A genetic association study of NLRP2 and NLRP7 genes in idiopathic recurrent miscarriage

Abstract

STUDY QUESTION: Do gene polymorphisms of two members of the human innate immune sensor nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing proteins (NLRP) family, NLRP2 and NLRP7, confer susceptibility to idiopathic recurrent miscarriage (RM)? SUMMARY ANSWER: We found a significant association of a tag single-nucleotide polymorphism (SNP) of NLRP7 (rs26949) with idiopathic RM, while a tag SNP of NLRP2 (rs127868) showed a marginally significant association. WHAT IS KNOWN ALREADY: Human NLRP2 and NLRP7 have been suggested to be maternal effect genes, regulating early embryonic development and establishment of maternal imprints. Anecdotal evidence showed women who had experienced at least three consecutive miscarriages without hydatidiform mole carried non-synonymous NLRP7 variants. Whether these two genes are associated with idiopathic RM remains obscure. STUDY DESIGN, SIZE AND DURATION: In this case-controlled study, 143 women who had experienced at least two consecutive spontaneous miscarriages (n = 91 women with two miscarriages, n = 52 with three or more) and 149 controls were included between 2004 and 2010. MATERIALS, SETTING, METHODS: A total of five tag SNPs of NLRP2 and eight tag SNPs of NLRP7 were genotyped using the primer extension analysis. The deviation from the Hardy-Weinberg equilibrium was checked using χ(2) analysis. The logistic odds ratios (ORs) of RM were estimated with a 95% confidence interval (CI) in multivariate analysis after maternal age adjustment. The false discovery rate (FDR) was used to adjust for multiple testing. Tests for haplotype association with RM were performed. Gene-gene interactions among loci of the two genes were evaluated by using the multifactor dimensionality reduction (MDR) method. MAIN RESULTS AND THE ROLE OF CHANCE: One tag SNP rs269949 of NLRP7 showed significant difference between patients and controls in a recessive model (FDR P = 0.0456, age-adjusted OR (AOR) = 16.49, 95% CI = 2.00-136.11 for the GG genotype). The difference was significant in patients with two consecutive miscarriages and also in those with three or more consecutive miscarriages. Meanwhile, one tag SNP of NLRP2 (rs12768) showed marginal significance between patients and controls in a co-dominant model (FDR P = 0.0505, AOR = 2.15, 95% CI = 1.29-3.58 for the AC genotype). In the haplotype analysis, NLRP2 and NLRP7 did not show any significant difference between the patients and controls. MDR test revealed that there is no significant gene-gene interaction among loci of NLRP2 and NLRP7. LIMITATIONS, REASONS FOR CAUTION: The results may be biased by heterogeneous ethnicities of the Taiwanese Han and a small sample size. The genetic loci responsible for the disease as well as their functional significance also await further investigation. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests the role of the NLRP family proteins in RM. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the National Science Council of the Republic of China (NSC-100-2314-B-006-011-MY3). None of the authors have any conflicts of interest.