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      Association of tumor necrosis factor-alpha 308G/A polymorphism with recurrent miscarriages in women

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          Abstract

          BACKGROUND:

          Recurrent miscarriage (RM) is the most common pregnancy loss in the first trimester affecting approximately 0.5–2% of women. It is a heterogeneous condition and remains an enigma as the underlying cause is still difficult to track down.

          AIM:

          This study was aimed to investigate the distribution of tumor necrosis factor-alpha ( TNF-α) 308G/A polymorphism and its association with RM in females. The comparative picture was also demonstrated by comparing genotyping results with healthy control women having no history of miscarriage.

          METHODS:

          This clinical study was conducted among 115 women aged 21–44 years with history of recurrence of miscarriage. The samples were collected from women attending the outpatient departments of various hospitals, nursing homes, and infertility clinics of this region. In the present study, 111 fertile healthy women aged 24–46 years with at least one live birth and no history of miscarriage were also included.

          RESULTS:

          Mean age of women with RM was found to be 28 ± 5.6 years by recall method, whereas it was found to be 30 ± 7.4 in context to healthy women with no history of pregnancy loss. In the present study, 66% of women with RM had homozygous wild type genotype ( GG) while 30% and 4% of women had heterozygous ( GA) and homozygous mutant genotype ( AA), respectively. Among control group, 79%, 16%, and 5% of women showed GG, GA, and AA genotype, respectively.

          CONCLUSION:

          The current study supports the concept of TNF-α 308G/A variant in particular with reproductive failure, GG and GA alleles showing 1-fold risk association with RM (odds ratio: 1.86 and 1.43, respectively).

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          Most cited references26

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          Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation.

          Tumor necrosis factor alpha (TNF alpha) is a potent immunomodulator and proinflammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. For example, plasma levels of TNF alpha are positively correlated with severity and mortality in malaria and leishmaniasis. We have previously described a polymorphism at -308 in the TNF alpha promoter and shown that the rare allele, TNF2, lies on the extended haplotype HLA-A1-B8-DR3-DQ2, which is associated with autoimmunity and high TNF alpha production. Homozygosity for TNF2 carries a sevenfold increased risk of death from cerebral malaria. Here we demonstrate, with reporter genes under the control of the two allelic TNF promoters, that TNF2 is a much stronger transcriptional activator than the common allele (TNF1) in a human B cell line. Footprint analysis using DNase I and B cell nuclear extract showed the generation of a hypersensitive site at -308 and an adjacent area of protection. There was no difference in affinity of the DNA-binding protein(s) between the two alleles. These results show that this polymorphism has direct effects on TNF alpha gene regulation and may be responsible for the association of TNF2 with high TNF alpha phenotype and more severe disease in infections such as malaria and leishmaniasis.
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            Th1-type immunity is incompatible with successful pregnancy.

            Several years ago, the rather provocative question was raised: is successful pregnancy a T helper 2 (Th2) phenomenon? Implicit in this argument is the corollary that unsuccessful pregnancy is a Th1-type situation. Here, evidence from murine and human pregnancy is presented to show that, since Th1-type cytokines mediate pregnancy loss, a shift towards Th1-type immunity may help resolve 'unexplained' pregnancy failure.
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              Frequency of factors associated with habitual abortion in 197 couples.

              To determine the frequency of factors associated with habitual abortion in 197 couples. Prospective cohort study. The British Columbia Recurrent Pregnancy Loss Program, located in a tertiary care academic center. Diagnostic screening protocol. Genetic, endocrine, infectious, anatomical, and autoimmune factors associated with habitual abortion. A structural genetic factor was identified in 3.5% of the couples. An endocrine factor, including luteal phase deficiency and hypothyroidism, was identified in 20% and an infectious factor was identified in 0.5% of the couples. An anatomical factor, including various müllerian tract anomalies and severe intrauterine adhesions, was found in 16% and an autoimmune factor, including the antiphospholipid antibody syndrome and the undifferentiated connective tissue syndrome, was identified in 20% of the couples. Eighty-four couples who completed the diagnostic screening protocol were classified as having unexplained habitual abortion. Of these 84 couples, 65% were subclassified as primary, 27% were subclassified as secondary, and 7% had unclassified unexplained habitual abortion. This large-scale study identified genetic, endocrine, infectious, anatomical, or autoimmune factors in approximately 60% of couples with habitual abortion.
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                Author and article information

                Journal
                J Hum Reprod Sci
                J Hum Reprod Sci
                JHRS
                Journal of Human Reproductive Sciences
                Medknow Publications & Media Pvt Ltd (India )
                0974-1208
                1998-4766
                Apr-Jun 2016
                : 9
                : 2
                : 86-89
                Affiliations
                [1]Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
                Author notes
                Address for correspondence: Dr. Anupam Kaur, Department of Human Genetics, Guru Nanak Dev University, Amritsar - 143 005, Punjab, India. E-mail: anupamkaur@ 123456yahoo.com
                Article
                JHRS-9-86
                10.4103/0974-1208.183516
                4915291
                27382232
                93193974-e039-463e-ab68-7293fb34a9c5
                Copyright: © Journal of Human Reproductive Sciences

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

                History
                : 22 May 2015
                : 10 July 2015
                : 29 March 2016
                Categories
                Original Article

                Human biology
                polymorphism,recurrent miscarriage,reproductive failure,tumor necrosis factor
                Human biology
                polymorphism, recurrent miscarriage, reproductive failure, tumor necrosis factor

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