Genomic architecture of sickle cell disease in West African children

Jacklyn Quinlan,Jean-Christophe Grenier,Philip Awadalla,Selma Gomez,Elias Gbeha,Thibault De Malliard,Mohamed C Rahimy,Youssef Idaghdour,Vanessa Bruat,Ambaliou Sanni,Jean-Philippe Goulet

doi:10.3389/fgene.2014.00026

Jacklyn Quinlan, Jean-Christophe Grenier + Show 9 more

Open Access

https://doi.org/10.3389/fgene.2014.00026

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Abstract

Sickle cell disease (SCD) is a congenital blood disease, affecting predominantly children from sub-Saharan Africa, but also populations world-wide. Although the causal mutation of SCD is known, the sources of clinical variability of SCD remain poorly understood, with only a few highly heritable traits associated with SCD having been identified. Phenotypic heterogeneity in the clinical expression of SCD is problematic for follow-up (FU), management, and treatment of patients. Here we used the joint analysis of gene expression and whole genome genotyping data to identify the genetic regulatory effects contributing to gene expression variation among groups of patients exhibiting clinical variability, as well as unaffected siblings, in Benin, West Africa. We characterized and replicated patterns of whole blood gene expression variation within and between SCD patients at entry to clinic, as well as in follow-up programs. We present a global map of genes involved in the disease through analysis of whole blood sampled from the cohort. Genome-wide association mapping of gene expression revealed 390 peak genome-wide significant expression SNPs (eSNPs) and 6 significant eSNP-by-clinical status interaction effects. The strong modulation of the transcriptome implicates pathways affecting core circulating cell functions and shows how genotypic regulatory variation likely contributes to the clinical variation observed in SCD.

Highlights

Sickle cell disease (SCD) is an autosomal recessive genetic disorder common among individuals of Sub-Saharan African ancestry, affecting 1 in 100 West African individuals and 1 in 500 African-Americans (World Health Organization, 2006)
We distinguish between two groups of SCD patients: those who were newly admitted into the program and were labeled as entry (E) and those sampled after being followed and were labeled as FU
We first identified the extent of gene expression variation in SCD patients that is explained by clinical phenotypes and measured the magnitude and significance of gene expression differences for SCD clinical status in an initial discovery phase

Summary

Introduction

Sickle cell disease (SCD) is an autosomal recessive genetic disorder common among individuals of Sub-Saharan African ancestry, affecting 1 in 100 West African individuals and 1 in 500 African-Americans (World Health Organization, 2006). Genetic mutations that cause SCD result in structural changes to wild-type hemoglobin (HbAA), the oxygen carrying protein inside red blood cells (RBCs). The most common form of SCD in West Africa is caused by a single point mutation in codon 6 of the β-globin gene which leads to an amino acid substitution of glutamic acid to valine (HbSS). The second most common abnormal Hb mutation in West Africa, HbC, results in an amino acid change at the same position in the beta globin gene, but with lysine replacing glutamic acid. These hemoglobin mutations compromise the delivery of oxygen and result in tissue and organ damage. Inter-individual clinical variation is pervasive within each of these SCD groups, but its basis is poorly understood and likely reflects a combination of the effects of several factors including haplotypic variation in the β-globin locus region, the action of genetic modifiers elsewhere in the genome, and a wide range of environmental factors (Weatherall, 2001; Sankaran et al, 2010)

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