The genetics of red blood cell density in sickle cell disease patients. (Poster Presentation)


Sickle cell disease is a monogenic blood disorder caused by mutations in the β-globin gene. Although a single gene is involved in this disorder, the clinical symptoms are heterogeneous. Dehydrated red blood cell density (DRBC) is a typical attribute of sickle cell disease (SCD) patients. Recent studies have linked higher percentage of DRBC with increased incidence of SCD-related pathophysiologies caused by the deformation of erythrocytes in blood vessels. Based on these novel fi ndings, we sought to identify the genetic determinants of DRBC in SCD patients.We conducted a genome-wide association study (GWAS) in 405 SCD patients from the GEN-MOD study. These participants are of recent African descent and were recruited in France. Genotyping was done on the Illumina HumanOmni2.5Exome array and imputation was performed using 1000 Genomes Phase 3 haplotypes (v.5). We also performed gene-based tests (SKAT & VT), focusing on non-synonymous and splice site variants with a minor allele frequency <5%. DRBC was analyzed using an additive linear regression model, correcting for age, sex, and the first 10 principal components. Finally, we selected 65 patients from the GEN-MOD study for whole-exome sequencing (WES), and investigated the association between DRBC and rare detrimental mutations in strong candidate genes that play a role in red blood cell biology.The GWAS analyses were inconclusive as none of the variants reached array-wide signifi cance (P<2x10-7). This lack of association probably refl ects our modest sample size to fi nd association between DRBC and common variants of weak effects. The WES experiment identifi ed 230 mutations in 50 candidate genes. Of interest, we found that the patient with the highest percentage of DRBC (37%) had a missense mutation in ATP1B2, the beta2 subunit of the ouabain-sensitive Na+/K+ -ATPase. This gene is also known as AMOG (Ca2+-dependent adhesion molecule of glia) and is expressed abundantly in the brain and the retina. It binds to retinoschisin, a retinal degeneration gene for X-linked human juvenile retinoschisis. We present the fi rst genetic study of DRBC, a biomarker and potential modifier of severity in SCD. We found no evidence of common variants with strong effect on DRBC variation. Our candidate-gene approach based on WES highlighted several promising candidate mutations, although functional validation is required to confi rm their mechanistic effect.

Oct 18, 2016 12:00 AM — Oct 22, 2016 12:00 AM
Vancouver Convention Centre
999-1055 Canada Place, Vancouver, British Columbia V6C 0C3