Role of tumor necrosis factor-alpha -238 G>A promoter region polymorphism on recurrent miscarriage: An association study and meta-analysis.

BACKGROUND: Recurrent miscarriage (RM) is defined as the loss of two or more consecutive pregnancies. A functional SNP, -238G>A in the promoter region of TNF-α, affects the gene transcription activity with implications on human pregnancy. Previous limited studies, linking the TNF-α -238 G>A to the risk of recurrent miscarriage have been inconclusive. MATERIAL AND METHOD: The PCR-RLFP technique was used to evaluate this polymorphism in 199 RM cases and 215 control women from Amritsar, Punjab. For a meta-analysis, a total of 13 eligible studies (including the present study) comprising 2947 cases and 2933 controls were included. To evaluate the association among different genetic models, odds ratio with a 95% confidence interval (CI) and chi-square were used. RESULTS: Genotype and allelic frequency did not differ significantly between both groups (p = .07 and p = .24, respectively). In the present meta-analysis, a significant association was found with the recessive model (OR-1.78 CI:1.24-2.55, p = .002). CONCLUSION: Although, TNF-α -238 G>A polymorphism did not provide any risk in the case-control study but provided risk towards the development of RM with the recessive genetic model in the pooled analysis.

Impact of Interleukin-10 Promoter Region Polymorphisms on Recurrent Miscarriage: A Case-Control Approach.

Background: Recurrent miscarriage (RM), defined as two or more consecutive miscarriages prior to the 20th week of gestation is characterised by multifactorial aetiology. The prevalence of RM varies from 0.8% to 13.5% amongst women of reproductive age. The aetiological basis of RM has been traced to chromosomal, anatomic, hormonal and immunologic factors while half of the cases remain idiopathic. Aims: This study aimed to investigate the association of interleukin-10 (IL-10) polymorphisms with RM amongst the Indian population. Settings and Design: The present study included a total of 414 individuals including RM women (n = 199) with two or more pregnancy losses and healthy women (n = 215) without any previous history of pregnancy loss were taken as the control group. Materials and Methods: Demographic features and reproductive history of women with RM and healthy women were taken. Genotype analysis of IL-10 polymorphisms rs1800872 and rs1800896 was performed using the polymerase chain reaction (PCR) restriction fragment length polymorphism and amplification mutation refractory system PCR, respectively. Statistical Analysis Used: Student's t-test was used to compare the demographic features and reproductive history amongst both groups. Pearson's Chi-square was used to calculate the Hardy-Weinberg equilibrium, allelic and genotypic frequencies. All the statistical analyses were performed using the SPSS (version 21, IBM SPSS, NY, USA). Results: Our results suggested that the genotypic and allelic frequency of rs1800872 polymorphism did not differ significantly between RM cases and control women (P = 0.07 and P = 0.23, respectively). The GG genotype (P = 0.007) and G allele (P = 0.003) of rs1800896 were significantly associated with an increased risk of RM. A statistically significant difference was also found for the distribution of genetic models (dominant and co-dominant model) between both groups for rs1800896. However, haplotype analysis revealed that none of the haplotypes provides a risk for the progression of RM. Conclusion: The study is the first of its kind from our region and provides baseline data on the genetics of RM.

Association Analysis of CYP11A1 Variants with Polycystic Ovary Syndrome: a Case-Control Study from North India.

The most common multifactorial endocrine disorder in females of reproductive age is polycystic ovary syndrome (PCOS), affecting about 5-10% of females worldwide and 9.3% of females in India. Androgen excess in PCOS is caused as a result of defects in steroidogenesis genes. CYP11A1 is an imperative marker in the steroid synthesis pathway, and the altered expression of CYP11A1 has been reported to disrupt the synthesis of steroids and hence conferring risk for the development of PCOS. The present study aimed to analyze genetic variants (rs11632698, rs4077582, rs4887139) of CYP11A1 with PCOS from North India. The study included 270 PCOS females diagnosed according to Rotterdam 2003 criteria and 270 age-matched healthy non-PCOS females. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for the genotypic analysis of the selected genetic variants. Association analysis of biochemical parameters (cholesterol, triglyceride, high-density lipoprotein) and anthropometric measurements with PCOS cases was done. The genetic variants of CYP11A1 (rs11632698, rs4077582, and rs4887139) demonstrated significant association with PCOS cases (p=1.0E-12, p=3.0E-3, p=1.0E-2, respectively). Binary logistic regression revealed that the dominant model of rs11632698 conferred 2.0 risk, and dominant as well as the co-dominant model of rs4887139 conferred risk of 2.2 and 2.4 fold, respectively, towards the progression of PCOS. The overall mean triglyceride levels were elevated, and mean HDL levels were lower in PCOS cases as compared to threshold values. The significant association of studied genetic variants suggested the important role of CYP11A1 in susceptibility to PCOS. The study was the first of its kind from our region and provided baseline data of genetics of PCOS.

Cytogenetic analysis in couples with recurrent miscarriages: a retrospective study from Punjab, north India.

Human reproduction is considered as the most inefficient event as ~15-20% of human pregnancies end in miscarriage and in the product of miscarriages, chromosomal anomalies are a common occurrence. The aim of the present retrospective study was to assess the frequency of chromosomal aberrations in couples with recurrent miscarriages in the region of Punjab and to compare with worldwide frequencies. In this study, a total of 440 cases were referred between the period 1995-2015. After lymphocyte culturing, giemsa-trypsin banding was done for each case to assess the chromosomal anomalies. The frequency of chromosomal aberrations among couples was found to be 3.41% in our study. Among these aberrations, balanced reciprocal translocations formed the largest group with 60% anomalies. We would conclude that clinicians should understand the importance of chromosomal analysis in these couples and refer them for karyotyping after two miscarriages to rule out the possible genetic cause of recurrent miscarriages.

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

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).