ALBERT

Description: Sickle hemoglobin polymerization involves not only ß6 Val in a largely hydrophobic acceptor pocket but other contact sites. We recently found that the ß73 His Hb S variant (ß6 Val and ß73 His) promoted polymerization compared to deoxy Hb S, while ß73 Leu Hb S (ß6 Val and ß73 Leu) inhibited polymerization like deoxy Hb C-Harlem (ß6 Val and ß73 Asn). In fact, ß73 Asp in Hb S makes a hydrogen bond with ß4 Thr in deoxy Hb S polymers, and this is a unique position to promote or inhibit polymerization by amino acid change [Adachi et al., Biochemistry (2003), 42, 4476]. Kinetics of polymerization, solubility and minimum concentration required for polymerization of the ß73 Hb S variants were affected by ß73 amino acid (inhibition of polymerization: His 〈

Description: Renal insufficiency is the source of significant morbidity and mortality in adults with sickle cell disease (SCD). A population of adult patients with SCD and end-stage renal disease (ESRD) requiring hemodialysis was examined for factors that predict ESRD. ESRD patients (mean age 36.8 +/− 7.74) were compared with patients without ESRD over 50 years old (mean age 59.3 +/− 8.31). We found that the ESRD population was characterized by more males (14 males, 8 females ESRD vs. 4 males, 15 females non-ESRD), a higher occurrence of the CAR beta-like globin cluster haplotype (44 % ESRD vs. 11 % non-ESRD) and relatively lower fetal hemoglobin levels (3.6 +/− 2.16 ESRD vs. 8.6 +/− 6.35 non-ESRD). In order to further examine potential predictors of renal disease, including genetic modifiers unlinked to the beta-globin cluster, we examined a broader population of patients with elevated creatinine, defined as levels greater than 1.0 mg/dl, who did or did not require hemodialysis. We hypothesize that gender, beta-like globin cluster haplotype, fetal hemoglobin levels and polymorphisms in critical regulators of vasomotor tone are predictors of renal insufficiency in SCD. Genotyping of a single nucleotide polymorphism (SNP) in endothelial nitric oxide synthase (eNOS or NOS3) and an insertion/deletion polymorphism (I/D) in the angiotensin-converting enzyme (ACE) gene will allow us to determine if these polymorphisms are over-represented in this cohort. The eNOS T-786C SNP alters the level of transcription of the eNOS gene and the amount of eNOS activity. We recently showed that this polymorphism was associated with a history of acute chest syndrome in females with SCD (Br. J. Haematol., 2004, 124:240). The ACE I/D polymorphism has been associated with altered plasma ACE levels. Twenty-one adult patients with sickle cell disease with renal insufficiency and 25 age- and gender-matched control patients seen at Thomas Jefferson University are being examined. Genotype results and statistical analysis will be presented. It is hoped that identification of predictors of renal insufficiency in patients with SCD might lead to early identification of at-risk patients, allowing for therapeutic intervention.