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Background <p>Thalidomide has been found to augment fetal hemoglobin (HbF) synthesis, thereby decreasing transfusion requirements in patients with β-thalassemia. Elevated fetal hemoglobin, influenced by genetic polymorphisms, can significantly modify the clinical severity of β-thalassemia. The study aimed to determine the frequency of the XmnI (rs7482144), BCL11A (rs766432), and HBS1L-MYB (rs9399137) polymorphisms in patients with β-thalassemia and to evaluate their association with the response to thalidomide therapy.</p> Methods <p>This prospective observational study was conducted at Baqai Medical university. One hundred transfusion-dependent β-thalassemia patients on low-dose thalidomide (2&#xa0;mg/kg/day) were enrolled from Muhammadi blood bank and diagnostics center, Karachi. The outcome measures of response were defined as an increase in hemoglobin (Hb) levels and reduction in blood transfusion frequency following three months of thalidomide treatment, based on which participants were classified as excellent responders, good responders, or non-responders. The Xmn1 (rs7482144), BCL11A (rs766432) and HBS1L-MYB (rs9399137) single nucleotide polymorphisms (SNPs) were detected using the Amplification Refractory Mutation System Polymerase chain reaction (ARMS-PCR).</p> Results <p>Among the 100 patients, the rs7482144 was present in 68% of cases, rs766432 in 47%, and rs9399137 in 20%. Following three months of thalidomide treatment, Hb levels (9.3 ± 1.5&#xa0;g/dl) increased significantly compared to baseline levels (5.4 ± 1.6&#xa0;g/dl) (<i>p</i>&lt;.001). An overall response rate of 87% was recorded. Results showed that minor allele–containing genotypes of three SNPs were significantly associated with an increased likelihood of excellent response [rs7482144: <i>p</i>=.001, RR:1.733; rs766432: <i>p</i>&lt;.001, RR:3.070; rs9399137: <i>p</i>=.023, RR:4.043]. Post-treatment HbF increment was correlated with the cumulative number of minor alleles across the three significant SNPs among excellent responders, with HbF being lower in individuals having ≤ 1 polymorphism (74.0%±19.2%) compared with those carrying 2 (83.0%±8.6%; <i>p</i>=.033) or 3 polymorphisms (97.3%±0.5%; <i>p</i>=.01).</p> Conclusion <p>Our study indicates that SNPs within HBG2(rs7482144), BCL11A(rs766432), and HBS1L–MYB (rs9399137) region are strongly associated with thalidomide responsiveness in β-thalassemia patients, with the overall number of minor alleles serving as a potential marker for therapeutic response.</p>

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Unlocking thalidomide response as a hemoglobin F augmentation agent in transfusion-dependent β-thalassemia: the genetic impact of BCL11A, HBS1L-MYB, and XmnI polymorphism

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  • 发表日期：

    2026年7月7日

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  • Iram Nazir,
  • Muhammad Younus Jamal Siddiqi,
  • Maeesa Wadood,
  • Muhammad Rizwan

摘要

Background

Thalidomide has been found to augment fetal hemoglobin (HbF) synthesis, thereby decreasing transfusion requirements in patients with β-thalassemia. Elevated fetal hemoglobin, influenced by genetic polymorphisms, can significantly modify the clinical severity of β-thalassemia. The study aimed to determine the frequency of the XmnI (rs7482144), BCL11A (rs766432), and HBS1L-MYB (rs9399137) polymorphisms in patients with β-thalassemia and to evaluate their association with the response to thalidomide therapy.

Methods

This prospective observational study was conducted at Baqai Medical university. One hundred transfusion-dependent β-thalassemia patients on low-dose thalidomide (2 mg/kg/day) were enrolled from Muhammadi blood bank and diagnostics center, Karachi. The outcome measures of response were defined as an increase in hemoglobin (Hb) levels and reduction in blood transfusion frequency following three months of thalidomide treatment, based on which participants were classified as excellent responders, good responders, or non-responders. The Xmn1 (rs7482144), BCL11A (rs766432) and HBS1L-MYB (rs9399137) single nucleotide polymorphisms (SNPs) were detected using the Amplification Refractory Mutation System Polymerase chain reaction (ARMS-PCR).

Results

Among the 100 patients, the rs7482144 was present in 68% of cases, rs766432 in 47%, and rs9399137 in 20%. Following three months of thalidomide treatment, Hb levels (9.3 ± 1.5 g/dl) increased significantly compared to baseline levels (5.4 ± 1.6 g/dl) (p<.001). An overall response rate of 87% was recorded. Results showed that minor allele–containing genotypes of three SNPs were significantly associated with an increased likelihood of excellent response [rs7482144: p=.001, RR:1.733; rs766432: p<.001, RR:3.070; rs9399137: p=.023, RR:4.043]. Post-treatment HbF increment was correlated with the cumulative number of minor alleles across the three significant SNPs among excellent responders, with HbF being lower in individuals having ≤ 1 polymorphism (74.0%±19.2%) compared with those carrying 2 (83.0%±8.6%; p=.033) or 3 polymorphisms (97.3%±0.5%; p=.01).

Conclusion

Our study indicates that SNPs within HBG2(rs7482144), BCL11A(rs766432), and HBS1L–MYB (rs9399137) region are strongly associated with thalidomide responsiveness in β-thalassemia patients, with the overall number of minor alleles serving as a potential marker for therapeutic response.