Associations of genetic variants contributing to gut microbiota composition in diabetic nephropathy.

Introduction: The gut microbiota is strongly associated with multiple kidney diseases, and since microbial composition is heritable, we hypothesized that genetic variations controlling gut microbiota composition were associated with diabetic nephropathy susceptibility or clinical subphenotypes. Methods: The genetic variations associated with gut microbiota were retrieved from the genome-wide association study database and analysed in our diabetic nephropathy susceptibility gene screening cohort. Candidate microorganisms with possible genetic associations were identified using the annotation of microbial quantitative trait loci. Finally, the candidate microorganisms were verified by 16S rDNA gene sequencing. Results: There were 13 genetic variation loci associated with susceptibility to diabetic nephropathy. The TCF7L2 risk genotype was associated with a long duration of diabetes and high diastolic blood pressure, the ZCWPW2 risk genotype was associated with increased glycosylated hemoglobin, and the ZNRF3 risk genotype was associated with an increased urinary microalbumin-to-creatinine ratio. Both the ZNRF3 and SPECC1L risk genotypes were associated with the abundance of Lactococcus. 16S rDNA sequencing confirmed that there was indeed a significant difference in the Lactococcus genus between DN and DM patients. Conclusions: In this study, we preliminarily confirmed that the gut microbiota of diabetic nephropathy patients is influenced by host genetics and provide a new basis for future accurate diagnosis and treatment.