Age-related macular degeneration (AMD), a slowly progressive, neurodegenerative disease, is a leading cause of irreversible blindness worldwide. The number of people with AMD is projected to increase from 196 million in 2020 to 288 million in 2040. While lifestyle factors, such as diet and smoking, are associated with the risk of advanced AMD, it is known that polymorphisms and rare variants in genes encoding certain complement system proteins play a predisposing role.
Anuja Java, MD, Assistant Professor of Medicine, Nephrology, is first author of a recent publication in Human Molecular Genetics that details the involvement of complement factor I (CFI) variants in advanced AMD. The clinical impact of these variants has been in question since a majority have not been functionally characterized and are classified as “variants of uncertain significance” (VUS).
In a previous study by Java, et al., CFI variants in 35 patients were stratified into three groups based on antigenic and functional assessments. Type 1 variants caused a quantitative deficiency of FI; Type 2 variants caused a qualitative deficiency; and Type 3 variants consisted of VUS that were less dysfunctional than Types 1 and 2 but were not as biologically active as wild-type (WT).
In the current study of 37 patients, the research team used an in-depth biochemical analysis to clarify the significance of nine Type 3 variants. Their results led to re-categorization of four CFI variants as Type 1 variants, two variants as Type 2 variants, and three variants remained as Type 3 variants (and are likely considered benign). This study highlights the usefulness of an in-depth structure-function analysis to define the pathologic and clinical implications of complement variants underlying AMD.
The ability to identify individuals who carry dysfunctional CFI variants and are at risk of developing advanced AMD will provide critical guidance in targeting those most likely to benefit from complement pathway related therapies.
Please read the article “Functional Analysis of Rare Genetic Variants in Complement Factor I (CFI) in Advanced Age-related Macular Degeneration (AMD)” in Human Molecular Genetics (May 9, 2022). The research team is made up of investigators from Washington University in St. Louis, St. Louis University, and the University of Massachusetts Chan Medical School. Authors: Anuja Java, Nicola Pozzi, Molly C Schroeder, Zheng Hu, Huan Tianxiao, Johanna Seddon, John Atkinson.
Java is a renowned physician-scientist and expert in rare complement diseases and their involvement in kidney damage. She is the Director of Kidney Transplant at the John Cochran VA Medical Center.
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See more about Dr. Java in WashU Nephrology news:
- Nephrologist Anuja Java Co-chairs the ClinGen Complement Gene Curation Expert Panel
- Anuja Java, MD, Elected to Executive Council of Women in Nephrology
- Dr. Anuja Java Awarded Longer Life Foundation Grant to Study the Role of Complement Genetic Mutations in the Development of Preeclampsia
- Dr. Anuja Java Co-chairs Working Group in an International Committee for Revising aHUS Nomenclature
- Physician-Scientist Anuja Java’s Complement Research Tackles COVID-19
- Dr. Anuja Java Heads New Kidney Transplant Clinic at St. Louis VA