Walid Zammiti

Association of factor V gene polymorphisms (Leiden; Cambridge; Hong Kong and HR2 haplotype) with recurrent idiopathic pregnancy loss in Tunisia. A case-control study

Inherited thrombophilia has been shown to be linked with fetal loss. We performed a case-control study on the association between thrombosis-related polymorphisms in the factor V (FV) gene (Leiden, Cambridge, Hong Kong; HR2 haplotype) and idiopathic recurrent pregnancy loss (RPL) in Tunisian women. A total of 348 women with RPL, and 203 control women were studied, corresponding to 1,250 pregnancy losses and 1,200 successful pregnancies. FV Leiden was seen in 19.4% of patients (4.3% in the homozygous state) and in 5.5% of controls. The prevalence of the FV HR2 haplotype was similar in patients and controls, but with 7 homozygous patients for 1 control. FV Cambridge and Hong Kong were absent from both patients and controls. The study of all pregnancy losses evidenced that the frequency of the factor V Leiden polymorphism was zero in women who had mis-carried before 7 weeks of gestation, and then sharply increased to a plateau. After categorization of pregnancy losses (before 8 weeks of gestation; weeks 8 and 9; weeks 10 to 12; from the 13th week of gestation onwards), heterozygous and homozygous factor V Leiden polymorphisms, and homozygous FV HR2 haplotype, were associated with significant and independent risks of pregnancy loss during weeks 8 and 9, which increased during weeks 10 to 12, then culminated after week 12. In Tunisian women with idiopathic RPL, factor V Leiden polymorphism and homozygous FV HR2 haplotype are not a risk factor for very early pregnancy loss, before 8 weeks of gestation, but are thereafter associated with significant clinical risks, which gradually increase from the 8th week onwards.

ORIGINAL ARTICLE: Lack of Consistent Association Between Endothelial Nitric Oxide Synthase Gene Polymorphisms, Homocysteine Levels and Recurrent Pregnancy Loss in Tunisian Women

Problem  Polymorphisms of the endothelial nitric oxide synthase (eNOS) gene have been associated with reduced vascular NO production or increased level of homocysteine, and evaluated as risk factors for recurrent pregnancy loss (RPL). Therefore, in this case‐control study, we aimed to determine the effects of some eNOS functional polymorphisms: the 27‐bp intron 4 repeat, the 894G/T of exon 7, and the promoter substitution ‐786T/C, in women with RPL.

Tumor necrosis factor α and lymphotoxin α haplotypes in idiopathic recurrent pregnancy loss

OBJECTIVE To investigate the contribution of the -238G/A and -308G/A tumor necrosis factor (TNF) alpha, and +252A/G lymphotoxin (LT) alpha gene polymorphisms to idiopathic recurrent miscarriage (RM). DESIGN A retrospective case-control study. SETTING Outpatient maternity center. PATIENT(S) Study subjects comprised 372 RM women and 274 age-matched parous control women. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The TNFalpha and LTalpha gene variants and idiopathic RM. RESULT(S) Higher prevalence of TNFalpha -238A and LTalpha +252G alleles and LTalpha +252G/G genotype and lower frequencies of TNFalpha -308G/A were seen in RM cases. Three-loci haplotype analysis (TNFalpha -308GA/TNFalpha -238GA/LTalpha +252AG) demonstrated significant association between TNFalpha-LTalpha gene variants and RM. Both protective [-308A/-238G/+252A], and susceptible [-308G/-238A/+252G] haplotypes were identified. Mutlivariate regression analysis confirmed the association of -308G/-238A/+252G haplotype with exclusively early RM, after controlling for a number of covariates; no specific TNFalpha and LTalpha genotypes or haplotypes were linked with either late or combined early and late RM. CONCLUSION(S) The TNFalpha -238G/A and LTalpha +252A/G, but not TNFalpha -308G/A, polymorphic variants are associated with exclusively early idiopathic RM.

Common polymorphisms in the P-selectin gene in women with recurrent spontaneous abortions

BACKGROUND To investigate possible associations of P-selectin polymorphisms with idiopathic recurrent pregnancy loss (RPL). METHODS Study subjects comprised 270 consecutive RPL cases attending outpatient maternity services, and 322 multi-parous control women. P-selectin genotyping was done by PCR-RFLP and PCR-ASA methods. RESULTS The P-selectin variants rs1800807, rs1800805, and rs6127, were in Hardy Weinberg equilibrium, and low linkage disequilibrium was noted between the three studied SNPs. The frequency of rs6127 A allele (P<0.001I), but not rs1800807 C allele (P=0.957) or rs1800805 A allele (P=0.760), was higher in RPL cases than in control women. Significant differences in the distribution of rs6127 (P<0.001), but not rs1800807 (P=0.444) or rs1800805 (P=0.391) genotypes were seen between cases and controls, and only rs6127 showed a significant association with RPL, with increments of 2.65 and 4.96 in disease risk seen for heterozygous and homozygous carriers, respectively. Among the 8 three-locus Pselectin haplotypes constructed (rs1800807/rs1800805/rs6127), increased frequency of GGG (Pc=0.0249), CGG (Pc=0.0256), and CAG (Pc=0.0174) haplotypes, and lower frequency of CGA haplotype (Pc=0.0091) were seen in RPL cases, thus conferring disease susceptibility and protective nature to these haplotypes, respectively. CONCLUSIONS P-selectin gene polymorphisms and haplotypes contribute to RPL development.