Mild or severe presentation of sickle cell disease; characterisation of genetic causes

• Grant number: 17/50428-8
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2018
• End date: November 30, 2020
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Agreement: King's College London
• Principal Investigator: Fernando Ferreira Costa
• Grantee: Fernando Ferreira Costa
• Principal researcher abroad: Stephan Menzel
• Institution abroad: King's College London, England
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Sickle cell disease (SCD) is a devastating genetic condition, prevalent in African-Brazilian and African-British communities. While most patients are affected by severe organ complications, some patients have mild disease, which offers hope for the development of new treatment strategies. The KCL lab has been at the forefront of studies identifying genes and gene variants that cause part of the clinical variability of the condition. The variants act by influencing a persistence of fetal hemoglobin (HbF). HbF is not affected by the sickle mutation, which occurs in the adult form of hemoglobin (HbA). The UNICAMP group has shown subsequently that the same genetic factors can affect the rate of organ complications occurring in Brazilian patients. Thus, the study of fetal hemoglobin has offered a way to identify genes that modulate the disease severity. The challenge is now to extend these studies to secondary pathological pathways, i.e. the ones that do the actual damage to patients' lungs, kidneys, brains, and other organs. Such a key process is inflammation, but the underlying pathways are exceedingly complex. The present project offers two significant tools to approach this problem: (1) A joint study of our two patient cohorts (200 patients will be specifically recruited at each, KCL and UNICAMP) will pool our strengths and statistical power to detec effects. Genetic differences between our two patient populations will increase the spectrum of genetic variation we can probe. (2) Our joint experience with HbF genetic modifiers provides us with the ability to investigate a highly-relevant candidate gene system. HbF persistence reduces the mutated hemoglobin, HbS, and thus removes part of the trigger that starts inflammatory processes. After genotyping the most important HbF modifier variants, we will compare the genotypes with biomarkers of inflammation (cytokine plasma levels and neutrophil counts) and with clinical outcomes. A proportion of the patients we will recruit receive hydroxycarbamide, a drug that - increases HbF and reduces inflammation. Thus, in addition to measuring genetic, we will also study the effect of hydroxycarbamide treatment on inflammatory processes. We plan to use the trips to exchange experimental and clinical know-how, which will be applied directly to this study. (AU)