TY - JOUR
T1 - Associations of Genetic Variants Contributing to Gut Microbiota Composition in Immunoglobin A Nephropathy
AU - He, Jia-Wei
AU - Zhou, Xu-Jie
AU - Li, Ya-Feng
AU - Wang, Yan-Na
AU - Liu, Li-Jun
AU - Shi, Su-Fang
AU - Xin, Xiao-Hong
AU - Li, Rong-Shan
AU - Falchi, Mario
AU - Lv, Ji-Cheng
AU - Zhang, Hong
N1 - Funding Information:
This work was supported by the Beijing Natural Science Foundation under grant Z190023; the National Science Foundation of China under grants 82022010, 81970613, 81925006, 81670649, and 82070733; the King's College London-Peking University Health Science Center Joint Institute for Medical Research; the Fok Ying Tung Education Foundation under grant 171030; the Beijing Nova Program Interdisciplinary Cooperation Project under grant Z191100001119004; the Beijing Youth Top-Notch Talent Support Program under grant 2017000021223ZK31; the Clinical Medicine Plus X-Young Scholars Project of Peking University under grant PKU2020LCXQ003; the University of Michigan Health System-Peking University Health Science Center Joint Institute for Translational and Clinical Research under grant BMU2017JI007; and the Chinese Academy of Medical Sciences Research Unit under grant 2019RU023. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of themanuscript. We report no conflict of interest. H.Z. and X.-J.Z. conceived and designed the study; H.Z., J.-C.L., X.-J.Z., and L.-J.L. collaborated in patient recruitment, data acquisition, and organization; S.-F.S., J.-W.H., and Y.-N.W. performed the laboratory analyses; X.-H.X., Y.-F.L., and R.-S.L. performed the 16S rRNA gene sequencing; X.-J.Z., J.-W.H., Y.-N.W., and M.F. analyzed the data; X.-J.Z. and J.-W.H. made the figures; and J.-W.H., X.-J.Z., and H.Z. drafted and revised the manuscript. All authors approved the final version of the manuscript.
Funding Information:
This work was supported by the Beijing Natural Science Foundation under grant Z190023; the National Science Foundation of China under grants 82022010, 81970613, 81925006, 81670649, and 82070733; the King’s College London-Peking University Health Science Center Joint Institute for Medical Research; the Fok Ying Tung Education Foundation under grant 171030; the Beijing Nova Program Interdisciplinary Cooperation Project under grant Z191100001119004; the Beijing Youth Top-Notch Talent Support Program under grant 2017000021223ZK31; the Clinical Medicine Plus X-Young Scholars Project of Peking University under grant PKU2020LCXQ003; the University of Michigan Health System-Peking University Health Science Center Joint Institute for Translational and Clinical Research under grant BMU2017JI007; and the Chinese Academy of Medical Sciences Research Unit under grant 2019RU023. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We report no conflict of interest.
Publisher Copyright:
© 2021 American Society for Microbiology. All rights reserved.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/12
Y1 - 2021/1/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85100386274&partnerID=8YFLogxK
U2 - 10.1128/mSystems.00819-20
DO - 10.1128/mSystems.00819-20
M3 - Article
C2 - 33436510
SN - 2379-5077
VL - 6
JO - mSystems
JF - mSystems
IS - 1
M1 - e00819
ER -