Host Genetic Factors Associated with Vaginal Microbiome Composition in Kenyan Women

Abstract

Bacterial vaginosis (BV) affects 20% of women worldwide and is associated with adverse reproductive health outcomes and increased risk for HIV. Typically, BV represents a shift in the vaginal microbiome from one that is dominated by Lactobacillus to one that is diverse. Persistent racial differences in BV and diverse vaginal microbiome composition overlap with racial disparities in risks for HIV and sexually transmitted infection, especially among women of African descent. Risk factors for BV and nonoptimal vaginal microbiome include sexual practices, yet racial differences persist when adjusted for behavioral factors, suggesting a host genetic component. Here, we perform a genome-wide association study on vaginal microbiome traits in Kenyan women. Linear regression and logistic regression were performed, adjusting for age and principal components of genetic ancestry, to evaluate the association between Lactobacillus crispatus, Lactobacillus iners, Gardnerella vaginalis, Shannon diversity index, and community state type (CST) with host genetic single nucleotide polymorphisms (SNPs). We identified novel genomic loci associated with the vaginal microbiome traits, though no SNP reached genome-wide significance. During pathway enrichment analysis, Toll-like receptors (TLRs), cytokine production, and other components of innate immune response were associated with L. crispatus, L. iners, and CST. Multiple previously reported genomic loci were replicated, including IL-8 (Shannon, CST), TIRAP (L. iners, Shannon), TLR2 (Shannon, CST), MBL2 (L. iners, G. vaginalis, CST), and MYD88 (L. iners, Shannon). These genetic associations suggest a role for the innate immune system and cell signaling in vaginal microbiome composition and susceptibility to nonoptimal vaginal microbiome. IMPORTANCE Globally, bacterial vaginosis (BV) is a common condition in women. BV is associated with poorer reproductive health outcomes and HIV risk. Typically, BV represents a shift in the vaginal microbiome from one that is dominated by Lactobacillus to one that is diverse. Despite many women having similar exposures, the prevalence of BV and nonoptimal vaginal microbiome is increased for women of African descent, suggesting a possible role for host genetics. We conducted a genome-wide association study of important vaginal microbiome traits in Kenyan women. We identified novel genetic loci and biological pathways related to mucosal immunity, cell signaling, and infection that were associated with vaginal microbiome traits; we replicated previously reported loci associated with mucosal immune response. These results provide insight into potential host genetic influences on vaginal microbiome composition and can guide larger longitudinal studies, with genetic and functional comparison across microbiome sites within individuals and across populations.

Neutrophils Dominate the Cervical Immune Cell Population in Pregnancy and Their Transcriptome Correlates With the Microbial Vaginal Environment

“…Our attempts to further understand the interaction between neutrophils and cervicovaginal microbiota revealed that genes associated with neutrophil activation, degranulation and responses were negatively correlated with G. vaginalis , positively correlated with L. iners, and were not associated with maternal age or BMI. This suggests that bacteria can modify the host response within the vaginal environment or vice versa, as supported by previous studies ( Beghini et al, 2013 ; Mehta et al, 2020 ; Florova et al, 2021 ). Metha et al reported the associations between vaginal species such as G. vaginalis and L. iners using GWAS, with pathways associated with innate immune responses and neutrophil degranulation.…”

Modeling the temporal dynamics of cervicovaginal microbiota identifies targets that may promote reproductive health

“…Microbial composition and dynamics can be influenced by a wide variety of factors including sexual and vaginal hygiene practices [7,33,34], hormonal and menstrual state (including effects of contraception) [20,35], pregnancy and childbirth [1,20], antibiotic exposure [36], smoking [37], genetics [37,38], and socioeconomic factors, the combined effects of which likely account for geographic and racial/ethnic differences between populations [11,12,[14][15][16]. Our study's strength relies on its analysis of an observational cohort of young women with few major exclusion criteria except HIV infection, major preexisting illness, or pregnancy [26,39].…”

Contribution of Lactobacillus iners to Vaginal Health and Diseases: A Systematic Review

“…Presently, it is believed that the vaginal microbiome in black women does not play an important role in the pathogenesis of PTB, as it does in Caucasians and Asians ( Kindinger et al., 2017 ). Furthermore, the limited sample size, the time of sample collection, differences in the definition of PTB, ethnical and geographical variations, and differences in the methodology of strain identification, as well as complicated clinical conditions such as genetic abnormalities or a history of PTB, were confounding factors that impacted the results ( Ravel et al., 2011 ; Jespers et al., 2012 ; Mehta et al., 2020 ; Wells et al., 2020 ).…”