{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T22:15:30Z","timestamp":1767651330566},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2007,4,25]],"date-time":"2007-04-25T00:00:00Z","timestamp":1177459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,4,25]]},"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>Systemic sclerosis (SSc) is a complex and heterogeneous autoimmune disorder with a multi-factorial pathogenesis. Like other autoimmune disorders, the possible role of specific cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms in predisposing to SSc has been hypothesized, but it remains controversial. CTLA-4 promoter (\u2212318C\/T) and exon 1 (+49\u2003A\/G) polymorphisms have been analysed in 43 Italian females with SSc and in 93 unrelated matched healthy controls by a newly designed tetra-primer amplification refractory mutation system\u2013polymerase chain reaction (T-ARMS\u2013PCR) method. No significant association has been found with either polymorphisms. Nevertheless, SSc patients without concomitant Hashimoto's thyroiditis (HT) were carrying both the \u2212318T allele (P\u2003=\u20030\u00b7031) and the +49 G allele (P\u2003=\u20030\u00b7076) more frequently than SSc patients with HT [defined by positivity for anti-thyroperoxidase (TPO) and anti-thyroglobulin (TGA) autoantibodies] than controls. Haplotype analysis confirms this association (P\u2003=\u20030\u00b7028), and suggests the predominant role of the \u2212318T, whereas that of the +49 G, if any, seems weak. Thus, in Italian SSc patients the CTLA-4\u2003\u2212318C\/T promoter polymorphism appears to be associated with the susceptibility to develop SSc without thyroid involvement. Larger studies are needed to confirm these findings and to clarify whether the \u2212318C\/T polymorphism is the functional responsible or whether it reflects the presence of another linked genetic element in the same chromosomal region.<\/jats:p>","DOI":"10.1111\/j.1365-2249.2007.03394.x","type":"journal-article","created":{"date-parts":[[2010,8,12]],"date-time":"2010-08-12T14:21:06Z","timestamp":1281622866000},"page":"40-47","source":"Crossref","is-referenced-by-count":40,"title":["Association of \u2212318 C\/T and +49\u2003A\/G cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms with a clinical subset of Italian patients with systemic sclerosis"],"prefix":"10.1093","volume":"149","author":[{"given":"G","family":"Balbi","sequence":"first","affiliation":[{"name":"Department of Oncology, Biology and Genetics"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F","family":"Ferrera","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (DIMI)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Rizzi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (DIMI)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P","family":"Piccioli","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics, Medical Oncology C"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Morabito","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Research A, National Cancer Research Institute, Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L","family":"Cardamone","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (DIMI)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Ghio","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (DIMI)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G L","family":"Palmisano","sequence":"additional","affiliation":[{"name":"Department of Biology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P","family":"Carrara","sequence":"additional","affiliation":[{"name":"Transfusion Service, Galliera Hospital, Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Pedemonte","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics, Medical Oncology C"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Sessarego","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (DIMI)"},{"name":"CEBR, University of Genoa, Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"De Angioletti","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018Adriano Buzzati-Traverso\u2019 (IGB-CNR), Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R","family":"Notaro","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics, Medical Oncology C"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F","family":"Indiveri","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (DIMI)"},{"name":"CEBR, University of Genoa, Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M P","family":"Pistillo","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Research A, National Cancer Research Institute, Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2007,4,25]]},"reference":[{"key":"2022010406293183000_b1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S1568-9972(03)00005-3","article-title":"Systemic sclerosis: current views of its pathogenesis","volume":"2","author":"Derk","year":"2003","journal-title":"Autoimmun Rev"},{"key":"2022010406293183000_b2","doi-asserted-by":"crossref","first-page":"37","DOI":"10.7326\/0003-4819-140-1-200401060-00010","article-title":"Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis","volume":"140","author":"Jimenez","year":"2004","journal-title":"Ann Intern Med"},{"key":"2022010406293183000_b3","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0889-857X(03)00022-X","article-title":"Scleroderma epidemiology","volume":"29","author":"Mayes","year":"2003","journal-title":"Rheum Dis Clin North Am"},{"key":"2022010406293183000_b4","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0889-857X(03)00015-2","article-title":"Systemic sclerosis: the susceptible host (genetics and environment)","volume":"29","author":"Tan","year":"2003","journal-title":"Rheum Dis Clin North Am"},{"key":"2022010406293183000_b5","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s11926-002-0004-2","article-title":"The genetics of systemic sclerosis","volume":"4","author":"Johnson","year":"2002","journal-title":"Curr Rheumatol Rep"},{"key":"2022010406293183000_b6","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/nature01621","article-title":"Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease","volume":"423","author":"Ueda","year":"2003","journal-title":"Nature"},{"key":"2022010406293183000_b7","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1146\/annurev.immunol.24.021605.090535","article-title":"A molecular perspective of CTLA-4 function","volume":"24","author":"Teft","year":"2006","journal-title":"Annu Rev Immunol"},{"key":"2022010406293183000_b8","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1002\/ijc.21155","article-title":"CTLA-4 is constitutively expressed on tumor cells and can trigger apoptosis upon ligand interaction","volume":"117","author":"Contardi","year":"2005","journal-title":"Int J Cancer"},{"key":"2022010406293183000_b9","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1182\/blood-2002-06-1668","article-title":"CTLA-4 is not restricted to the lymphoid cell lineage and can function as a target molecule for apoptosis induction of leukemic cells","volume":"101","author":"Pistillo","year":"2003","journal-title":"Blood"},{"key":"2022010406293183000_b10","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.4049\/jimmunol.165.3.1352","article-title":"CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression","volume":"165","author":"Carreno","year":"2000","journal-title":"J Immunol"},{"key":"2022010406293183000_b11","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1111\/j.0105-2896.2005.00249.x","article-title":"CTLA4 gene polymorphism and autoimmunity","volume":"204","author":"Gough","year":"2005","journal-title":"Immunol Rev"},{"key":"2022010406293183000_b12","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/S0198-8859(03)00171-X","article-title":"CTLA4 polymorphism in Spanish patients with systemic lupus erythematosus","volume":"64","author":"Aguilar","year":"2003","journal-title":"Hum Immunol"},{"key":"2022010406293183000_b13","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.clim.2005.09.017","article-title":"Genetic analysis and functional evaluation of the C\/T (-318) and A\/G (-1661) polymorphisms of the CTLA-4 gene in patients affected with Graves' disease","volume":"118","author":"Chistiakov","year":"2006","journal-title":"Clin Immunol"},{"key":"2022010406293183000_b14","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1111\/j.1365-2249.1997.t01-1-512-ce1410.x","article-title":"CTLA-4 gene polymorphism confers susceptibility to insulin-dependent diabetes mellitus (IDDM) independently from age and from other genetic or immune disease markers","volume":"110","author":"Van der Auwera","year":"1997","journal-title":"The Belgian Diabetes Registry. Clin Exp Immunol"},{"key":"2022010406293183000_b15","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1093\/rheumatology\/41.2.180","article-title":"An association between the CTLA4 exon 1 polymorphism and early rheumatoid arthritis with autoimmune endocrinopathies","volume":"41","author":"Vaidya","year":"2002","journal-title":"Rheumatology (Oxf)"},{"key":"2022010406293183000_b16","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/sj.gene.6363816","article-title":"CDS1 and promoter single nucleotide polymorphisms of the CTLA-4 gene in human myasthenia gravis","volume":"3","author":"Wang","year":"2002","journal-title":"Genes Immun"},{"key":"2022010406293183000_b17","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.yexmp.2004.10.001","article-title":"CTLA4 and multiple sclerosis in the Italian population","volume":"78","author":"Malferrari","year":"2005","journal-title":"Exp Mol Pathol"},{"key":"2022010406293183000_b18","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0198-8859(02)00782-6","article-title":"CTLA-4 +49 A\/G dimorphism in Italian patients with celiac disease","volume":"64","author":"Mora","year":"2003","journal-title":"Hum Immunol"},{"key":"2022010406293183000_b19","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/sj.gene.6364313","article-title":"Association of CTLA-4 gene promoter polymorphisms with systemic sclerosis in Iranian population","volume":"7","author":"Almasi","year":"2006","journal-title":"Genes Immun"},{"key":"2022010406293183000_b20","first-page":"85","article-title":"Ethnic differences in cytotoxic T lymphocyte associated antigen 4 genotype associations with systemic sclerosis","volume":"31","author":"Hudson","year":"2004","journal-title":"J Rheumatol"},{"key":"2022010406293183000_b21","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s00296-005-0047-6","article-title":"Exon-1 polymorphism of CTLA-4 gene is not associated with systemic sclerosis in Iranian patients","volume":"26","author":"Rajaee","year":"2006","journal-title":"Rheumatol Int"},{"key":"2022010406293183000_b22","first-page":"823","article-title":"Association of CTLA-4 with systemic sclerosis in Japanese patients","volume":"20","author":"Takeuchi","year":"2002","journal-title":"Clin Exp Rheumatol"},{"key":"2022010406293183000_b23","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/art.1780230510","article-title":"Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee","volume":"23","author":"American Rheumatism Association","year":"1980","journal-title":"Arthritis Rheum"},{"key":"2022010406293183000_b24","first-page":"202","article-title":"Scleroderma (systemic sclerosis): classification, subsets and pathogenesis","volume":"15","author":"LeRoy","year":"1988","journal-title":"J Rheumatol"},{"key":"2022010406293183000_b25","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1093\/nar\/20.5.1152","article-title":"Allele specific amplification by tetra-primer PCR","volume":"20","author":"Ye","year":"1992","journal-title":"Nucl Acids Res"},{"key":"2022010406293183000_b26","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1111\/j.1349-7006.2000.tb01026.x","article-title":"Polymerase chain reaction with confronting two-pair primers for polymorphism genotyping","volume":"91","author":"Hamajima","year":"2000","journal-title":"Jpn J Cancer Res"},{"key":"2022010406293183000_b27","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1373\/clinchem.2005.060137","article-title":"Multiplex tetra-primer amplification refractory mutation system PCR to detect 6 common germline mutations of the MUTYH gene associated with polyposis and colorectal cancer","volume":"52","author":"Piccioli","year":"2006","journal-title":"Clin Chem"},{"key":"2022010406293183000_b28","doi-asserted-by":"crossref","first-page":"S89","DOI":"10.1038\/sj.bmt.1704855","article-title":"The polymorphisms \u2212318C\u2003&gt;\u2003T in the promoter and 49A\u2003&gt;\u2003G in exon 1 of CTLA4 and the risk of aplastic anemia in a Caucasian population","volume":"35","author":"Svahn","year":"2005","journal-title":"Bone Marrow Transplant"},{"key":"2022010406293183000_b29","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.4049\/jimmunol.167.5.2457","article-title":"Technical note. linkage disequilibrium and disease-associated CTLA4 gene polymorphisms","volume":"167","author":"Holopainen","year":"2001","journal-title":"J Immunol"},{"key":"2022010406293183000_b30","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1744-313X.2006.00574.x","article-title":"Thyroid autoantibody production is influenced by exon 1 and promoter CTLA-4 polymorphisms in patients with Hashimoto's thyroiditis","volume":"33","author":"Zaletel","year":"2006","journal-title":"Int J Immunogenet"},{"key":"2022010406293183000_b31","first-page":"43","article-title":"Hashimoto's thyroiditis is associated with peripheral lymphocyte activation in patients with systemic sclerosis","volume":"23","author":"Farzati","year":"2005","journal-title":"Clin Exp Rheumatol"},{"key":"2022010406293183000_b32","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1677\/jme.0.0310021","article-title":"CTLA-4 and its role in autoimmune thyroid disease","volume":"31","author":"Chistiakov","year":"2003","journal-title":"J Mol Endocrinol"},{"key":"2022010406293183000_b33","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1089\/105072501300042901","article-title":"Association of DRB1*04-DQB1*0301 haplotype and lack of association of two polymorphic sites at CTLA-4 gene with Hashimoto's thyroiditis in an Italian population","volume":"11","author":"Petrone","year":"2001","journal-title":"Thyroid"},{"key":"2022010406293183000_b34","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/sj.gene.6363869","article-title":"A CTLA-4 gene polymorphism at position -318 in the promoter region affects the expression of protein","volume":"3","author":"Wang","year":"2002","journal-title":"Genes Immun"},{"key":"2022010406293183000_b35","doi-asserted-by":"crossref","first-page":"3596","DOI":"10.1002\/(SICI)1521-4141(199911)29:11<3596::AID-IMMU3596>3.0.CO;2-Y","article-title":"A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells","volume":"29","author":"Magistrelli","year":"1999","journal-title":"Eur J Immunol"},{"key":"2022010406293183000_b36","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1093\/rheumatology\/keh303","article-title":"Serum soluble CTLA-4 levels are increased in diffuse cutaneous systemic sclerosis","volume":"43","author":"Sato","year":"2004","journal-title":"Rheumatology (Oxf)"},{"key":"2022010406293183000_b37","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/ng1001-233","article-title":"Haplotype tagging for the identification of common disease genes","volume":"29","author":"Johnson","year":"2001","journal-title":"Nat Genet"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1365-2249.2007.03394.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/149\/1\/40\/42037403\/j.1365-2249.2007.03394.x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/149\/1\/40\/42037403\/j.1365-2249.2007.03394.x.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T06:48:40Z","timestamp":1641278920000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/149\/1\/40\/6457737"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,4,25]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2007,4,25]]},"published-print":{"date-parts":[[2007,4,25]]}},"URL":"https:\/\/doi.org\/10.1111\/j.1365-2249.2007.03394.x","relation":{},"ISSN":["0009-9104","1365-2249"],"issn-type":[{"value":"0009-9104","type":"print"},{"value":"1365-2249","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2007,7]]},"published":{"date-parts":[[2007,4,25]]}}}