title: Genetic modifiers of Hb E/beta0 thalassemia identified by a two-stage genome-wide association study.
abstract: BACKGROUND
  Patients with Hb E/beta0 thalassemia display remarkable variability in disease severity. To identify genetic modifiers influencing disease severity, we conducted a two-stage genome scan in groups of 207 mild and 305 severe unrelated patients from Thailand with Hb E/beta0 thalassemia and normal alpha-globin genes.
  
  
  METHODS
  First, we estimated and compared the allele frequencies of approximately 110,000 gene-based single nucleotide polymorphisms (SNPs) in pooled DNAs from different severity groups. The 756 SNPs that showed reproducible allelic differences at P < 0.02 by pooling were selected for individual genotyping.
  
  
  RESULTS
  After adjustment for age, gender and geographic region, logistic regression models showed 50 SNPs significantly associated with disease severity (P < 0.05) after Bonferroni adjustment for multiple testing. Forty-one SNPs in a large LD block within the beta-globin gene cluster had major alleles associated with severe disease. The most significant was bthal_bg200 (odds ratio (OR) = 5.56, P = 2.6 x 10(-13)). Seven SNPs in two distinct LD blocks within a region centromeric to the beta-globin gene cluster that contains many olfactory receptor genes were also associated with disease severity; rs3886223 had the strongest association (OR = 3.03, P = 3.7 x 10(-11)). Several previously unreported SNPs were also significantly associated with disease severity.
  
  
  CONCLUSIONS
  These results suggest that there may be an additional regulatory region centromeric to the beta-globin gene cluster that affects disease severity by modulating fetal hemoglobin expression.
authors.affiliation: Department of Medicine, Genetics Program, Boston University School of Medicine, Boston 02118, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Sherva
authors.forename: Orapan
authors.initials: O
authors.lastname: Sripichai
authors.forename: Kenneth
authors.initials: K
authors.lastname: Abel
authors.forename: Qianli
authors.initials: Q
authors.lastname: Ma
authors.forename: Johanna
authors.initials: J
authors.lastname: Whitacre
authors.forename: Vach
authors.initials: V
authors.lastname: Angkachatchai
authors.forename: Wattanan
authors.initials: W
authors.lastname: Makarasara
authors.forename: Pranee
authors.initials: P
authors.lastname: Winichagoon
authors.forename: Saovaros
authors.initials: S
authors.lastname: Svasti
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.forename: Andreas
authors.initials: A
authors.lastname: Braun
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
mesh_terms: D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006446:Hemoglobin E / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000235:genetics*
chemical_list: D055544:beta-Globins; D006446:Hemoglobin E