Creatinine Clearance in Sickle Cell Anemia Is Modulated by Genes in the TGF-β/BMP Pathway.

Renal failure is common in sickle cell anemia. The CSSCD, a longitudinal study of the natural history of sickle cell disease, enrolled 4,082 patients observing them for about 5 years, while obtaining laboratory data that included renal function estimated by serum creatinine. Blood samples were obtained for globin gene analysis and were used for SNP genotyping. We studied only patients with sickle cell anemia, with or without coincident α thalassemia. DNA samples and sufficient clinical and laboratory data were available for 779 patients. An adjusted creatinine clearance, using the Cockcroft-Gault and Schwartz formulas was computed for adults and children, respectively. These formulas were used since glomerular hyperfiltration and increased secretion of creatinine reduces the utility of serum creatinine as a measure of renal function in sickle cell anemia. DNA samples were screened for SNPs in candidate genes that included inflammatory mediators, modulators of oxidant injury and NO biology, vasoregulatory molecules and cell adhesion factors and that might be associated with the renal failure phenotype. Genotyping was first done using the Sequenom mass spectrometry SNP genotyping system. For quality control purposes about 3% of the DNA samples were regenotyped and Hardy-Weinberg equilibrium was assessed for each SNP among controls. In this initial screen, we considered a SNP to be associated with renal function when the p-value was less than or equal to 0.01, or more than one SNPs in the same gene was significant at the 0.05 level. If a SNP met these criteria, a second phase of genotyping was done to study additional haplotype tagging (ht) SNPs. We have previously reported the association of genes in the TGF-β/BMP pathway with sickle cell subphenotypes (