The Carrier State for Sickle Cell Disease Is Not Completely Harmless

Sickle cell disease (SCD) is a clinical syndrome caused by the presence of hemoglobin S (HbS), in which glutamic acid in position 6 of the β chain of hemoglobin is substituted by valine (β^Glu6Val). It is generally recognized as an autosomal recessive disorder, in that individuals who have inherited one copy of the HbS allele and one normal HbA allele (i.e. have HbAS or sickle cell trait, SCT), are typically asymptomatic and spared the serious complications associated with possessing two copies of the mutant allele (i.e. HbSS). It is estimated that 300 million people (~5% of the world’s population) carry the HbS allele, and nearly 5.5 million births are affected annually.¹

Individuals with SCD die prematurely, but the life expectancy of individuals with SCT is similar to that of people without the trait.² However, early literature attributed a number of possible disease associations to this heterozygous state, partly as a result of unreliable diagnostic laboratory testing for hemoglobinopathies and partly due to questionable conclusions drawn from uncontrolled observational studies, individual case reports, and small case series.^3,4 Nevertheless, while some of the associations historically attributed to SCT are unfounded, recent meta-analyses found high-quality evidence that SCT is indeed a risk factor for a handful of complications common to SCD.²