Associations of Genetic Variants Contributing to Gut Microbiota Composition in Immunoglobin A Nephropathy

The gut microbiota has been implicated in immunoglobin A nephropathy (IgAN) because the intestinal immune response is assumed to be one of the disease triggers. Since the microbial composition is heritable, we hypothesize that genetic variants controlling gut microbiota composition may be associated with susceptibility to IgAN or clinical phenotypes. A total of 175 gut-microbiome-associated genetic variants were retrieved from the Genome-Wide Association Study (GWAS) Catalog. Genetic associations were examined in 1,511 patients with IgAN and 4,469 controls. Subphenotype associations and microbiome annotations were undertaken for a better understanding of how genes shaped phenotypes. Likely candidate microbes suggested in genetic associations were validated using 16S rRNA gene sequencing in two independent data sets with 119 patients with IgAN and 45 controls in total. Nine genetic variants were associated with susceptibility to IgAN. Risk genotypes of LYZL1 were associated with higher serum levels of galactose-deficient IgA1 (Gd-IgA1). Other significant findings included the associations between the risk genotype of SIPA1L3 and early age at onset, PLTP and worse kidney function, and AL365503.1 and more severe hematuria. Besides, risk genotypes of LYZL1 and SIPA1L3 were associated with decreased abundances of Dialister and Bacilli, respectively. Risk genotypes of PLTP and AL365503.1 were associated with increased abundances of Erysipelotrichaceae and Lachnobacterium, respectively. 16S data validated a decreased tendency for Dialister and an increased tendency for Erysipelotrichaceae in IgAN. In this pilot study, our results provided preliminary evidence that the gut microbiota in IgAN was affected by host genetics and shed new light on candidate bacteria for future pathogenesis studies.IMPORTANCE The gut microbiota and host genetics are implicated in the pathogenesis of IgAN. Recent studies have confirmed that microbial compositions are heritable (microbiome quantitative trait loci [QTL]). The relationship between host genetics and the microbiota and the role of the microbiota in IgAN are unclear. We retrieved the GWAS Catalog and associated microbiome QTL in IgAN, observing that nine genetic variants were associated with IgAN susceptibility and some clinical phenotypes. In a consistent way, the decreased abundance of Dialister was associated with higher serum levels of Gd-IgA1, and 16S rRNA gene analysis confirmed the decreased abundance of Dialister in IgAN. These data provided preliminary evidence that the gut microbiota in IgAN was affected by host genetics, which is a new strategy for future pathogenesis and intervention studies.