Tumour necrosis factor (TNF), an important proinflammatory cytokine, plays a role in the regulation of cell differentiation, proliferation and death, as well as in inflammation, innate and adaptive immune responses, and also implicated in a wide variety of human diseases. The presence of DNA sequence variations in regulatory region might interfere with transcription of TNF gene, influencing the circulating level of TNF and thus increases the susceptibility to human diseases (infectious, cancer, autoimmune, neurodegenerative and other diseases). In this review, we have comprehensively analysed various published case-control studies of different types of human diseases, in which TNF gene polymorphism played a role, and computationally predicted several single nucleotide polymorphisms (SNPs) lie in transcription factor-binding sites (TFBS) of transcription factors (TFs). It has been observed that TNF enhancer polymorphism is implicated in several diseases, and TNF rs1800629 and rs361525 SNPs are the most important in human disease susceptibility as these might influence the transcription of TNF gene. Thirty-two SNPs lies in TFBS of 20 TFs have been detected in the TNF upstream region. It has been found that TNF enhancer polymorphism influences the serum level of TNF in different human diseases and thus affects the susceptibility to diseases. The presence of DNA sequence variation in TNF gene causes the modification of transcriptional regulation and thus responsible for association of susceptibility/resistance with human diseases.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-3083.2011.02602.x

Tumour Necrosis Factor Gene Polymorphism and Disease Prevalence

BACKGROUND: The identification of polymorphisms associated with a disease can help to elucidate its pathogenesis, and this knowledge can be used to improve prognosis for women with a particular disorder, such as polycystic ovary syndrome ( PCOS). Since an altered response to ovarian stimulation is also a characteristic of the disease, further knowledge about its aetiology could help in defining the parameters that determine the response of an individual to ovarian stimulation. METHODS: PubMed and EMBASE databases were systematically searched for gene association studies published until the end of August 2007, using search criteria relevant to PCOS and ovarian response to stimulation. Data from additional papers identified through hand searches were also included; 139 publications were reviewed. RESULTS: Several genes involved in ovarian function and metabolism are associated with increased susceptibility to PCOS, but none is strong enough to correlate alone with susceptibility to the disease, or response to therapy. A single- nucleotide polymorphism in exon 10 of the FSH receptor ( FSHR) gene, FSHR p. N680S, was consistently identified as having a significant association with ovarian response to FSH. CONCLUSIONS: No consistent association between gene polymorphism and PCOS could be identified. The FSHR gene may play a significant role in the success of ovarian stimulation, and can be used as a marker to predict differences in FSHR function and ovarian response to FSH. Genotyping the FSHR p. N680S polymorphism may provide a means of identifying a population of poor responders before in vitro fertilization procedures are initiated.

/pdf/functional-genetic-polymorphisms-and-female-reproductive-4lp7pqtrxs.pdf

Functional genetic polymorphisms and female reproductive disorders: Part I: polycystic ovary syndrome and ovarian response

BACKGROUND: Endometriosis has a strong genetic component, and numerous genetic studies have been reported. METHODS: We have systematically reviewed these studies and included 114 in our final selection. RESULTS: We found no consistent evidence linking endometriosis with specific polymorphisms in genes encoding inflammatory mediators, proteins involved in sex steroid metabolism, vascular function and tissue remodelling. Although a number of polymorphisms have been associated with endometriosis in selected populations, the associations have not been independently confirmed, either because only single studies were carried out on these markers/genes or because other studies reported no association. The most solid evidence linking specific polymorphisms to endometriosis came from studies investigating glutathione-S-transferase, a phase II detoxification enzyme. Carriage of the GSTT1 null deletion variant showed consistent association with endometriosis with a 29% increased risk; however, it cannot be excluded that this result was due to publication bias, and this association should be independently confirmed in large-scale, well-designed case–control studies. CONCLUSIONS: The evidence of an association between genetic polymorphisms and endometriosis is weak. Carriage of the GSTT1 null deletion may moderately increase the risk of this disease. We suggest that the methodology of association studies should be improved in order to identify and validate associations in endometriosis.

/pdf/functional-genetic-polymorphisms-and-female-reproductive-4eedax8tn3.pdf

Functional genetic polymorphisms and female reproductive disorders: Part II—endometriosis

Endometriosis is a benign gynecological disease with an unclear pathophysiology characterized by ectopic endometrium causing endometrium-like inflammatory lesions outside the uterine cavity. Recently, a number of studies have investigated genetic polymorphisms as a possible factor contributing to th

Endometriosis and genetic polymorphisms.

Susceptibility/resistance to Plasmodium falciparum malaria has been correlated with polymorphisms in more than 30 human genes with most association analyses having been carried out on patients from Africa and south-east Asia. The aim of this study was to examine the possible contribution of genetic variants in the TNF and FCGR2A genes in determining severity/resistance to P. falciparum malaria in Indian subjects. Allelic frequency distribution in populations across India was first determined by typing genetic variants of the TNF enhancer and the FCGR2A G/A SNP in 1871 individuals from 55 populations. Genotyping was carried out by DNA sequencing, single base extension (SNaPshot), and DNA mass array (Sequenom). Plasma TNF was determined by ELISA. Comparison of datasets was carried out by Kruskal-Wallis and Mann-Whitney tests. Haplotypes and LD plots were generated by PHASE and Haploview, respectively. Odds ratio (OR) for risk assessment was calculated using EpiInfo™ version 3.4. A novel single nucleotide polymorphism (SNP) at position -76 was identified in the TNF enhancer along with other reported variants. Five TNF enhancer SNPs and the FCGR2A R131H (G/A) SNP were analyzed for association with severity of P. falciparum malaria in a malaria-endemic and a non-endemic region of India in a case-control study with ethnically-matched controls enrolled from both regions. TNF -1031C and -863A alleles as well as homozygotes for the TNF enhancer haplotype CACGG (-1031T>C, -863C>A, -857C>T, -308G>A, -238G>A) correlated with enhanced plasma TNF levels in both patients and controls. Significantly higher TNF levels were observed in patients with severe malaria. Minor alleles of -1031 and -863 SNPs were associated with increased susceptibility to severe malaria. The high-affinity IgG2 binding FcγRIIa AA (131H) genotype was significantly associated with protection from disease manifestation, with stronger association observed in the malaria non-endemic region. These results represent the first genetic analysis of the two immune regulatory molecules in the context of P. falciparum severity/resistance in the Indian population. Association of specific TNF and FCGR2A SNPs with cytokine levels and disease severity/resistance was indicated in patients from areas with differential disease endemicity. The data emphasizes the need for addressing the contribution of human genetic factors in malaria in the context of disease epidemiology and population genetic substructure within India.

https://link.springer.com/content/pdf/10.1186%2F1475-2875-7-13.pdf

Polymorphisms of TNF -enhancer and gene for FcγRIIa correlate with the severity of falciparum malaria in the ethnically diverse Indian population

Background Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional proinflammatory cytokine, associated with various inflammatory and autoimmune diseases. Elevated TNF-alpha levels in peritoneal fluid have been reported in women with endometriosis, suggesting that TNF-alpha may be involved in the development of endometriosis. In this study, we investigated the possible association between endometriosis and the TNF-alpha gene promoter polymorphisms -238G/A, -308G/A, -857C/T, -863C/A and -1031T/C in a Japanese population. Methods We compared the distribution of the -238G/A, -308G/A, -857C/T, -863C/A and -1031T/C polymorphisms in the promoter region of TNF-alpha in 130 endometriosis cases and 185 controls using PCR-RFLP analysis. Results The allele frequencies of -238A, -308A, -857T, -863A and -1031C in controls were 2.0%, 1.3%, 19.4%, 17.0% and 18.6%, and in the cases 1.1%, 0.3%, 19.6%, 18.6% and 13.6%, respectively. No significant differences in frequencies were found between the crude endometriosis cases and controls. However, when the endometriosis group was divided into a subgroup of women with stage IV disease only, the frequency of the -1031C allele was significantly lower in this subgroup than controls. Conclusions The variability of the -1031T/C polymorphism of the TNF-alpha gene may be associated with susceptibility to (AUTHOR: as meant?) endometriosis.

The tumor necrosis factor-alpha promoter -1031C polymorphism is associated with decreased risk of endometriosis in a Japanese population.

Endometriosis is a complex trait, which means that multiple susceptibility genes interact with one another and the environment to produce the phenotype. One of the genes previously implicated in the disease is CYP17; this encodes the enzyme P450c17α, which plays a vital role in steroid biosynthesis in the ovary. The presence of a single nucleotide polymorphism (T→C) in the 5′-promoter region of the gene creates a new recognition site for the restriction enzyme MspA1 producing a mutant allele (A2), which affects circulating estrogen levels. In this study, we compared the frequency of the CYP17 MspA1 polymorphism in two different ethnic populations. DNA was obtained from (1) 94 women with revised American Fertility Society (rAFS) stage III–IV endometriosis and 97 male blood donors in the UK, and (2) 130 women with rAFS stage III–IV endometriosis and 179 female newborn infants in Japan. No significant differences in allele or genotype frequencies were seen in either population. The genotype distribution in t...

Tasneem Asghar

Papers

The tumor necrosis factor-alpha promoter -1031C polymorphism is associated with decreased risk of endometriosis in a Japanese population.

Lack of association between endometriosis and the CYP17 MspA1 polymorphism in UK and Japanese populations