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

ABSTRACT 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 a...

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Autores principales:	Jia-Wei He, Xu-Jie Zhou, Ya-Feng Li, Yan-Na Wang, Li-Jun Liu, Su-Fang Shi, Xiao-Hong Xin, Rong-Shan Li, Mario Falchi, Ji-Cheng Lv, Hong Zhang
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	IgA nephropathy genetics microbiome quantitative trait loci gut microbiota Dialister Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/b650f0292dd54ef9a684d91bd6e2dab5
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spelling	oai:doaj.org-article:b650f0292dd54ef9a684d91bd6e2dab52021-12-02T17:07:41ZAssociations of Genetic Variants Contributing to Gut Microbiota Composition in Immunoglobin A Nephropathy10.1128/mSystems.00819-202379-5077https://doaj.org/article/b650f0292dd54ef9a684d91bd6e2dab52021-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00819-20https://doaj.org/toc/2379-5077ABSTRACT 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.Jia-Wei HeXu-Jie ZhouYa-Feng LiYan-Na WangLi-Jun LiuSu-Fang ShiXiao-Hong XinRong-Shan LiMario FalchiJi-Cheng LvHong ZhangAmerican Society for MicrobiologyarticleIgA nephropathygeneticsmicrobiome quantitative trait locigut microbiotaDialisterMicrobiologyQR1-502ENmSystems, Vol 6, Iss 1 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	IgA nephropathy genetics microbiome quantitative trait loci gut microbiota Dialister Microbiology QR1-502
spellingShingle	IgA nephropathy genetics microbiome quantitative trait loci gut microbiota Dialister Microbiology QR1-502 Jia-Wei He Xu-Jie Zhou Ya-Feng Li Yan-Na Wang Li-Jun Liu Su-Fang Shi Xiao-Hong Xin Rong-Shan Li Mario Falchi Ji-Cheng Lv Hong Zhang Associations of Genetic Variants Contributing to Gut Microbiota Composition in Immunoglobin A Nephropathy
description	ABSTRACT 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.
format	article
author	Jia-Wei He Xu-Jie Zhou Ya-Feng Li Yan-Na Wang Li-Jun Liu Su-Fang Shi Xiao-Hong Xin Rong-Shan Li Mario Falchi Ji-Cheng Lv Hong Zhang
author_facet	Jia-Wei He Xu-Jie Zhou Ya-Feng Li Yan-Na Wang Li-Jun Liu Su-Fang Shi Xiao-Hong Xin Rong-Shan Li Mario Falchi Ji-Cheng Lv Hong Zhang
author_sort	Jia-Wei He
title	Associations of Genetic Variants Contributing to Gut Microbiota Composition in Immunoglobin A Nephropathy
title_short	Associations of Genetic Variants Contributing to Gut Microbiota Composition in Immunoglobin A Nephropathy
title_full	Associations of Genetic Variants Contributing to Gut Microbiota Composition in Immunoglobin A Nephropathy
title_fullStr	Associations of Genetic Variants Contributing to Gut Microbiota Composition in Immunoglobin A Nephropathy
title_full_unstemmed	Associations of Genetic Variants Contributing to Gut Microbiota Composition in Immunoglobin A Nephropathy
title_sort	associations of genetic variants contributing to gut microbiota composition in immunoglobin a nephropathy
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/b650f0292dd54ef9a684d91bd6e2dab5
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Associations of Genetic Variants Contributing to Gut Microbiota Composition in Immunoglobin A Nephropathy

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