Association of functional genetic variants of CTLA4 with reduced serum CTLA4 protein levels and increased risk to idiopathic recurrent miscarriages

Women with CTLA4 variants have reduced serum CTLA4 levels and an increased risk of idiopathic recurrent miscarriage. CTLA4 influences protein–protein interaction pathways of the human genome.

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Volume 106, Issue 5, Pages 1115-1123


Maneesh Kumar Misra, Ph.D., Aditi Mishra, M.Tech., Shubha R. Phadke, D.M., Suraksha Agrawal, Ph.D.



To determine whether idiopathic recurrent miscarriages (IRM) are associated with the alteration in serum CTLA4 protein levels and to evaluate their correlation with CTLA4 tag single-nucleotide polymorphisms (SNPs).


Retrospective case-control study.


Tertiary-care referral hospital.


Three hundred women with IRM (mean age: 28.6 ± 5.4 years) and 600 age-matched (mean age: 29.2 ± 6.8) control women.


Detection of genetic variants of CTLA4 markers rs231775, rs5742909, rs11571317, rs16840252, rs4553808, and rs3087243 by polymerase chain reaction followed by restriction fragment length polymorphism analysis and validated through DNA sequencing, and CTLA4 serum levels measured by enzyme-linked immunosorbent assay.

Main Outcome Measure(s)

Serum CTLA4 levels, genotypes, and haplotype frequencies compared in IRM cases versus controls.


We observed statistically significantly higher occurrence of minor allele homozygous of rs231775 and rs3087243 tag-SNPs in IRM cases, which suggests a risk association. A statistically significantly reduced level of CTLA4 protein was seen for mutant genotypes of rs231775 and rs3087243 tag-SNPs in women with IRM, revealing a risk association. Serum CTLA4 levels were statistically significantly reduced in women with IRM as compared with the control women. The mutant haplotype carriers of six studied tag-SNPs showed 2.34-fold higher frequencies in IRM cases. In silico analyses strengthened our observations and suggested that variation in CTLA4 gene content may influence the expression of this gene and directly or indirectly influence the function of other genes in the protein–protein interaction pathway.


These results suggest an effect of CTLA4 gene variants, with reduced sCTLA4 secretion and an increased risk for IRM. Reduced CTLA4 secretion and specific CTLA4 variants may contribute to the pathogenesis of IRM.

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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders.