Impact of SNPs interplay across the locus of MBL2, between MBL and Dectin-1 gene, on women\u2019s risk of developing recurrent vulvovaginal infections

Abstract

BackgroundHuman mannose binding lectin (MBL) and dendritic cell-associated C-type lectin-1 (Dectin-1) are the two prototypical PRRs of innate immunity, whose direct role in recurrent vulvovaginal infections (RVVI) defense has been defined. Previously, MBL insufficiency was proposed as a possible risk factor for the rapid progression of RVVI while, Dectin-1 was found to be playing an active role in the defense. However, the complete genetic bases for the observed low MBL levels are still lacking as our previous studies in harmony with others demonstrated the un-expected genotype–phenotype patterns. This suggested the presence of unidentified regulatory variants that may modulate sMBL levels and risk of RVVI. Therefore, the present study was designed for more inclusive locus-wide MBL2 analysis and for the possible non-linear interaction analysis of two PRRs that may impact RVVI susceptibility.MethodsThe present study has extended the previous findings by investigating (1) the role of chosen additional SNPs falling in the 5′ near region relating to sMBL levels and RVVI susceptibility, using polymerase chain reaction-restriction fragment length polymorphism, (2) interactions among SNPs within gene by comprehensive locus-wide haplotype analyses of two MBL2 blocks, (3) gene–gene interaction analyses between two PRRs, using multifactor dimensionality reduction.Resultsrs11003124_G, rs7084554_C, rs36014597_G, and rs11003123_A were observed as the minor alleles in the representative North Indian cohort. RVVI cases and its types showed an appreciably high frequency of C allele, its homozygosity and heterozygosity, explaining the observed dominant mode of inheritance of rs7084554 polymorphism in contributing 1.81 fold risk of RVVI. The rs36014597 polymorphism showed the overdominant mode of inheritance, which further depicts that the carrier of a heterozygous genotype of this polymorphism had more extreme phenotype than either of its homozygous carriers in developing 4.07 fold risk of RVVI. sMBL levels significantly varied for rs11003124, rs36014597 and rs11003123 polymorphisms in bacterial vaginosis, while for rs7084554 polymorphism in mixed infection. Independent analysis of 5′ and 3′ haplotype blocks suggested the risk-modifying effect of all the 5′ additional variants, Y/X secretor polymorphism and 3′-UTR SNP i.e. rs10824792. Combined 5′/3′ haplotype analyses depicted the importance of rs36014597; an additional 5′ variant, Y/X and rs10824792 polymorphisms from both the blocks in regulating sMBL levels and RVVI risk. Three gene–gene interaction models involving uni-variant, bi-variant and tri-variant appeared as significant predictors of RVVI risk with cross-validation consistency of 10/10, 9/10 and 5/10, respectively.ConclusionsThe study presented a low-cost reproducible screening design for additional 5′ variants i.e. rs11003124, rs7084554, rs36014597 and rs11003123 of MBL2 that can act as markers of susceptibility for RVVI or any other diseases. Two additional 5′ variants of MBL2 i.e. rs7084554 and rs36014597 were suggested as novel molecular markers that may contribute to RVVI risk by varying sMBL levels. Variants of two blocks were found to have more of a combined effect than the independent effect in modulating RVVI susceptibility and sMBL levels. The study presented weak synergistic interaction between MBL2 and CLEC7A in association with RVVI risk. The preliminary data will establish the foundation for the investigation of within gene and between genes interaction analyses towards RVVI susceptibility.