CR1 variants contribute to FSGS susceptibility across multiple populations.

Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome with an annual incidence in the United States in African-Americans compared to European-Americans of 24 cases and 5 cases per million, respectively. Among glomerular diseases in Europe and Latin-America, FSGS was the second most frequent diagnosis, and in Asia the fifth. We expand previous efforts in understanding genetics of FSGS by performing a case-control study involving ethnically-diverse groups FSGS cases (726) and a pool of controls (13,994), using panel sequencing of approximately 2,500 podocyte-expressed genes. Through rare variant association tests, we replicated known risk genes - KANK1, COL4A4, and APOL1. A novel significant association was observed for the gene encoding complement receptor 1 (CR1). High-risk rare variants in CR1 in the European-American cohort were commonly observed in Latin- and African-Americans. Therefore, a combined rare and common variant analysis was used to replicate the CR1 association in non-European populations. The CR1 risk variant, rs17047661, gives rise to the Sl1/Sl2 (R1601G) allele that was previously associated with protection against cerebral malaria. Pleiotropic effects of rs17047661 may explain the difference in allele frequencies across continental ancestries and suggest a possible role for genetically-driven alterations of adaptive immunity in the pathogenesis of FSGS.