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

Abstract

Background Human 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. Methods The 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. Results rs11003124 _ 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. Conclusions The study presented a low-cost reproducible screening design for additional 5′ variants i.e. rs11003124...

Host Genetic Factors Associated with Vaginal Microbiome Composition in Kenyan Women

“…We investigated the associations of previously reported SNPs in relation to BV or vaginal microflora to determine whether these associations are relevant in a Kenyan population ( 19 – 26 ). Figure 3 and Table S3 summarize these findings.…”

Impaired PRR expression modulates inflammation-triggered oxidative stress and pathogenesis of recurrent vulvovaginal infections

“…Human 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 defense against RVVI pathogens has been defined (Ip & Lau, 2004;Pellis et al, 2005;Ferwerda et al, 2009;Li et al, 2012b). Moreover, our studies along with others have suggested the involvement of these PRRs in determining RVVI susceptibility (Ferwerda et al, 2009;Babula et al, 2003;Liu et al, 2006;Milanese et al, 2008;Henić et al, 2010;Ghazanfari et al, 2017;Kalia et al, 2017Kalia et al, , 2018Kalia et al, , 2019aKalia et al, , 2019b. In addition, both MBL and Dectin-1 have been shown to mediate ROS release as a part of defense mechanism against pathogens (Li et al, 2012b;Underhill et al, 2005;Kalia et al, 2016;Lima-Junior et al, 2017).…”

Host Genetic Determinants of the Vaginal Microbiome in Kenyan Women

“…Several SNPs in the MBL2 region were significantly associated with L. iners, G. vaginalis, and CST. Kalia et al studied these previously reported MBL2 SNPs in association with BV in women in India due to associations between mannose binding lectin (MBL) insufficiency and increased susceptibility to infectious diseases [30]. Among Brazilian women, a specific MBL2 polymorphism was associated with increased odds of recurrent BV compared to controls [31], though a study among Italian women that screened for three specific MBL2 SNPs found no differences for women with recurrent BV as compared to controls [32].…”