A genome-wide association identified the common genetic variants influence disease severity in β0-thalassemia/hemoglobin E

Abstract

b-Thalassemia/HbE disease is clinically variable. In searching for genetic factors modifying the disease severity, patients were selected based on their disease severities, and a genome-wide association study (GWAS) was performed. Genotyping was conducted with the Illumina Human 610-Quad BeadChips array using DNAs from 618 Thai b0-thalassemia/HbE patients who were classified as 383 severe and 235 mild phenotypes by a validated scoring system. Twenty-three SNPs in three independent genes/regions were identified as being significantly associated with the disease severity. The highest association was observed with SNPs in the b-globin gene cluster (chr.11p15), and rs2071348 of the HBBP1 gene revealed the most significant association [P = 2.96 9 10(-13), odds ratio (OR) = 4.33 (95% confidence interval (CI), 2.74-6.84)]. The second was identified in the intergenic region between the HBS1L and MYB genes (chr.6q23), among which rs9376092 was the most significant [P = 2.36 9 10(-10), OR = 3.07 (95% CI, 2.16-4.38)]. The third region was located in the BCL11A gene (chr.2p16.1), and rs766432 showed the most significant association [P = 5.87 9 10-10, OR = 3.06 (95% CI, 2.15-4.37)]. All three loci were replicated in an independent cohort of 174 Indonesian patients. The associations to fetal hemoglobin levels were also observed with SNPs on these three regions. Our data indicate that several genetic loci act in concert to influence HbF levels of beta(0)-thalassemia/HbE patients. This study revealed that all the three reported loci and the alpha-globin gene locus are the best and common predictors of the disease severity in beta-thalassemia.

The Switch from Fetal to Adult Hemoglobin

“…Clinical observations in rare b-thalassemia patients with elevated production of HbF showed that these increased levels resulted in a milder clinical course and infants with b-thalassemia only begin to show symptoms after the expression of HbF declines in the months following birth (Weatherall 2001;Weatherall and Clegg 2001). Larger epidemiological studies of thalassemia populations have confirmed such findings (Premawardhena et al 2005;Galanello et al 2009;Nuinoon et al 2010). While it has been difficult to tease apart the extent to which increased HbF production can ameliorate symptoms in thalassemia because it is difficult to ascertain the extent of g-globin production directly in patients with the need for frequent blood transfusions and such a great extent of ineffective erythropoiesis, a recent analysis in untransfused patients with b-thalassemia shows the quantitative ameliorating effect of HbF levels on clinical severity in this disease as well (Musallam et al 2011).…”

“…Understanding the mechanism of action by which these variants result in alterations in HbF levels is important, as the genetic variants at this locus appear to have as great or perhaps even a greater effect on clinical morbidity in the b-hemoglobinopathies as those variants at the BCL11A locus (Galanello et al 2009;Nuinoon et al 2010). Interestingly, this region contains a variety of regulatory elements that have been suggested to have an important role in regulating expression of MYB in erythroid progenitors (Mukai et al 2006;Wahlberg et al 2009;Stadhouders et al 2011).…”

“…Therefore, partial inhibition of MYB may hold promise as a valuable strategy for HbF induction. The additivity of the effects of variants in the HBS1L-MYB intergenic region along with variants at the BCL11A locus Galanello et al 2009;Nuinoon et al 2010) suggests that targeting both of these pathways together could yield even more robust effects than targeting either pathway alone.…”

Genome-wide association studies of tuberculosis in Asians identify distinct at-risk locus for young tuberculosis

“…GWASs in Asian populations do not have the problem of sparse linkage disequilibrium like GWASs in African populations, and they have been successfully utilized to identify common variants with large effects in Thais. 16 Thus, the failure of the initial GWAS in Asian TB is not due to the problem of SNP coverage in the current microarray genotyping platform. Taking into consideration the caveats that might affect the power of a GWAS in identifying genetic risks to common diseases 17 and our experience of the increasing power of linkage analysis of TB by the subset-ordered analysis based on the age at onset of TB sibpairs, 10 we hypothesized that a gene-environmental effect (G X E) interaction, such as bacille calmette guerin (BCG) vaccination, exposure to different strains of M. tuberculosis, 18 or misclassification, might cause heterogeneity in TB.…”

Non-transfusion-dependent thalassemias

“…Recent clinical studies have substantiated the quantitative ameliorating effect of increased fetal hemoglobin production on the clinical course in a variety of patients with NTDT. 76,[95][96][97][98][99][100] The earliest attempts to induce fetal hemoglobin through DNA methylation inhibition with 5-azacytidine were encouraging, although these were later hampered by concerns about the safety of this agent. 101 More recently, this approach has been revisited with the use of a safer demethylating agent, decitabine.…”