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.
Thalassaemia is one of the most prevalent inherited blood disorders in Indonesia, with highly diverse mutations ranging from mild to severe that can be found across the nation. Nevertheless, thalassaemia management in Indonesia is still limited to supportive treatment, such as blood transfusion, iron chelation, complications monitoring, psychosocial support and a comfortable transition from child to adult clinic. However, these managements are still suboptimal in most parts of the nation. Indonesia still has a long way from implementing the optimal curative treatment for thalassaemia. Iron chelators are sometimes not available, especially in rural areas. The cost for optimal dosages of iron chelation also cannot be fully covered by the current national health insurance scheme. However, it still benefits our patients, considering it is the only treatment to decrease iron deposition in organs. With that situation, our patients, both paediatric and adults, have normal cardiac haemosiderosis, moderate-to-severe hepatic haemosiderosis and normal to mild pancreatic haemosiderosis. Therefore, the number of deaths, especially those due to heart failure and infection, was significantly reduced. An improvement in thalassaemia supportive treatments is in line with the increase in patients' life expectancy. Without curative treatment options, the lifelong cost for treatment will extremely burden the national health budget. To date, thalassaemia stands for the 5th most costly disease in Indonesia. Therefore, a screening programme must be realized soon; hence, the treatment cost can be allocated for initiating the transplant unit or improving other important areas.
We describe cases of hydrops fetalis associated with nondeletional α-thalassemia (α-thal), in three unrelated Indonesian families. The genotypes of the fetuses and their parents were generated by DNA sequencing and by a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP)-based method to rapidly identify mutations detected by sequencing. Two of the fetuses had hydrops fetalis and homozygous α59(E8)Gly→Asp (α2), also known as Hb Adana. The third fetus was also suspected to be homozygous for Hb Adana because both parents were carriers of this mutation. This study shows that homozygosity for Hb Adana is associated with hydrops fetalis in the Indonesian population. We discuss this mutation and its various phenotypes including compound heterozygosity with other α-thal mutations and describe a simple approach to genetic testing that will clarify the risk of hydrops fetalis in the offspring of couples carrying this nondeletional mutation.
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