Genetic modifiers of the severity of sickle cell anemia identified through a genome‐wide association study

Abstract

We conducted a genome-wide association study (GWAS) to discover single nucleotide polymorphisms (SNPs) associated with the severity of sickle cell anemia in 1,265 patients with either ''severe'' or ''mild'' disease based on a network model of disease severity. We analyzed data using single SNP analysis and a novel SNP set enrichment analysis (SSEA) developed to discover clusters of associated SNPs. Single SNP analysis discovered 40 SNPs that were strongly associated with sickle cell severity (odds for association >1,000); of the 32 that we could analyze in an independent set of 163 patients, five replicated, eight showed consistent effects although failed to reach statistical significance, whereas 19 did not show any convincing association. Among the replicated associations are SNPs in KCNK6 a K 1 channel gene. SSEA identified 27 genes with a strong enrichment of significant SNPs (P < 10 26 ); 20 were replicated with varying degrees of confidence. Among the novel findings identified by SSEA is the telomere length regulator gene TNKS. These studies are the first to use GWAS to understand the genetic diversity that accounts the phenotypic heterogeneity sickle cell anemia as estimated by an integrated model of severity. Additional validation, resequencing, and functional studies to understand the biology and reveal mechanisms by which candidate genes might have their effects are the future goals of this work. Am. J. Hematol. 85:29-35, 2010. V

Gene-centric association study of acute chest syndrome and painful crisis in sickle cell disease patients

“…Genotyping and quality-control filters for the Duke SCD cohort were described elsewhere. 20 We used identity-by-descent methods to identify patients who overlap in the CSSCD and Duke cohorts; these patients (N 5 23) were excluded from the analysis of the Duke cohort.…”

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“…Chernapalli * 1 , M. Komanduri 2 , S. Sabbella 2 1.Department of Bio-Chemistry, Government City College, Hyderabad, Telangana, India.…”

“…However, the nsSNPs with missense mutation usually lead to loss of function while in a few instances can cause a gain in protein function [1]. There are several instances where SNPs are proved to be involved in disorders like sickle cell anaemia, β thalassemia [2,3], rheumatoid arthritis [4] and even in cancer [5,6].PCNA is a cyclin protein which functions as a key factor in eukaryotic DNA polymerase [7]. PCNA is a ring-shaped protein complex that surrounds the DNA and increases the processivity of DNA replicases δ subunit and coordinates the various pathways in DNA replication [8,9] by encircling and freely sliding along the DNA helix by forming a ring of homo trimer.…”

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“…Polymers of HbS form in hypoxic conditions and deform the red blood cell (RBC) altering its rheology, blood viscosity and reducing the RBC lifespan [1,2]. Multiple clinical complications are characteristic of SCA; the specific pattern of disease in individuals is variable and likely, in part, determined by environmental factors and genetic modifier loci [3,4]. Pulmonary vascular disease, particularly the acute chest syndrome and pulmonary hypertension, are among the most common causes of morbidity and mortality in SCA and pulmonary hypertension, in particular, is reflective of disease severity.…”

“…Pulmonary vascular disease, particularly the acute chest syndrome and pulmonary hypertension, are among the most common causes of morbidity and mortality in SCA and pulmonary hypertension, in particular, is reflective of disease severity. [5,6] Recently, we reported genetic associations between SCA severity and single nucleotide polymorphisms (SNPs) in the ADP-ribosylation guanine nucleotide exchange factor-2 (ARFGEF2), a gene involved in release of tumor necrosis factor-α (TNF-α) receptor-1 (TNF-R1) from endothelial cells, and reported elevated plasma levels of both soluble TNF-R1 and soluble vascular cell adhesion molecule-1 (VCAM1, VCAM-1) in subjects with more severe SCA [3,7].…”