Heritability and Multipoint Linkage Analysis Suggest the Contribution of Angiopoietin-TEK Pathway to the Variation of Serum Creatinine and Glomerular Filtration Rate

Background: Serum creatinine and estimated glomerular filtration rate (eGFR) are keys to assess kidney function and suggest a propensity for development of renal failure. Genetic factors are reported in different ethnic groups to play a role in the variability of these phenotypes. In this study, we investigate the heritability and quantitative trait loci (QTL) of serum creatinine and eGFR. Multiple phenotypes were collected from a multi-generation pedigree of 281 subjects form Oman family study. Genotype analysis was used to calculate heritability and linkage was performed using variance components decomposition-based methods implemented in SOLAR. Results: The multivariate-adjusted heritability estimates for serum creatinine and eGFR were 0.70 and 0.63 (p-value 2.5x10-11 and 1.8x10-11), respectively. Genome-wide linkage analysis showed significant loci with LOD score ≥2 at chromosomes 9p21.1, 9p21.3, 15p26.3 and 16.p13.3. Functional annotation identified angiopoietin 1-TEK pathway as a candidate pathway where TEK is associated with chronic kidney disease and expressed in renal glomeruli. Conclusion: This study showed high heritability of serum creatinine and eGFR with significant QTLs in chromosomes 9, 15 and 16. Further research is needed to study the genetic association studies of angiopoietin 1-TEK axis with glomerulopathies like type 2 diabetes and to predict and diagnose progression of renal diseases.