KIDNEY DISEASE GENETICS AND THE IMPORTANCE OF DIVERSITY IN PRECISION MEDICINE

Abstract

Kidney disease is a well-known health disparity in the United States where African Americans are affected at higher rates compared with other groups such as European Americans and Mexican Americans. Common genetic variants in the myosin, heavy chain 9, non-muscle (MYH9) gene were initially identified as associated with non-diabetic end-stage renal disease in African Americans, and it is now understood that these variants are in strong linkage disequilibrium with likely causal variants in neighboring APOL1. Subsequent genome-wide and candidate gene studies have suggested that MYH9 common variants among others are also associated with chronic kidney disease and quantitative measures of kidney function in various populations. In a precision medicine setting, it is important to consider genetic effects or genetic associations that differ across racial/ethnic groups in delivering data relevant to disease risk or individual-level patient assessment. Kidney disease and quantitative trait-associated genetic variants have yet to be systematically characterized in multiple racial/ethnic groups. Therefore, to further characterize the prevalence of these genetic variants and their association with kidney related traits, we have genotyped 10 kidney disease or quantitative trait-associated single nucleotide polymorphisms (SNPs) (rs2900976, rs10505955, rs10502868, rs1243400, rs9305354, rs12917707, rs17319721, rs2467853, rs2032487, and rs4821480) in 14,998 participants from the population-based cross-sectional National Health and Nutrition Examination Surveys (NHANES) III and 1999-2002 as part of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study. In this general adult population ascertained regardless of health status (6,293 non-Hispanic whites, 3,013 non-Hispanic blacks, and 3,542 Mexican Americans), we observed higher rates of chronic kidney disease among non-Hispanic blacks compared with the other groups as expected. We performed single SNP tests of association using linear regressions assuming an additive genetic model adjusted for age, sex, diastolic blood pressure, systolic blood pressure, and type 2 diabetes status for several outcomes including creatinine (urinary), creatinine (serum), albumin (urinary), eGFR, and albumin-to-urinary creatinine ratio (ACR). We also tested for associations between each SNP and chronic kidney disease and albuminuria using logistic regression. Surprisingly, none of the MYH9 variants tested was associated with kidney diseases or traits in non-Hispanic blacks (p>0.05), perhaps attributable to the clinical heterogeneity of kidney disease in this population. Several associations were observed in each racial/ethnic group at p<0.05, but none were consistently associated in the same direction in all three groups. The lack of significant and consistent associations is most likely due to power highlighting the importance of the availability of large, diverse populations for genetic association studies of complex diseases and traits to inform precision medicine efforts in diverse patient populations.

Figure 1. Coded allele frequency of kidney disease or trait-associated SNPs by race/ethnicity

Allele frequencies (y-axis) are given for each of the ten SNPs genotyped in NHANES (x-axis) for each race/ethnicity. Race/ethnicity is color-coded (blue for non-Hispanic whites, red for non-Hispanic blacks, and green for Mexican Americans). Allele frequencies displayed here were calculated based on NHANES III and NHANES 1999-2002 frequencies combined.

Figure 2. Results of tests of association are displayed using Synthesis-View by SNP, quantitative trait, and race/ethnicity

Plotted are the p-values (y-axis is –log of the p-value). The triangles denote the direction of the genetic effect. The red line is a p-value threshold of 0.05. Abbreviations: Albumin-creatinine ratio (ACR); albumin (AL), estimated Glomerular Filtration Rate (eGFR), serum creatinine (CR), urinary creatinine (uCR); non-Hispanic white (NHW), non-Hispanic black (NHB), Mexican American (MA).