CR1 variants contribute to FSGS susceptibility across multiple populations

Rostislav Skitchenko; Zora Modrusan; Alexander Loboda; Jeffrey B Kopp; Cheryl A Winkler; Alexey Sergushichev; Namrata Gupta; Christine Stevens; Mark J Daly; Andrey Shaw; Mykyta Artomov

doi:10.1016/j.isci.2025.112234

CR1 variants contribute to FSGS susceptibility across multiple populations

iScience. 2025 Mar 18;28(4):112234. doi: 10.1016/j.isci.2025.112234. eCollection 2025 Apr 18.

Authors

Rostislav Skitchenko^{1

2}, Zora Modrusan³, Alexander Loboda^{1

2

4}, Jeffrey B Kopp⁵, Cheryl A Winkler⁶, Alexey Sergushichev¹, Namrata Gupta⁴, Christine Stevens⁴, Mark J Daly^{4

7

8}, Andrey Shaw³, Mykyta Artomov^{4

9

10}

Affiliations

¹ ITMO University, St. Petersburg, Russia.
² Almazov National Medical Research Centre, St. Petersburg, Russia.
³ Research Biology, Genentech Inc., San Francisco, CA, USA.
⁴ Broad Institute, Cambridge, MA, USA.
⁵ Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA.
⁶ Molecular Genetic Epidemiology Studies Section, National Cancer Institute (NCI), Frederick, MD, USA.
⁷ Massachusetts General Hospital, Boston, MA, USA.
⁸ Institute for Molecular Medicine Finland, Helsinki, Finland.
⁹ Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
¹⁰ Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.

Abstract

Focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome, with an annual incidence of 24 cases per million among African-Americans and 5 per million among European-Americans in the United States. It ranks as the second most common glomerular disease in Europe and Latin America and the fifth in Asia. We conducted a case-control study involving 726 FSGS cases and 13,994 controls from diverse ethnic backgrounds, using panel sequencing of ∼2,500 podocyte-expressed genes. Rare variant association tests confirmed known risk genes (KANK1, COLAPOL1) and identified a significant association with the CR1 gene. The CR1 variant rs17047661, which encodes the Sl1/Sl2 (R1601G) allele, was previously linked to cerebral malaria protection and is now identified as a risk variant for FSGS. This highlights an evolutionary trade-off between infectious disease resistance and kidney disease susceptibility, emphasizing the role of adaptive immunity in FSGS pathogenesis and potential therapeutic targets.

Keywords: Association analysis; Clinical syndrome; Human Genetics; Quantitative genetics.