Association of the R67X and W303X non-sense polymorphisms in the protein Z-dependent protease inhibitor gene with
F S AlShaikh1, R R Finan, A W Almawi
1Department of Medical Biochemistry, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.
Abstract:
Protein Z-dependent protease inhibitor (ZPI) is a 72 kDa single-chain serpin which inhibits the activated coagulation factors X and XI. Two non-sense polymorphisms of ZPI, R67X and W303X, were recently identified, and were linked with a prothrombotic state. Here, we investigated the association of the R67X (728C>T) and W303X (1438G>A) variants in the ZPI gene with recurrent spontaneous miscarriage (RSM). This was a case-control study involving a total of 288 women with a history of two consecutive or ≥3 non-consecutive pregnancy losses between 8 and 12th week of gestation, along with 304 age-matched and ethnically matched multiparous control women, with no personal or family history of pregnancy complications. The minor allele frequency of R67X (P = 0.003) and W303X (P = 0.014) were higher in RSM cases than in control women. Both single-nucleotide polymorphisms were significantly associated with RSM under the dominant genetic association model, and were in moderate linkage disequilibrium (D' = 0.412; P < 0.001). Taking the common (728)C/(1438)G haplotype as reference, multivariate analysis confirmed the positive association of (728)T/(1438)G [P = 0.043; odds ratio (OR) = 2.25; 95% confidence interval (CI) = 1.03-4.90], and (728)T/(1438)A (P = 0.022; OR = 3.93; 95% CI = 1.23-12.59) haplotypes with increased RSM risk. These differences remained significant after controlling for some covariates. These results demonstrate that both ZPI R67X and W303X non-sense variants and specific ZPI haplotypes are significantly associated with RSM.
Insights
Genetic variants in the Protein Z-dependent protease inhibitor (ZPI) gene, specifically R67X and W303X, are linked to an increased risk of recurrent spontaneous miscarriage (RSM). These findings highlight ZPI
Area of Science:
- Genetics
- Reproductive Medicine
- Hematology
Background:
- Protein Z-dependent protease inhibitor (ZPI) is a serpin regulating coagulation factors.
- ZPI gene polymorphisms R67X and W303X have been associated with prothrombotic states.
Purpose of the Study:
- To investigate the association between ZPI gene variants (R67X and W303X) and recurrent spontaneous miscarriage (RSM).
Main Methods:
- A case-control study involving 288 women with RSM and 304 ethnically matched controls.
- Genotyping of ZPI R67X (728C>T) and W303X (1438G>A) single-nucleotide polymorphisms.
- Analysis of linkage disequilibrium and haplotype associations with RSM.
Main Results:
- Higher minor allele frequencies for R67X and W303X in RSM cases compared to controls.
- Significant association of both R67X and W303X polymorphisms with RSM under a dominant model.
- Identified specific ZPI haplotypes, (728)T/(1438)G and (728)T/(1438)A, significantly increasing RSM risk.
Conclusions:
- ZPI R67X and W303X non-sense variants are significantly associated with recurrent spontaneous miscarriage.
- Specific ZPI haplotypes contribute to an elevated risk of recurrent spontaneous miscarriage.
Related Concept Videos
02:32Exon Recombination
Exon shuffling follows “splice frame rules.” Each exon has three reading...
01:05Single Nucleotide Polymorphisms-SNPs
01:29Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...