A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis
Haiyang Yu, … , Mark J. Daly, Andrey S. Shaw
Haiyang Yu, … , Mark J. Daly, Andrey S. Shaw
Published March 1, 2016; First published February 22, 2016
Citation Information: J Clin Invest. 2016;126(3):1067-1078. https://doi.org/10.1172/JCI82592.
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Research Article Nephrology

A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis

Abstract

Focal segmental glomerulosclerosis (FSGS) is a syndrome that involves kidney podocyte dysfunction and causes chronic kidney disease. Multiple factors including chemical toxicity, inflammation, and infection underlie FSGS; however, highly penetrant disease genes have been identified in a small fraction of patients with a family history of FSGS. Variants of apolipoprotein L1 (APOL1) have been linked to FSGS in African Americans with HIV or hypertension, supporting the proposal that genetic factors enhance FSGS susceptibility. Here, we used sequencing to investigate whether genetics plays a role in the majority of FSGS cases that are identified as primary or sporadic FSGS and have no known cause. Given the limited number of biopsy-proven cases with ethnically matched controls, we devised an analytic strategy to identify and rank potential candidate genes and used an animal model for validation. Nine candidate FSGS susceptibility genes were identified in our patient cohort, and three were validated using a high-throughput mouse method that we developed. Specifically, we introduced a podocyte-specific, doxycycline-inducible transactivator into a murine embryonic stem cell line with an FSGS-susceptible genetic background that allows shRNA-mediated targeting of candidate genes in the adult kidney. Our analysis supports a broader role for genetic susceptibility of both sporadic and familial cases of FSGS and provides a tool to rapidly evaluate candidate FSGS-associated genes.

Authors

Haiyang Yu, Mykyta Artomov, Sebastian Brähler, M. Christine Stander, Ghaidan Shamsan, Matthew G. Sampson, J. Michael White, Matthias Kretzler, Jeffrey H. Miner, Sanjay Jain, Cheryl A. Winkler, Robi D. Mitra, Jeffrey B. Kopp, Mark J. Daly, Andrey S. Shaw

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Figure 1

Comparability of patients and controls.

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Comparability of patients and controls. (A) PCA plot of FSGS patients an...
(A) PCA plot of FSGS patients and 1,000 genome samples. The inset shows the distribution of putative Northern European FSGS patients in the PCA plot in relationship to 1,000 genome samples. (B) Magnified view of the inset area in A. (C) PCA analysis of patients and controls is depicted as the distance from the origin. Thirty-two patients with a highly similar variant profile but with a distance of more than 0.9 were removed and used as a follow-up group. (D) Fisher’s exact test of the common (MAF >5%) variants showed the absence of stratification and confirmed the validity and quality of our method for case-control matching. (E) Comparison of the total number of variants per sample showed that patients and controls were similar. (F) Comparison of the total number of heterozygous genotypes showed that patients and controls were similar. (G) Comparison of the total number of heterozygous and homozygous genotypes containing an alternative allele showed that patients and controls were similar. EUR, European; HISP, Hispanic; AFR, African; EAS, East Asian; VAR, variants; HET, heterozygous; PC1, principal component 1; PC2, principal component 2; KG, from 1000 Genomes Database.