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.

中文翻译：

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免疫球蛋白A肾病中肠道菌群组成的遗传变异的关联。

肠道菌群与免疫球蛋白A肾病（IgAN）有关，因为肠道免疫应答被认为是疾病的诱因之一。由于微生物组成是可遗传的，我们假设控制肠道微生物群组成的遗传变异可能与对IgAN或临床表型的敏感性有关。从全基因组关联研究（GWAS）目录中检索到总共175种肠道微生物相关的遗传变异。在1,511例IgAN患者和4,469例对照中检查了遗传关联。为了更好地了解基因如何塑造表型，进行了亚表型关联和微生物组注释。在16个独立数据集中使用119S IgAN患者和45个对照的两个独立数据集，验证了可能在遗传关联中建议的候选微生物。九个遗传变异与对IgAN的易感性有关。的风险基因型LYZL1与半乳糖缺陷型IgA1（Gd-IgA1）的较高血清水平相关。其他重要发现包括SIPA1L3的危险基因型与发病年龄，PLTP和肾功能恶化以及AL365503.1和更严重的血尿之间的关联。此外，LYZL1和SIPA1L3的风险基因型分别与Dialister和Bacilli的丰度降低有关。风险基因型PLTP和AL365503.1用增加的丰度相关丹毒和Lachnobacterium， 分别。16S数据验证了IgAN中Dialister的减少趋势和Erysipelotrichaceae的增加趋势。在这项初步研究中，我们的结果提供了初步证据，证明IgAN中的肠道菌群受到宿主遗传学的影响，并为候选细菌提供了新的亮点，以供将来进行发病机理研究。