Association of the R67X and W303X non-sense polymorphisms in the protein Z-dependent protease inhibitor gene with idiopathic recurrent miscarriage.
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.
Department of Medical Biochemistry, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.
F S
FS
AlShaikh
R R
RR
Finan
A W
AW
Almawi
F E
FE
Mustafa
W Y
WY
Almawi
D000026:Abortion, Habitual / Q000235:genetics*; D000328:Adult; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015843:Serpins / Q000235:genetics*
C416370:SERPINA10 protein, human; D015843:Serpins