 95% CI, 1.17-14.5) could be associated with response to the treatment. No significant association was observed for occurrence of severe autoimmune reactions (grade III/IV) either by single SNP or haplotype analyses. Our results suggest that genetic variation in CTLA4 could influence response to CTLA-4 blockade therapy in metastatic melanoma patients, but further studies are necessary to confirm the observed associations.

SUBMITTER: Breunis WB

PROVIDER: S-EPMC3276400 | biostudies-literature | 2008 Jul-Aug

REPOSITORIES: biostudies-literature

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Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade.

Breunis Willemijn B WB Tarazona-Santos Eduardo E Chen Renee R Kiley Maureen M Rosenberg Steven A SA Chanock Stephen J SJ

Journal of immunotherapy (Hagerstown, Md. : 1997) 20080701 6

Blockade of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a down-regulator of T-cell activation, can cause cancer regression in patients with metastatic melanoma. However, not all patients respond well to the therapy and some develop severe autoimmune reactions. We hypothesized that common genetic variation in the CTLA4 gene could contribute to response to CTLA-4 blockade and the occurrence of autoimmune reactions. We investigated 7 common single nucleotide polymorphisms, SNPs, (rs73 ...[more]

PMID: 18528295

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Project description:Autoimmune hypothyroidism is known to be caused by immune responses related to the thyroid gland and its immunological feature includes presence of autoimmune antibodies. Therefore the aim was to analyze presence of anti-TPO antibodies in hypothyroidism patients in Gujarat. Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) is one of the susceptibility genes for various autoimmune diseases. Hence, exon1 +49A/G and 3'UTR CT60A/G single nucleotide polymorphisms (SNPs) in CTLA4 and its mRNA expression levels were investigated in autoimmune hypothyroidism patients. Thyroglobulin (TG) is known to be associated with autoimmune thyroid disorders and thus exon 33 (E33) SNP in TG was investigated. We analyzed the presence of anti-TPO antibodies in the plasma samples of 84 hypothyroidism patients and 62 controls by ELISA. PCR-RFLP technique was used for genotyping of polymorphisms. sCTLA4 and flCTLA4 mRNA expression levels were assessed by real time PCR. 59.52% of hypothyroid patients had anti-TPO antibodies in their circulation. The genotype and allele frequencies differed significantly for +49A/G (p = 0.0004 for +49AG, p = 0.0019 for +49GG & p = 0.0004 for allele), CT60 (p = 0.0110 for CT60AG, p = 0.0005 for CT60GG & p<0.0001 for allele) and TG E33 (p = 0.0003 for E33TC p<0.0001 for E33CC& p<0.0001 for allele) SNPs between patients and controls. Patients had significantly decreased mRNA levels of both sCTLA4 (p = 0.0017) and flCTLA4 (p<0.0001) compared to controls. +49A/G and CT60 polymorphisms of CTLA4 were in moderate linkage disequilibrium. Logistic regression analysis indicated significant association of CT49A/G, CT60A/G and TG exon 33 polymorphisms with susceptibility to autoimmune hypothyroidism when adjusted for age and gender. Our results suggest +49A/G and CT60 polymorphism of CTLA4 and E33 polymorphism of TG may be genetic risk factors for autoimmune hypothyroidism susceptibility and down regulation of both forms of CTLA4 advocates the crucial role of CTLA4 in pathogenesis of autoimmune hypothyroidism.

Dataset Information

Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade.

Publications

Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade.

Similar Datasets

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