The genetics of red blood cell density, a biomarker of clinical severity in sickle cell disease
Sickle cell disease is one of most common blood disorder amongst human. The complications associated with the disease are systemic. They damage virtually all the organs of the body, causing severe, unpredictable pain episodes, which repercussions can eventually lead to death. The process through which a biconcave, healthy red blood cell assumes a crescent-shape is well described in the literature; under deoxygenation, as water and solutes leave erythrocytes the concentration of hemoglobin S increases thus giving us dense dehydrated cells and subsequently sickled cells. Today’s current therapies are for the most part experimental, costly, and vary widely in their long-term effectiveness from patient to patient. There is, therefore, a pressing need, to identify a biomarker that is cost-effective and provides positive health outcomes to patients. The density of red blood cell is a biological indicator largely ignored by the medical community in sickle cell disease. Exploring erythrocytes density can facilitate the development of new therapies by targeting channels to rehydrate cells back to their normal shape. Clinical and physiological characterizations of this phenotype exist in many studies, but the genetic characterization is absent. We attempted to elucidate the genetic underpinning of this phenotype, by conducting a genome-wide scan, and examining the whole-exome sequences of individuals with extreme red blood cell density. Our genome-wide association study did not highlight any new loci due to our limited statistical power reflected by the cohort’s small sample size. However, our prioritization approach highlighted an intronic variant that controls the expression of ATP2B4, the main calcium pump in erythrocytes. Our whole-exome sequencing experiment pointed out two rare missense mutations in the same patient; one in ATP1B2, a Na+/K+ transporter, and the other in SPTB, the β-spectrin gene. These variants could explain why he has the highest measured density of red blood cells amongst all of our sequenced patients, and why this person experiences several of the disease-related complications. Another rare missense mutation in two patients with elevated levels of dense cells was discovered in PIEZO1, the mechanosensitive ion channel. The mutation is predicted to be deleterious by both protein function prediction algorithms.
Genome wide association Whole-exome sequencing Sickle cell disease Erythrocyte density Red blood cell hydration