Clinical and genetic ancestry profile of a large multi-centre sickle cell disease cohort in Brazil

Abstract

Approximately 3500 children with sickle cell disease (SCD) are born in Brazil each year, but the burden of SCD morbidity is not fully characterised. A large, multi-centre cohort was established to characterise clinical outcomes in the Brazilian SCD population and create the infrastructure to perform genotype-phenotype association studies. Eligible patients were randomly selected from participating sites and recruited at routine visits. A biorepository of blood samples was created and comprehensive demographic and clinical outcome data were entered in a centralized electronic database. Peripheral blood genome-wide single nucleotide polymorphism (SNP) genotyping was performed using a customized Transfusion Medicine (TM) Array. A total of 2795 participants at six Brazilian sites were enrolled between 2013 and 2015. The cohort included slight predominance of children <18 years (55·9%) and females (53·0%). Haemoglobin (Hb) SS was the most common SCD genotype (70·7%), followed by HbSC (23%), Sβ0 (3·0%) and Sβ+ (2·9%). SNP data from the TM Array were analysed to evaluate the genetic ancestry of the cohort and revealed significant admixture among the population. Demographics and clinical complications, stratified by age and SCD genotype, are summarized and future studies in this cohort are discussed.

Keywords: clinical aspects; sickle cell disease; single nucleotide polymorphisms.

Figure 1. Principle Component Analysis Comparison of TM-Array Data of REDS-III SCD Cohort to 1000G Reference Population by Self-Reported Race

Plot of top principle components of the Brazilian sickle cell disease (SCD) cohort are co-graphed with the 1000 Genome Project (1000G) reference population. 1000G participants are coloured purple, with subpopulations indicated by the three-lettered coding. REDS-III Brazilian SCD patients are shown as dots. The race in focus, as identified in the header, is coloured red; while the remaining REDS-III SCD patients are coloured green. 1000G three-lettered coding: GWD: Gambian in Western Division, The Gambia – Mandinka, MSL: Mende in Sierra Leone, ESN: Esan in Nigeria, CLM: Colombian in Medellin, Colombia, PEL: Peruvian in Lima, Peru, TSI: Toscani in Italy, IBS: Iberian populations in Spain, MXL: Mexican Ancestry in Los Angeles, California, GWJ: Gambian in Western Division, The Gambia – Jola, GBR: British in England and Scotland, CEU: Utah residents (CEPH) with Northern and Western European ancestry, YRI: Yoruba in Ibadan, Nigeria, LWK: Luhya in Webuye, Kenya, GWF: Gambian in Western Division, The Gambia – Fula, ASW: African Ancestry in Southwest US, ACB: African Caribbean in Barbados, PUR: Puerto Rican in Puerto Rico, FIN: Finnish in Finland, GWW: Gambian in Western Division, The Gambia – Wolof

Figure 2:. Prevalence of Select SCD Clinical Complications and Treatments within Age Groups of the REDS-III Brazil SCD Cohort

The proportion of REDS-III patients within defined age group categories with a history of select sickle cell disease (SCD) clinical complications is shown - ischaemic stroke (a), priapism (b), bacteraemia (c), avascular necrosis (AVN) and leg ulcers (d). (e) The proportion of patients with a hospitalization for vaso-occlusive pain episode (VOE) or acute chest syndrome (ACS) in the year prior to enrolment into the cohort. (f) The prevlance of patients treated with chronic transfusion therapy and hydroxycarbamide (HC tx) at the time of enrolment into the cohort. In all graphs, sickle cell anemia (SCA) patients (SS, Sβ⁰, SD) are shown in blue and HbSC patients are shown in red. Because of the significant heterogentiy of clinical outcomes in only 81 Sβ⁺ patients, the Sβ⁺ patients are not included in the figures. Specific phenotypes are indicated with circle/solid line or triangle/dashed line as defined in the key in each panel.