Exploring putative genetic determinants of inter-individual phenotypic heterogeneity in sickle cell disease: A cross-sectional Jamaican cohort-based study

Abstract Patients with sickle cell disease (SCD) display puzzling inter-individual phenotypic heterogeneity, conceivably related to inherent differences in antioxidant protection, hemoglobinbinding, bilirubin catabolism and methyl group handling. Therefore, we explored putative associations between clinically important phenotypic measures and functional polymorphisms within specific candidate genes encoding glutathione S-transferase, haptoglobin, uridine 5′-diphospho- glucuronosyltransferase1A1 , methyl tetrahydrofolatereductase , 5-methyltetrahydrofolate-homocysteine methyltransferase, and cystathionine beta-synthase. Two-hundred and thirty SCD participants (mean age 25.1 ± 2.8) were recruited from Jamaica's Annual Sickle Cell Unit Cohort Review – two-hundred and five had homozygous hemoglobinSS (HbSS) disease, twenty-five had hemoglobinSC (HbSC) disease. Regression analyses revealed some novel genotype-phenotype associations. HbSC participants had significantly lower mean lactate dehydrogenase ( p  = 0.01) and glutathione ( p Glutathione S-transferaseP1 ( GSTP1) was significantly associated with mean corpuscular hemoglobin concentrationusing univariate ( p  = 0.044) and multivariable regression ( p  = 0.012). 5-methyltetrahydrofolate-homocysteine methyltransferase( MTR ) was significantly associated with hemoglobin F% using univariate ( p  = 0.010) and multivariable regression ( p  = 0.009). In conclusion, this exploratory cross-sectional study generated novel, useable, and informative genotype-phenotype estimates of association, but larger studies are needed to determine whether these specific variants are related to inter-individual phenotypic variability in SCD.