Department of Medicine, Genetics Program, Boston University School of Medicine, Boston 02118, USA.
BMC Med Genet. 2010 Mar 30;11:51. doi: 10.1186/1471-2350-11-51.
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.
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.
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.
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.
患有 HbE/β0 地中海贫血的患者其疾病严重程度存在显著差异。为了确定影响疾病严重程度的遗传修饰因子，我们对来自泰国的 207 例轻度和 305 例重度无相关 HbE/β0 地中海贫血且正常α珠蛋白基因的患者进行了两阶段的全基因组扫描。
首先，我们在不同严重程度的患者混合 DNA 中估算并比较了大约 110000 个基于基因的单核苷酸多态性（SNP）的等位基因频率。通过混合，有 756 个 SNP 显示出在 P<0.02 时有可重复的等位基因差异，这些 SNP 被选为个体基因分型。
在调整年龄、性别和地理位置因素后，逻辑回归模型显示，在多重检验校正后，有 50 个 SNP 与疾病严重程度显著相关（P<0.05）。β-珠蛋白基因簇内一个大 LD 块中的 41 个 SNP 具有与重度疾病相关的主要等位基因。最显著的是 bthal_bg200（比值比（OR）=5.56，P=2.6×10（-13））。在β-珠蛋白基因簇附近一个包含许多嗅觉受体基因的区域内两个不同 LD 块中的 7 个 SNP 也与疾病严重程度相关；rs3886223 的关联最强（OR=3.03，P=3.7×10（-11））。还有一些以前未报道的 SNP 也与疾病严重程度显著相关。
这些结果表明，β-珠蛋白基因簇着丝粒附近可能存在一个额外的调控区域，通过调节胎儿血红蛋白的表达来影响疾病的严重程度。
