Association of −318 C/T and +49 A/G cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms with a clinical subset of Italian patients with systemic sclerosis

Abstract

SummarySystemic 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 (-318C/T) and exon 1 (+49 A/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-polymerase chain reaction (T-ARMS-PCR) method. No significant association has been found with either polymorphisms. Nevertheless, SSc patients without concomitant Hashimoto's thyroiditis (HT) were carrying both the -318T allele (P = 0·031) and the +49 G allele (P = 0·076) 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 = 0·028), and suggests the predominant role of the -318T, whereas that of the +49 G, if any, seems weak. Thus, in Italian SSc patients the CTLA-4 -318C/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 -318C/T polymorphism is the functional responsible or whether it reflects the presence of another linked genetic element in the same chromosomal region.

Updated analysis of studies on the cytotoxic T-lymphocyte-associated antigen-4 gene A49G polymorphism and Hashimoto's thyroiditis risk

“…Our meta-analysis, including 2295 patients with HT and 4521 controls, investigated the association of A49G polymorphism with HT in all studies and in ethnicity and age subgroups from the 24 studies. We included 11 novel case-control studies (Balbi et al, 2007;Dallos et al, 2008;Yesilkaya et al, 2008;Yu et al, 2008;Bicek et al, 2009;Kucharska et al, 2009;Sahin et al, 2009;Shi et al, 2010;Benhatchi et al, 2011;Yang et al, 2012;Farra et al, 2012). Furthermore, we excluded studies when the genotype distribution in controls was not in HWE (Shi et al, 2010).…”

“…In total, 2165 HT patients and 4284 controls were examined. Of these 24 articles, 17 were published in English (Donner et al, 1997;Awata et al, 1998;Kouki et al, 2000;Petrone et al, 2001;Tomoyose et al, 2002;Terauchi et al, 2003;Ueda et al, 2003;Balbi et al, 2007;Kavvoura et al, 2007;Dallos et al, 2008;Yesilkaya et al, 2008;Bicek et al, 2009;Kucharska et al, 2009;Sahin et al, 2009;Benhatchi et al, 2011;Yang et al, 2012;Farra et al, 2012), and 4 were in Chinese (Wang et al, 2001;Zhou et al, 2003;Yu et al, 2008;Shi et al, 2010). Three unpublished articles contained results of a study by Kavvoura et al (2007).…”

“…Of the 24 case-controls studies examining the association between the CTLA-4 A49G polymorphism and HT risk, 11 included East Asians [Awata et al, 1998;Park et al, 2000;Wang et al, 2001;Tomoyose et al, 2002;Terauchi et al, 2003;Zhou et al, 2003;Kavvoura et al, 2007 (a metaanalysis, which included 2 unpublished studies: Ban et al and Ghaderi et al); Yu et al, 2008;Shi et al, 2010;Yang et al, 2012]; 9 included whites (Donner et al, 1997;Kouki et al, 2000;Petrone et al, 2001;Ueda et al, 2003;Balbi et al, 2007;Dallos et al, 2008;Bicek et al, 2009;Kucharska et al, 2009;Benhatchi et al, 2011); 4 included the Middle Easterners: two studies that included Turks (Yesilkaya et al, 2008;Sahin et al, 2009), one that included Iranians (Kavvoura et al, 2007), and one that included Lebanese (Farra et al, 2012). Twenty-one studies were performed in adults, whereas 3 were in children (Dallos et al, 2008;Yesilkaya et al, 2008;Kucharska et al, 2009).…”

“…Based on our search strategy, the primary screening produced 33 potentially relevant articles, of which 24 studies met the inclusion criteria after evaluating the association of the A49G polymorphism with HT [Donner et al, 1997;Awata et al, 1998;Kouki et al, 2000;Park et al, 2000;Petrone et al, 2001;Wang et al, 2001;Tomoyose et al, 2002;Terauchi et al, 2003;Ueda et al, 2003;Zhou et al, 2003;Balbi et al, 2007;Kavvoura et al, 2007 (a meta-analysis, which included 3 unpublished studies: Ban et al; Akazumi et al; Ghaderi et al); Dallos et al, 2008;Yesilkaya et al, 2008;Yu et al, 2008;Bicek et al, 2009;Kucharska et al, 2009;Sahin et al, 2009;Shi et al, 2010;Benhatchi et al, 2011;Yang et al, 2012;Farra et al, 2012]. In total, 2165 HT patients and 4284 controls were examined.…”

Polymorphism analysis of the CTLA-4 gene in paracoccidioidomycosis patients

“…CTLA-4 is an inhibitory receptor expressed transiently on activated CD4 + and CD8 + T lymphocytes and constitutively on CD4 + CD25 + T regulatory lymphocytes (Treg) and a few non-lymphoid cells (Balbi et al 2007). CTLA-4, a receptor structurally homologous to CD28, acts as a negative regulator of T cell responses by interacting with B7 molecules on antigen presenting cells; in contrast, a costimulatory signal is evoked by CD28-B7 interaction (Ling et al 2001, Butty et al 2007).…”