Elsevier

Gene

Volume 568, Issue 2, 1 September 2015, Pages 196-202
Gene

Research paper
Lack of association between cytotoxic T-lymphocyte antigen-4 + 49A/G polymorphism and psoriasis and vitiligo: A meta-analysis of case–control studies

https://doi.org/10.1016/j.gene.2015.05.051Get rights and content

Highlights

  • CTLA-4 + 49A/G was not associated with psoriasis in overall analyses.

  • CTLA-4 + 49A/G showed a protective effect for psoriasis in some subgroup analyses.

  • CTLA-4 + 49A/G did not seem to contribute to vitiligo susceptibility.

Abstract

Background

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a critical negative regulator of T-cell activation and proliferation. Several studies have assessed the association between CTLA-4 + 49A/G polymorphism and psoriasis and vitiligo, but the results are inconsistent.

Aims

This study was conducted to examine the association between CTLA-4 + 49A/G polymorphism and psoriasis and vitiligo susceptibility.

Methods

The PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases were searched according to predefined criteria for all relevant studies published prior to July 3, 2014. Odds ratios (ORs) with 95% confidence intervals (CIs), and heterogeneity and publication bias tests were performed to estimate the strength of the association.

Results

Fourteen studies comprising six on psoriasis (700 cases, 781 controls) and eight on vitiligo (1514 cases, 2049 controls) were included. Overall, no significant association was detected between CTLA-4 + 49A/G polymorphism and psoriasis. There was still no significant relationship when the studies were limited to ethnicity (Asian and Caucasian), HWE or heterogeneity, except the limitation to heterogeneity in the dominant (OR = 0.69, 95% CI = 0.51–0.93, I2 = 0.0%) and additive (OR = 0.69, 95% CI = 0.48–0.98, I2 = 0.0%) models, and the limitation to both heterogeneity and HWE in the dominant model (OR = 0.68, 95% CI = 0.48–0.98, I2 = 0.0%). Both overall and subgroup analyses based on ethnicity, genotype frequencies, and heterogeneity also failed to demonstrate an association between CTLA-4 + 49A/G polymorphism and vitiligo.

Conclusion

CTLA-4 + 49A/G polymorphism may not contribute to psoriasis and vitiligo susceptibility, but further well-designed studies with large sample size are warranted to confirm this conclusion.

Introduction

Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation and accumulation of activated T cells in the epidermis and dermis of psoriatic lesions (Bhalerao and Bowcock, 1998). Vitiligo is another skin disorder distinguished by progressive loss of pigmentation owing to autoimmune attack against melanocytes in the epidermis (van Geel et al., 2014). The pathogenesis underlying both diseases is still unknown, but it is widely accepted that complex interactions between genetic and environmental factors predisposing patients to autoimmune destruction contribute to disease development. In fact, both conditions often occur together with other autoimmune diseases, e.g., autoimmune thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, and autoimmune diabetes (Alkhateeb et al., 2003, Karn and Kc, 2012). Environmental triggers, particularly stress, infection, and trauma, have been correlated with both diseases (Barisic-Drusko and Rucevic, 2004). Association studies have implicated several genes in susceptibility to both diseases, such as those for the major histocompatibility complex (Mabuchi et al., 2007), TNF-α (Zhuang et al., 2013), protein tyrosine phosphatase non-receptor type 22 (PTPN22) (Song et al., 2013), and cytotoxic T-lymphocyte antigen-4 (CTLA-4) (Muto et al., 2011, Song et al., 2013), which are thought to play important roles in the development of autoimmunity. These genes may, at the least, represent a common affected event in the pathologic processes of psoriasis and vitiligo, although a recent retrospective study failed to find an increased prevalence of psoriasis in individuals with vitiligo, or vice versa (Sawchuk et al., 2012).

CTLA-4 (also known as CD152), down-regulates T-cell activation and proliferation and plays an essential role in immunologic homeostasis. The CTLA-4 gene, localized on human chromosome 2q33, is a glycoprotein receptor expressed on activated and regulatory T cells. CTLA-4 exerts its immunomodulatory effects through competition with CD28 for binding to the CD80 and CD86 ligands, and thereby inhibits a second signal required for optimal T-cell activation (Kristiansen et al., 2000, Leibson, 2004). Thus, any variation in CTLA-4 expression and function, such as that caused by polymorphisms at certain locations of the gene, might conceivably lead to the breakdown of the delicate homeostasis of the immune system (Wang et al., 2002). More than 100 single-nucleotide polymorphisms (SNPs) have been identified in the CTLA-4 gene, of which the CTLA-4 + 49A/G polymorphism is the most widely studied (Song et al., 2013). This SNPresides in the first exon changes the primary amino acid sequence (threonine to alanine), which reduces cell surface expression (Maurer et al., 2002). Furthermore, individuals with the G/G genotype at position + 49 show higher proliferation and activation of T cells than the A/A genotype (Kouki et al., 2000, Maurer et al., 2002).

Some studies have looked for a possible association between CTLA-4 + 49A/G polymorphism and psoriasis (Hao et al., 2003, Kim et al., 2003, Tsunemi et al., 2003, Luszczek et al., 2008, Fernandez-Mestre et al., 2009, Muto et al., 2011) or vitiligo (Blomhoff et al., 2005, Gao et al., 2005, Tang, 2007, Birlea et al., 2009, Pehlivan et al., 2009, Deeba et al., 2010, Dwivedi et al., 2011), but the findings have been inconclusive. Therefore, the aim of our study was to conduct a meta-analysis to clarify the relationship between CTLA-4 + 49A/G polymorphism and psoriasis and vitiligo.

Section snippets

Literature search strategy

This meta-analysis was performed in accordance with the PRISMA guidelines (Moher et al., 2009). Studies examining the association between CTLA-4 + 49A/G polymorphism and psoriasis or vitiligo published prior to July 3, 2014 were systematically retrieved from the PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases using the following key terms: ‘cytotoxic T lymphocyte antigen-4’ or ‘CTLA-4’ or ‘rs231775’ plus ‘polymorphism (s)’ or ‘SNP (s)’ or ‘variation’ or ‘genotype (s)’

Characteristics of studies

Seventy-four studies that matched our predefined search strategy were identified in PubMed (n = 22), Embase (n = 34), and CNKI (n = 18) and in manual searches. Of these studies, 18 were selected for a full-text review based on title and abstract details. Another five studies were excluded because one was carried out without a control population (LaBerge et al., 2008), two reported duplicated data (Zhang, 2003, Luszczek et al., 2006), one did not provide relevant data (Alenius et al., 2004), and one

Discussion

Several studies have examined the hypothesis that CTLA-4 + 49A/G polymorphism is relevant to psoriasis or vitiligo, but a decisive answer has not been attained. We found no significant association between CTLA-4 + 49A/G polymorphism and psoriasis in our overall analysis. In fact, only one case–control study (Hao et al., 2003) has reported increased risk of psoriasis in allele G carriers, whereas all other case–control studies showed no association between them (Kim et al., 2003, Tsunemi et al., 2003

Conflict of interest statement

None declared.

Acknowledgments

This study was supported by the National Natural Science Foundation of China (Grant No. 81071286), the Guangdong Natural Science Foundation (Grant No. 07001961), and the Guangzhou Science and Technology Planning Project (Grant No. 12C33151651).

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