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Genetic Variation Contributing to Nephrotic Syndrome

Genetic Variation Contributing to Nephrotic Syndrome 1024 683 Abbie Miller

Genetic variants in CR1 have significantly different population-specific frequencies and are linked with focal segmental glomerulosclerosis (FSGS) – the leading cause of nephrotic syndrome.

Focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome — a kidney disorder that causes proteins to leak into the urine causing a variety of complications. FSGS has an prevalence of 24 cases per million among African Americans and 5 per million among European Americans in the United States. The increased prevalence persists globally for individuals of African descent. A new study suggests the difference is related to an evolutionary tradeoff between infectious disease resistance and kidney disease susceptibility. This connection further emphasizes the role of adaptive immunity in FSGS pathogenesis and supplies targets for new therapeutic approaches.

Investigating Podocyte Gene Expression

Mykyta Artomov, PhD, principal investigator in the Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, and his collaborators recently published the results of a case-control study involving 726 FSGS cases and 13,994 controls from diverse ethnic backgrounds. The team used a panel sequencing about 2,500 genes expressed in podocytes, key kidney cell types involved in FSGS. They confirmed known risk genes (KANK1 and COLAPOL1) and identified a significant association with the CR1 gene.

“The original design of the podocyte exome panel has been inspired by our previous study of FSGS where we have used this panel to discover several novel FSGS susceptibility genes and validate them in mouse models,” says Dr. Artomov. The podocyte exome panel included the five genes associated with FSGS, 200 genes functionally linked to the known FSGS genes, 677 genes highly expressed in human glomeruli and 1,600 genes highly expressed in primary podocytes.

CR1 and a Malarial Connection

The protein coded by CR1 is involved in immune system regulation — specifically in regulating the complement system.

The CR1 variants known as the Knops group polymorphisms were previously linked to cerebral malaria protection in African-decent populations. This highlights an evolutionary trade-off between infectious disease resistance and kidney disease susceptibility, emphasizing the role of adaptive immunity in FSGS pathogenesis.

Mykyta Artomov, PhD

“FSGS is known to have significantly higher prevalence among African-descent individuals. In part, this has been connected to evolutionary adaptation, as shown by — variants in APOL1 that are very prevalent in African-descent individuals are conferring protection against trypanosomiasis, also known as African sleeping sickness, but significantly increase the risk of FSGS,” explains Dr. Artomov. “This is thought to be one of the reasons why such genetic variants are common in African-descent individuals and extremely rare in European-descent individuals. We show that genetic variants in CR1 show similar properties, likely contributing to the differences in FSGS prevalence across populations.”

Clinical Context

Better understanding of the role of CR1 and the complement system in FSGS may also supply new therapeutic targets. However, screening for CR1 variants may offer clinical support even sooner.

“CR1’s involvement in FSGS disease has been known for a while, but mostly from the standpoint of gene expression dysregulation in podocytes, which is challenging to assess in a patient,” says Dr. Artomov.

Screening for CR1 risk alleles could help flag patients or family members who are at elevated genetic risk for FSGS before they develop overt clinical symptoms such as proteinuria or decline in glomerular filtration rate (GFR), he suggests. Furthermore, knowledge of an inherited CR1 risk could guide discussions around recurrence risk in relatives, timing of surveillance urinalysis, and lifestyle or blood-pressure targets to delay onset.

 

 

References:

  1. Skitchenko R, Modrusan Z, Loboda A, Kopp JB, Winkler CA, Sergushichev A, Gupta N, Stevens C, Daly MJ, Shaw A, Artomov M. CR1 variants contribute to FSGS susceptibility across multiple populations. iScience. 2025;28:112234.
  2. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010;329:841–845.
  3. Yu H*, Artomov M*, Brähler S*, Stander MC, Shamsan G, Sampson MD, White JM, Kretzler M, Miner JH, Jain S, Winkler CA, Mitra RD, Kopp JB, Daly MJ, Shaw AS. A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis. Journal of Clinical Investigation. 2016;126(4):1603.

Image credits: Adobe Stock (header); Nationwide Children’s (portrait)

About the author

Abbie (Roth) Miller, MWC, is a passionate communicator of science. As the manager, medical and science content, at Nationwide Children’s Hospital, she shares stories about innovative research and discovery with audiences ranging from parents to preeminent researchers and leaders. Before coming to Nationwide Children’s, Abbie used her communication skills to engage audiences with a wide variety of science topics. She is a Medical Writer Certified®, credentialed by the American Medical Writers Association.

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