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CTLA-4 gene polymorphisms and risk of idiopathic recurrent pregnancy loss in a Tunisian population


An aberrant regulation of immunological, metabolic, vascular and endocrine processes leads to obstetric complications, including recurrent pregnancy loss (RPL) [1]. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a negative regulator of T cell activation [2] expressed in placental fibroblasts and may modulate peripheral self-tolerance of the allogenic fetus [3, 4]. It is a stimulatory molecule involved in T-cell activation at the maternal–fetal interface in women with unexplained pregnancy loss [5, 6]. In this study, we investigate the possible associations of Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene polymorphisms with idiopathic recurrent pregnancy loss (RPL).

Materials and methods

We investigated the association of the CTLA-4 gene single nucleotide polymorphisms (SNPs) -318 C/T (rs5742909), +49A/G (rs231775), and CT60 A/G (rs3087243), by TaqMan assays in analysis in 470 Tunisian women comprising 235 RPL cases and 235 multi-parous controls. The association of CTLA-4 alleles, genotypes, and haplotypes with RPL was evaluated by Fisher's exact test and regression analysis.


The CTLA-4 variants rs5742909, rs231775, and rs3087243, were in Hardy Weinberg equilibrium, and low linkage disequilibrium was noted between the three studied SNPs. The frequency of rs231775 G allele (P=0.04), but not rs3087243 G allele (P=0.61) or rs5742909 T allele (P=1), was higher in RPL cases than in control women. Significant differences in the distribution of rs231775 (P<0.02), but not rs5742909 (P=0.21) or rs3087243 (P=0.49) genotypes were seen between cases and controls, and only rs231775 showed a significant association with RPL, with increments of 1.74 in disease risk seen for heterozygous carriers. Only rs231775 (+49/A/G), previously shown associated with the immuno-pathogenesis of RPL, and it confers susceptibility to RPL in Chinese population [5] and North Indian Women [7], was significantly associated with RPL. Among the six three-locus CTLA-4 haplotypes constructed (rs5742909/rs231775/rs3087243), increased frequency of CGA (P=0.0046), and CAG (P=0.036) haplotypes were seen in RPL cases, thus conferring disease susceptibility nature to these haplotypes.


The rs231775 AG genotype and CGA and CAG haplotypes may contribute to RPL development in a Tunisian Population.


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Correspondence to Safia Messaoudi.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Messaoudi, S., Houas, I., Yaseen, K. et al. CTLA-4 gene polymorphisms and risk of idiopathic recurrent pregnancy loss in a Tunisian population. BMC Genomics 15 (Suppl 2), P11 (2014).

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