Genetic modifiers of Hb E/β0 thalassemia identified by a two-stage genome-wide association study

Abstract

BackgroundPatients with Hb E/β0 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/β0 thalassemia and normal α-globin genes.MethodsFirst, 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.ResultsAfter 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 β-globin gene cluster had major alleles associated with severe disease. The most significant was bthal_bg200 (odds ratio (OR) = 5.56, P = 2.6 × 10-13). Seven SNPs in two distinct LD blocks within a region centromeric to the β-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 × 10-11). Several previously unreported SNPs were also significantly associated with disease severity.ConclusionsThese results suggest that there may be an additional regulatory region centromeric to the β-globin gene cluster that affects disease severity by modulating fetal hemoglobin expression.

GWAS study using DNA pooling strategy identifies association of variant rs4910623 in OR52B4 gene with anti-VEGF treatment response in age-related macular degeneration

“…Their analysis of eye tissue expression confirmed the presence of many olfr, with one of them, olfr547 representing a homolog of the human OR52B4 gene (85% identity). Interestingly, olfr547 is a close relative of olfr78, which has recently been shown to function in regulation of blood pressure in smooth muscle cells2223. Expression of genes in the olfr pathway in mouse ocular tissues is mediated by the olfaction specific Gα protein, localised in the nuclear layer of the retina and previously thought to be only expressed in the olfactory epithelium21.…”

“…Expression of genes in the olfr pathway in mouse ocular tissues is mediated by the olfaction specific Gα protein, localised in the nuclear layer of the retina and previously thought to be only expressed in the olfactory epithelium21. Moreover, olfactory genes have been shown to be associated with cancer and other blood diseases, suggesting expression and function of olfactory proteins in a number of different pathways232425. Interestingly, another olfactory receptor ( OR10J5 ) was recently reported by Kim and colleagues 26 to control cell migration and phosphorylation of signaling during angiogenesis in mice.…”

“…We chose to use a pooled DNA GWAS strategy to investigate response to anti-VEGF treatment in AMD as this provided a cost-effective and efficient approach to identify genetic associations2330313233. We were able to technically validate ~70% of the 44 SNPs that were identified in the pooling strategy at a nominal significance level.…”

A Single Nucleotide Polymorphism in theHBBP1Gene in the Human β-Globin Locus is Associated with a Mild β-Thalassemia Disease Phenotype

“…A number of studies have assessed the β-thal and sickle cell disease severity, correlated with Hb F levels, in relation with several SNPs residing within the human β-globin cluster, such as the G γ XmnI (HBG2:g.-158C>T) polymorphism (13,20), the intergenic A γ-δ haplotypes and region (16,21), the 3 0 HS1 (3 0 hypersensitive site 1) (þ179C>T) variant that generates a GATA-1 binding site (17), and the recently identified association of variants centromeric to the β-globin region, lying within the olfactory receptor cluster (22). In addition, modifier genes outside the β-globin gene cluster have been shown to play a role in Hb F expression; apart from the well-established associations of SNPs residing in the intergenic HBS1L-MYB region (10) and the BCL11A locus (4), polymorphic variants in other regions have been associated with Hb F expression in adults, including chromosomes 6q22-q23, 8q11-q12, and Xp22 (23)(24)(25) as well as with disease severity in β-thal (Tafrali et al, submitted).…”

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“…However, they could easily be converted to a C or C++ program or developed as stand-alone packages. Sherva et al 28 have examined the severity of the health effects due to mutations in the β-globin gene. Their data show that a particular mutation in a single gene can have mild or severe effects depending on the existence or otherwise of mutations in other genes and also on environmental factors.…”