MTHFR (rs1801133) and SERPINE1/PAI-1 (-675 4G/5G) gene polymorphisms and their association with spontaneous abortion and missed pregnancy in an ethnic Uzbek population: a case-control study.

Spontaneous abortion and missed (non-developing) pregnancy are common early reproductive losses in which disturbed folate metabolism and inherited thrombophilia are implicated. Variants of methylenetetrahydrofolate reductase (MTHFR) and of the plasminogen activator inhibitor-1 gene (SERPINE1/PAI-1) may increase this risk, but data from Central Asian populations are scarce. We assessed the association of MTHFR rs1801133 (c.665C>T; p.Ala222Val, classically C677T) and the SERPINE1/PAI-1 -675 4G/5G promoter insertion/deletion polymorphism (rs1799889) with early pregnancy loss in a case-control study of ethnic Uzbek women. Eighty-one women with a history of spontaneous abortion (n = 40) or missed pregnancy (n = 41) and 83 women with a physiologically progressing pregnancy were genotyped. In controls, both loci conformed to Hardy-Weinberg equilibrium. The MTHFR Val allele (40.1% vs. 20.5%) and the Val/Val genotype (22.2% vs. 3.6%) were significantly more frequent in cases, the mutant homozygote conferring an approximately sevenfold increase in odds (OR 7.6, 95% CI 2.5-23.3; p < 0.01), whereas the Ala/Ala genotype was associated with lower odds of loss (OR 0.4). Similarly, the PAI-1 4G allele (46.9% vs. 30.1%) and the 4G/4G genotype (25.9% vs. 6.0%) were over-represented in cases (4G/4G: OR 5.5, 95% CI 2.1-14.2; p < 0.01). Associations were strongest in women with spontaneous abortion. Exploratory ROC analysis indicated moderate, high-specificity discrimination, greatest for the mutant homozygous genotypes (MTHFR Val/Val AUC 0.69; PAI-1 4G/4G AUC up to 0.73). In ethnic Uzbek women, the MTHFR Val/Val and PAI-1 4G/4G genotypes were associated with spontaneous abortion and missed pregnancy; given the case-control design, these are associations requiring confirmation in larger studies.