Associations between tumor necrosis factor-alpha and lymphotoxin-alpha polymorphisms and idiopathic recurrent miscarriage.

Heightened expression of tumor necrosis factor (TNF)-alpha and lymphotoxin-alpha (LT-alpha) was associated with pregnancy complications, including idiopathic recurrent miscarriage (RM). Whereas TNF-alpha and LT-alpha gene polymorphisms affect serum cytokine concentrations, their contribution to RM is controversial. The single nucleotide polymorphisms (SNPs) TNF-alpha (-238G/A, -308G/A) and LT-alpha (+252A/G) were investigated in 350 RM women and 200 control women. Higher frequency of the TNF-alpha -238A, but not the TNF-alpha -308A or the LT-alpha+252G, allele was seen in patients, with comparable frequencies of TNF-alpha -238G/A, TNF-alpha -308G/A, and LT-alpha+252A/G genotypes seen between both groups, except for TNF-alpha -238G/G, which was lower in patients. Regression analysis confirmed the association of the TNF-alpha -238G/A SNP with idiopathic RM, and both TNF-alpha -308A/TNF -238G/LT-alpha+252G and TNF-alpha -308G/TNF-alpha -238A/LT-alpha+252G haplotypes played a susceptible role in idiopathic RM. TNF-alpha -238G/A and -238A/A, and LT-alpha+252G/G genotypes were positively associated only with exclusively early RM. This supports the concept of the association of TNF-alpha (-238G/A) and LT-alpha (+252A/G) polymorphic variants in idiopathic RM.

Lupus anticoagulant and antibodies to beta 2-glycoprotein I, annexin V, and cardiolipin as a cause of recurrent spontaneous abortion.

The prevalence of lupus anticoagulant (LAC), anticardiolipin (ACA), anti-beta(2) glycoprotein I (beta(2)GPI), and antiannexin V antibodies were determined in 200 recurrent spontaneous abortion (RSA) patients and 200 age-matched control women. ACA IgG was associated with early, while antiannexin V IgG and LAC were associated with late, and ACA IgG, antiannexin V IgG, and LAC were associated with combined early + late RSA, thereby recommending inclusion of their screening in RSA workout.

Association of -592C/A, -819C/T and -1082A/G interleukin-10 promoter polymorphisms with idiopathic recurrent spontaneous abortion.

Increasing evidence supports a role for altered T helper 1 (Th1)-Th2 cytokine balance in idiopathic recurrent spontaneous abortion (RSA). The aim of this study was to investigate the association of the interleukin 10 (IL-10) promoter polymorphisms -592C/A, -819C/T and -1082A/G with RSA. Women (n = 350) with at least three consecutive spontaneous abortions (RSA cases) and 200 control women with at least two successful pregnancies were included. The frequency of the -819T allele [P = 0.05, odds ratio (OR) = 1.51], but not other single-nucleotide polymorphisms (SNPs), was higher among RSA patients. Complete linkage disequilibrium (LD) was seen between -592C and -819C and -1082G alleles, as well as between -592A and -819T and between -819C and -1082G alleles only among patients. Although the genotype frequencies (except for -819C/C) of the three polymorphisms were comparable between patients and controls, higher frequency of -592A/-819T/-1082A haplotype (OR = 4.01, 95% CI = 1.83-7.95) was seen in cases versus controls. Regression analysis indicated that, after adjusting for potential variables, -592C/A (OR = 3.32, 95% CI = 1.76-6.27) and -819C/T (OR = 5.06, 95% CI = 2.59-9.91) were associated with exclusively early but not exclusively late RSA, where negative association for both was noted. This supports the notion of involvement of IL-10-592C/A and -819C/T polymorphisms as inherited risk factors of idiopathic RSA.

Antibodies to beta2-glycoprotein I and annexin V in women with early and late idiopathic recurrent spontaneous abortions.

Anti-phospholipid antibodies (APA) are heterogeneous group of autoantibodies that target phospholipid or phospholipid-binding proteins. APAs were previously shown to induce several thrombotic states, including idiopathic recurrent spontaneous abortion (RSA). Unlike the contribution of the classical lupus anticoagulant (LAC) and anticardiolipin antibodies (ACA), the contribution of anti-beta2 glycoprotein 1 (beta2GPI) and anti-annexin V antibodies to RSA risk remain poorly understood. We assessed anti-beta2GPI and anti-annexin V IgM and IgG antibodies as RSA risk factors for RSA in 172 Tunisian women with >3 consecutive idiopathic pregnancy losses, together with 173 matched control women. The prevalence of anti-beta2GPI IgG (P=0.41, OR=1.64) and IgM (P=0.50, OR=1.70) were comparable between cases and controls. Higher anti-annexin V IgG (P=0.02, OR=5.28), but not IgM (P=0.25, OR=1.78), levels were seen in cases. Regression analysis showed that anti-beta2GPI IgM (OR=8.90; 95% CI=1.23-64.63) was associated with early RSA, while anti-annexin V IgG (OR=9.35, 95% CI=1.44-60.86) was associated with late RSA. For combined early + late RSA, the only variable selected was BMI (OR=0.93; 95% CI=0.87-0.99), and neither anti-annexin V nor anti-beta2GPI IgM and IgG were associated with early + late RSA. Anti-annexin V and anti-beta2GPI appear to be independent risk markers of RSA.

Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and changes in homocysteine concentrations in women with idiopathic recurrent pregnancy losses.

Because they have been described as strong risk factors for idiopathic recurrent pregnancy losses (RPLs), we assessed the association between the methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) C677T and A1298C and hyperhomocysteinemia in Tunisian women with idiopathic RPL. Study subjects comprised 200 patients with more than three consecutive RPLs, and 200 age-matched parous control women. C677T and A1298C SNPs were analyzed by PCR-RFLP analysis, and fasting serum homocysteine was measured with ELISA. The frequency of MTHFR 677T/T (30.0 vs 7.0%) and 1298C/C (13.5 vs 4.0%) genotypes was significantly higher in patients. While it was similar among patients and controls (P = 0.095), higher homocysteine was seen with the T/T (but not 1298A/C and 1298C/C) genotype among patients and controls compared with non-T/T carriers (P < 0.05), and in patients vs controls. Higher prevalence of MTHFR 677T/T was seen in late (P < 0.05) and early-late (P < 0.001) RPL, while higher prevalence of 1298C/C genotype was seen only in early-late RPL (P < 0.001), and the prevalence of double heterozygotes was statistically not significant between patients and controls (P = 0.10; odds ratio = 2.73). Logistic regression analysis showed that, after adjusting for all variables, homozygosity for MTHFR C677T was associated with late (P < 0.001), and combined early-late (P < 0.001), while homozygosity for A1298C was associated only with combined early-late (P = 0.026), as was secondary-level education, which was associated with early (P = 0.005), late (P = 0.026) and combined early-late (P = 0.004) abortions. Homozygosity for MTHFR C677T (late and early-late) and A1298C (early-late) are risk factor for RPLs, irrespectively of total homocysteine levels.