ABSTRACT

Objective: To explore potential associations between four biallelic variants within three genes that code for enzymes involved in either the transmethylation (methylene tetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR)) or trans-sulphuration (cystathionine beta-synthase (CBS)) metabolic pathways, and clinically relevant phenotypic measures in sickle cell anaemia [homozygous haemoglobin SS] (HbSS).

Methods: A total of 371 participants with HbSS disease were recruited from the Sickle Cell Clinic of the Sickle Cell Unit at The University of the West Indies, Mona, Jamaica. Genotypes at four sites (MTHFR C677T, MTHFR A1298C, MTR A2756G and CBS 844ins68) within the three genes were determined using polymerase chain reaction-based assays.

Results: Univariate regression analyses showed statistically significant associations between MTHFR C677T and red blood cell (RBC) count (p = 0.019) and between MTHFR C677T and mean corpuscular volume (p = 0.015). Multivariable regression analyses showed statistically significant associations between MTHFR C677T and packed cell volume values (p = 0.019), between MTHFR C677T and RBC count (p = 0.013), and between MTHFR A1298C and mean corpuscular haemoglobin concentration (p = 0.026).

Conclusion: This exploratory cross-sectional study has generated novel and informative genotype-phenotype estimates of association, but larger studies are needed to determine whether the specific variants within these genes underlying the transmethylation and trans-sulphuration pathways are related to inter-individual phenotypic variability in HbSS.