# APOL1 as a model to quantify and identify environmental modifiers of genetic associations in diverse populations > **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $437,443 ## Abstract PROJECT SUMMARY Complex human traits and outcomes have substantial genetic and environmental contributions that, when identified, lead to a better understanding of underlying biological process and are potential targets of prevention, intervention, and treatment strategies. Advances in genotyping and sequencing technologies over the last 20 years has enabled a golden age of genomic discovery, resulting in the identification of thousands of genome- wide genotype-phenotype associations. Comparatively, the identification of modifiers of these genetic associations has been slow. And most interrogations of modifiers of genetic associations have been limited to select non-genetic variables such as sex and age or exposures such as smoking. Relatively few have explored the impact of social determinants of health despite their independent associations with health disparities. Regardless of the modifier under study, their identification requires large, well-phenotyped and diverse cohorts with exposure and genome-wide data available for powerful statistical analysis. Compounding the challenge is defining the phenotype or outcome of interest generalizable to populations but still useful in specific clinic settings. The relatively recent availability of UK Biobank and All of Us, among other diverse datasets linked to phenotypes, exposures, and genome-wide data, makes the earnest search for environmental modifiers of genetic associations possible. Here we propose to use APOL1 as a model and possible framework for the methodical search for environmental “second hits” that distinguish truly at-risk participants and eventually patients from others. APOL1, associated strongly with negative kidney outcomes that disproportionately affect African Americans, is an ideal model given that its renal risk variants are 1) common among African-descent and admixed groups and 2) found exclusively on African-specific haplotypes. We aim to access NEPTUNE, UK Biobank, and All of Us to quantify the evidence that APOL1 genetic risk for rare (focal segmental glomerulosclerosis or FSGS) and common negative kidney outcomes (albuminuria, kidney-disease related eGFR, and composite chronic kidney disease) is modified using observed heterogeneity in its effect sizes across populations (African Americans, British Blacks, and Hispanics). We further aim to interrogate potential modifying effects of heavy metal exposure, a quantitative marker association with social determinant of health. The Specific Aims proposed here, when accomplished, will provide additional data toward at-risk profiles for APOL1 renal risk variant carriers useful for clinical risk prediction models as well as targets for prevention efforts and/or development of novel therapeutics. The accomplished Aims will also provide a framework for the systematic interrogation of “second hits” relevant for human outcomes with known genetic associations. ## Key facts - **NIH application ID:** 10983483 - **Project number:** 1R21HG013814-01 - **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY - **Principal Investigator:** DANA C CRAWFORD - **Activity code:** R21 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $437,443 - **Award type:** 1 - **Project period:** 2024-09-09 → 2025-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10983483 ## Citation > US National Institutes of Health, RePORTER application 10983483, APOL1 as a model to quantify and identify environmental modifiers of genetic associations in diverse populations (1R21HG013814-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10983483. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*