Itzel Vazquez-Vidal 1, Geetha Chittoor 1, Baba Mass 1, Karin Haack 2, Sandra Laston 3, Nitesh Mehta 4, Anthony G Comuzzie 2, Shelley Cole 2, Nancy Butte 4 and V. Saroja Voruganti 1 (2017). Genetics of acute kidney injury markers in Hispanic children: the Viva La Familia Study. The FASEB Journal 31(1).
1. Department of Nutrition, University of North Carolina-Chapel Hill, Nutrition Research Institute, Kannapolis, NC
2. Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX
3. South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX
4. Department of Pediatrics, US Department of Agriculture/Agricultural Research Service Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX
Studies have demonstrated that chronic kidney disease in adults may develop from acute kidney injury during childhood. Thus, increases in acute kidney injury (AKI) markers that are indicative of sharp decline in kidney function are a cause of concern for later kidney disease. AKI markers are also under considerable genetic influence. Our aim in this study was to identify genetic determinants of urinary AKI markers: neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CysC), beta-2-microglobulin (β2M), osteopontin (OST) and trefoil-factor 3 (TFF3) in Hispanic children of the Viva La Family Study. Urinary concentrations of NGAL, CysC, β2M, OST and TFF3 were measured in 837 children. We conducted a genome-wide association analysis of AKI markers after accounting for family kinships. All methods were implemented in SOLAR. Empirical thresholds for genome-wide significant and suggestive associations were defined as p <1 × 10−7, and p <1 × 10−6, respectively. Significant heritabilities were found for all AKI markers (range 35 – 68%), with CysC showing the highest heritability (h2= 0.68, p= 1.9×10−15). The GWAS analysis showed strong association of rs7555367 of phospholipid phosphatase related 5 (PLPPR5) gene with OST (p = 3.5 × 10−8, MAF = 0.09, β coefficient = −0.58 (0.10)) and suggestive association with TFF3 and β2M (p < 2.7 × 10−6, MAF = 0.09, β coefficient = −0.48 and −0.55 (0.11)). We also found suggestive association between OST and 8 SNPs (rs10169879, rs10210408, rs16856600, rs2075252, rs2284675, rs2389589, rs3821125, rs4668123) in lipoprotein-related protein 2 (LRP2)/megalin gene (p < 3 × 10−7) and between NGAL and rs12947457, rs7216231 and rs4968239 of N-ethylmaleimide sensitive factor, vesicle fusing ATPase (NSF) (p < 3.4 × 10−7). These genes have key roles in cell signaling and signal transduction. In summary, we observed significant genetic influence on the variation in AKI markers and identified a potential role for PLPPR5, LRP2 and NSFin AKI in children.