Associations between tumor necrosis factor- and lymphotoxin- polymorphisms and idiopathic recurrent miscarriage (original) (raw)
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REPRODUCTION, 2008
Heightened expression of tumor necrosis factor (TNF)-α and lymphotoxin-α (LT-α) was associated with pregnancy complications, including idiopathic recurrent miscarriage (RM). Whereas TNF-α and LT-α gene polymorphisms affect serum cytokine concentrations, their contribution to RM is controversial. The single nucleotide polymorphisms (SNPs) TNF-α (−238G/A, −308G/A) and LT-α (+252A/G) were investigated in 350 RM women and 200 control women. Higher frequency of the TNF-α −238A, but not the TNF-α −308A or the LT-α+252G, allele was seen in patients, with comparable frequencies of TNF-α −238G/A, TNF-α −308G/A, and LT-α+252A/G genotypes seen between both groups, except for TNF-α −238G/G, which was lower in patients. Regression analysis confirmed the association of the TNF-α −238G/A SNP with idiopathic RM, and both TNF-α −308A/TNF −238G/LT-α+252Gand TNF-α −308G/TNF-α −238A/LT-α+252Ghaplotypes played a susceptible role in idiopathic RM. TNF-α −238G/A and −238A/A, and LT-α+252G/G genotypes were...
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‑) 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‑ 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).
Polymorphisms in the tumor necrosis factor and lymphotoxin-α gene region and preeclampsia
Obstetrics & Gynecology, 2001
To investigate potential association or linkage among nine polymorphisms in the genes encoding tumor necrosis factor (TNF) ␣ or lymphotoxin (LT) ␣ and preeclampsia. METHODS: Four di-allelic polymorphisms and five microsatellite markers in the genes encoding TNF-␣ (TNF) and LT␣ (LTA) and their haplotypes were studied in 150 Dutch families. These families contained sib-pairs of women affected with preeclampsia; eclampsia; the hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (strict criteria); or pregnancy-induced hypertension (mild criteria). Frequencies were compared with 98 healthy controls. Nonparametric affected sib-pair analyses for allele sharing among siblings were carried out for all nine markers. Each sibship was composed of an affected index woman and one or more affected sisters. RESULTS: Although we found a striking association with the TNF-I haplotype in 30 index women with (pre-)eclampsia or HELLP syndrome compared with controls (odds ratio [OR] 3.8; 95% confidence interval [CI] 1.6, 8.9), this association was not found in their 30 sisters meeting similar disease criteria. Analyses in all 150 families showed a similar TNF-I association in 122 index women meeting the strict criteria compared with controls (OR 1.9; 95% CI 1.1, 3.3), but, again, not in their 91 sisters meeting similar disease criteria. This association was stronger in a subgroup of 75 index women with preeclampsia only (OR 2.3; 95% CI 1.2, 4.2). No excess allele sharing for any marker was seen between the siblings. CONCLUSION: The nine polymorphisms studied in the TNF-LTA region did not show evidence for association or linkage with familial preeclampsia.
Some disease-associated ancestral haplotypes carry a polymorphism of TNF
Human Immunology, 1989
We describe here an Nco I restriction fragment length polymorphism of tumor necrosis factor carried by the 8.1 (HLA-A1,B8,BfS,C4AQO,C4B1,DR3) and the 44.l (HLA-B44,BfS, C4A3, C4BQO, DR4) ancestral haplotypes associated with complications of rheumatoid arthritis. By examining multiple examples of these and other ancestral haplotypes it was seen that 8.1 and 44.1 ancestral haplotypes yield fragments of approximately 5.5 kb while many other ancestral haplotypes carry fragments of approximately 10.5 kb. The polymorphism is associated with the ancestral haplotype rather than the HLA-B or -DR allele defined by conventional serology. ABBREVIATIONS
Association of CTLA-4 and TNF-α polymorphism with recurrent miscarriage among North Indian women
Cytokine, 2012
Context: CTLA-4 is engaged on effector cells that may alter signal transduction and subsequently cytokine production. The transmission of longer repeats of (AT) n alleles of CTLA-4 is also associated with women undergoing recurrent miscarriage. The TNF-a known as an embryo-toxic cytokine is reported to be greater in placentas of abortion prone pregnancies. Objectives: The present study investigated the role of CTLA-4 +49 A/G, CTLA-4 (AT) n 3 0 UTR, TNF-a-308G/A and TNF-a-238G/A polymorphisms as a susceptibility marker for recurrent miscarriage (RM). Participants and methods: We genotyped CTLA4 +49A/G, TNF-a-308 and TNF-a-238 gene polymorphisms in 300 patients with RM and 500 age and ethnically matched negative controls using PCR-RFLP method. While gene sequencing method was adopted for studying the CTLA-4 (AT) n 3 0 UTR polymorphism. Results: The mutant homozygous genotype GG of CTLA4 +49A/G, AA genotype and A allele of TNF-a-308, G allele of TNF-a-238 were observed to be predisposing among RM cases along with the 104 bp, 106 bp, 110 bp and 116 bp alleles of CTLA-4 (AT) n microsatellite repeat. GA and AG haplotypes of TNF-a were low risk associated haplotypes among recurrent miscarriage women. Conclusions: Roles of CTLA-4 A49G, CTLA-4 (AT) n 3 0 UTR, TNF-a-308 and TNF-a-238 polymorphisms in RM cases from North India is reflected through this study.
TNF-? gene polymorphism: Clinical and biological implications
Microscopy Research and Technique, 2000
TNF-␣ is a proinflammatory cytokine that has been implicated in the severity of different immune-regulated diseases including autoimmune diseases and transplantation. The gene for TNF-␣ is located within the MHC region on chromosome 6p21.3. This is a highly polymorphic region, and the TNF-␣ itself contains a large number of polymorphisms. Some of these polymorphisms form extended haplotypes with the HLA class I and II alleles. TNF polymorphisms have been investigated in different diseases and most often whenever there is an HLA association with the disease (for example IDDM and RA) association(s) with TNF polymorphisms has been described. There are many studies on the function of the TNF polymorphisms showing the influence of the different alleles on the in vitro and in vivo levels of TNF production. However, recent studies in animal models suggest that not only polymorphisms within the TNF cluster are important in the regulation of TNF production but also the receptors as well (TNF R). This suggests that investigating polymorphisms within the TNF cluster and TNF receptors will be important in understanding the role of TNF regulation in a given disease.
Cytokine Gene Polymorphisms in Recurrent Pregnancy Loss of Unknown Cause
American Journal of Reproductive Immunology, 2004
PROBLEM: According to previous investigations, certain cytokines may play a role in recurrent pregnancy loss (RPL). Significantly different levels of Th1/Th2 cytokines are produced by normal pregnant women compared with women with RPL of unknown cause. OBJECTIVE: We have studied the polymorphism of cytokine genes which are related to the amount of the cytokine produced. High (H), intermediate (I) and low (L) cytokine responses can be predicted from the cytokine genotype. MATERIAL AND METHODS: The genetic polymorphism of Th1 cytokine [i.e. interferon (IFN)-c and tumor necrosis factor (TNF)-a] and Th2 cytokines [i.e. interleukin (IL)-6, IL-10] and the transforming growth factor (TGF)-b were studied by polymerase chain reactionsequence specific primers (PCR-SSP) in the DNA of PBC from 41 women with RPL and 54 control women who had at least two children and without known pregnancy losses. RESULTS: The results showed: (i) no evidence of associations between patients and controls concerning the Th1: TNF-a; the Th2: IL-6 and IL-10 and the TGF-b genotype, (ii) significative association between RPL versus controls concerning IFN-c +874 A fi T: T/A genotype was increased in the patient group in comparison with the control group (65% versus 35.8%) (P ¼ 0.01) and there was a statistical disminution in the frequency of the A/A (L) genotype between the patient groups in comparison with the control group (20% versus 41.5%) (P ¼ 0.04). CONCLUSION: This finding would support the concept of involvement of IFN-c +874 A fi T in the pathogenesis of RPL of unknown cause in the Caucasian Argentine population.
Clinical & Experimental Immunology, 2001
Variant alleles of the mannose binding lectin (MBL) gene are associated with increased susceptibility to infection and polymorphisms of tumour necrosis factor and lymphotoxin alpha genes (TNF, LTA) are associated with increased severity of infection. Studies have associated recurrent miscarriage with low serum mannose binding lectin concentrations and premature membrane rupture and preterm delivery with elevated maternal and fetal levels of TNF and the TNF (2 308) polymorphism. In this study the frequencies of variant MBL, TNF and LTA alleles in 76 Caucasian couples with idiopathic recurrent miscarriage were compared with those in 69 Caucasian control couples with no history of miscarriage and at least one previous live birth. A new assay based on hybridization to immobilized sequencespecific oligonucleotides (SSO) was used to rapidly detect nine MBL, two TNF and two LTA sequence variants. The assay genotyped all the structural and promoter MBL variants known to influence serum MBL concentrations. This assay was more reliable than restriction digestion or nested allele-specific PCR for the structural variants at codon 54 or 52, respectively. Reliability for codon 57 alleles was not assessed because of the low frequency in this population. The MBL haplotype frequencies in antenatal controls were similar to those reported in other control populations. The frequencies of structural variant MBL genes and of low, medium and high MBL level haplotypes were similar in the recurrent miscarriage and control couples. The TNF and LTA haplotype frequencies were similar in the recurrent miscarriage and control couples. In this carefully defined population no association has been found between recurrent miscarriage and variant alleles of the MBL, TNF or LTA genes.