Impact of TNF-α profile in recurrent pregnancy loss pathogenesis: A patient based study from Assam.

BACKGROUND: Lacunae exist in understanding the underlying etiology in majority of recurrent pregnancy loss (RPL) cases. Given the significance of regulated immune-modulation in pregnancy, and the central role of pro-inflammatory TNF-α plays in it; this study targeted to appraise the significance of TNF-α profile in RPL pathogenesis in an ethnically distinct population from Assam, India. METHODS: Term delivery, medically terminated pregnancy (MTP) and RPL cases (based on ASRM criteria) were enrolled with no anatomical and chromosomal abnormalities or pathological infections; and blood and/or placenta/product of conceptus (POC) tissue samples were collected with informed consent. Serum level and tissue level TNF-α expression profile were screened using specific molecular tools, and was correlated with TNF-α -308 G/A genotype; for its association with RPL predisposition. RESULTS: A significant gestation specific increase in serum TNF-α levels was observed in MTP cases (19.932 ± 4.407 pg/mL) compared to term delivery subjects (p = 0.001), while a comparable levels were observed with RPL cases (22.709 ± 5.833 pg/mL) (p = 0.646). A site specific (POC) increased expression was observed in RPL compared to MTP cases at both at transcript (6.37 ± 3.714 folds) and protein levels. The TNF-α -308 variant genotype was associated with increased predisposition to RPL (OR = 1.721) compared to MTP as well as significantly increased serum TNF-α levels (p = 0.017); especially in subjects with a homozygous TNF-α -308 A/A genotype. CONCLUSION: Our data emphasizes on the importance of site specific TNF-α expression levels in RPL pathogenesis in the studied population, and underlines its importance in screening, clinical stratification, and therapeutics by molecular targeting using TNF-α inhibitors.

Genetic and expression changes in TNF-α as a risk factor for rheumatoid arthritis pathogenesis in northeast India.

Antitumour necrosis factor-alpha (TNF-α) therapy is used as a clinical intervention for rheumatoid arthritis (RA) but differences exist in response to the treatment which makes the candidature of the screening of TNF-α alteration(s) at genetic and expression levels an important agenda prior to treatment. This study aims to determine the associative role of TNF-α -308G/A polymorphism and differential expression of TNF-α in the pathogenesis of RA. A case-control study where a total of 126 RA patients were enrolled based on ACR-EULAR (2010) criteria, along with 160 community matched age and sex controls over a period of three years. The differential expression level of TNF-α mRNA and protein level was studied and TNF-α -308G/A polymorphism was screened by T-ARMS PCR assay. All statistical analysis was performed using SPSS software. mRNA expression level of TNF-α was upregulated in RA cases (avg. 15.85 ± 9.52 fold) compared to control. TNF-α protein level was found to be higher in RA cases (28.62±7.17 pg/mL) compared to control (23.14±6.91 pg/mL). TNF-α -308 variant GA genotype was higher in RA (46.03%) than in control (25%). The presence of TNF-α -308 variant A allele was associated with increased risk of RA susceptibility (odds ratio (OR) = 2.559 at 95% confidence interval (CI), P< 0.001) but not severity (OR = 1.617 at 95% CI, P = 0.571). The presence of -308 variant genotype was associated with a higher TNF-α mRNA and protein expression. The presence of TNF-α -308A allele is associated with increased risk of RA susceptibility and differential TNF-α expression, and has prognostic significance. Association of higher TNF-α pro-inflammatory cytokine levels with northeast Indian patients makes them suitable subjects for anti-TNF-α therapy.

MTHFR (C677T) polymorphism and PR (PROGINS) mutation as genetic factors for preterm delivery, fetal death and low birth weight: A Northeast Indian population based study.

UNLABELLED: Preterm delivery (PTD) is one of the most significant contributors to neonatal mortality, morbidity, and long-term adverse consequences for health; with highest prevalence reported from India. The incidence of PTD is alarmingly very high in Northeast India. The objective of the present study is to evaluate the associative role of MTHFR gene polymorphism and progesterone receptor (PR) gene mutation (PROGINS) in susceptibility to PTD, negative pregnancy outcome and low birth weights (LBW) in Northeast Indian population. METHODS: A total of 209 PTD cases {extreme preterm (< 28 weeks of gestation, n = 22), very preterm (28-32 weeks of gestation, n = 43) and moderate preterm (32-37 weeks of gestation, n = 144) and 194 term delivery cases were studied for MTHFR C677T polymorphism and PR (PROGINS) gene mutation. Statistical analysis was performed using SPSS software. RESULTS: Distribution of MTHFR and PR mutation was higher in PTD cases. Presence of MTHFR C677T polymorphism was significantly associated and resulted in the increased risk of PTD (p < 0.001), negative pregnancy outcome (p < 0.001) and LBW (p = 0.001); more significantly in extreme and very preterm cases. Presence of PR mutation (PROGINS) also resulted in increased risk of PTD and negative pregnancy outcome; but importantly was found to increase the risk of LBW significantly in case of very preterm (p < 0.001) and moderately preterm (p < 0.001) delivery cases. CONCLUSIONS: Both MTHFR C677T polymorphism and PR (PROGINS) mutation are evident genetic risk factors associated with the susceptibility of PTD, negative pregnancy outcome and LBW. MTHFR C677T may be used as a prognostic marker to stratify subpopulation of pregnancy cases predisposed to PTD; thereby controlling the risks associated with PTD.