Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Phutthamonthon, Nakhonpathom 73170, Thailand.
Hum Genet. 2010 Mar;127(3):303-14. doi: 10.1007/s00439-009-0770-2.
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.
β-地中海贫血/血红蛋白 E 病具有临床变异性。在寻找影响疾病严重程度的遗传因素时，根据疾病严重程度选择患者，并进行全基因组关联研究 (GWAS)。使用 Illumina Human 610-Quad BeadChips 阵列对来自 618 名泰国β0-地中海贫血/血红蛋白 E 患者的 DNA 进行基因分型，这些患者根据验证评分系统分为 383 例严重和 235 例轻度表型。在三个独立的基因/区域中发现了 23 个 SNP 与疾病严重程度显著相关。在β-珠蛋白基因簇 (chr.11p15) 中观察到最高的关联，而 HBBP1 基因的 rs2071348 显示出最显著的关联 [P = 2.96 9 10(-13)，优势比 (OR) = 4.33 (95%置信区间 (CI)，2.74-6.84)]。第二个位于 HBS1L 和 MYB 基因之间的基因间区域 (chr.6q23)，其中 rs9376092 最为显著 [P = 2.36 9 10(-10)，OR = 3.07 (95% CI，2.16-4.38)]。第三个区域位于 BCL11A 基因 (chr.2p16.1)，rs766432 显示出最显著的关联 [P = 5.87 9 10-10，OR = 3.06 (95% CI，2.15-4.37)]。所有三个区域在 174 名印度尼西亚患者的独立队列中得到了复制。这些 SNP 与胎儿血红蛋白水平也存在关联。我们的数据表明，几个遗传位点协同作用，影响β0-地中海贫血/血红蛋白 E 患者的 HbF 水平。本研究表明，所有三个报道的位点和α-珠蛋白基因位点是β-地中海贫血疾病严重程度的最佳和共同预测因子。
