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Platform-dependent effects of genetic variants on plasma APOL1
Qingbo S Wang1, Jinguo Huang1, Leanne Chan1
1Calico Life Sciences LLC, South San Francisco, CA, USA.
Biorxiv : the Preprint Server for Biology
|February 20, 2025
Summary
Genetic variants in apolipoprotein L1 (APOL1) are linked to kidney disease risk. This study reveals how APOL1 variants and the kallikrein-kinin pathway influence circulating APOL1 levels, potentially explaining disease mechanisms.
Area of Science:
- Genetics
- Proteomics
- Nephrology
Background:
- Apolipoprotein L1 (APOL1) gene variants are strongly associated with kidney disease risk in individuals of African ancestry.
- The precise mechanisms linking APOL1 variants to kidney disease remain largely unknown.
- Plasma proteomics offers a method to investigate the impact of genetic variants on circulating protein levels.
Purpose of the Study:
- To examine the genetic drivers of circulating APOL1 levels across diverse ancestries and cohorts.
- To investigate the influence of APOL1 variants and the kallikrein-kinin pathway on plasma APOL1.
- To elucidate the mechanisms underlying APOL1-associated kidney disease.
Main Methods:
- Analysis of four independent cohorts (UK Biobank, AASK, deCODE, Health ABC) including individuals of African and European ancestry.
- Utilized three proteomic technologies: Olink, SomaLogic, and mass spectrometry.
- Performed quantitative trait loci (pQTL) analysis to identify genetic associations with plasma APOL1 levels.
Main Results:
- Disease-associated APOL1 G1 and G2 variants were identified as significant pQTLs for plasma APOL1, with platform-dependent directional effects.
- A common European variant (rs2239785) in APOL1 showed similar platform-dependent discrepancies.
- Variants in the kallikrein-kinin pathway (KLKB1, F12, KNG1) demonstrated trans-pQTL effects on APOL1 measured by Olink but not SomaLogic.
Conclusions:
- A proposed model suggests APOL1 mutations and the kallikrein-kinin pathway alter the relative abundance of two APOL1 forms, differentially recognized by proteomic platforms.
- This shift in APOL1 forms' relative abundance may contribute to the pathogenesis of APOL1-associated kidney disease.
- Platform-specific effects highlight the complexity of APOL1 measurement and its association with kidney disease.
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