Genetic modifiers of response to thalidomide in transfusion-dependent beta-thalassemia patients: a whole-exome sequence analysis.

PMID 41081085 | PMCID PMC12513377 | DOI 10.7717/peerj.20038 · PeerJ · 2025 · View on PubMed ↗

BACKGROUND: Thalidomide induces fetal hemoglobin and renders most thalassemia patients transfusion-independent. Some patients, however, do not respond. Underlying genetic variations responsible for variable responses to thalidomide are unexplored. AIMS AND OBJECTIVES: To discover genetic variations that influence response to thalidomide in transfusion-dependent beta-thalassemia patients. METHODS: Twenty beta-thalassemia patients (14 excellent responders and six non-responders) who had received thalidomide were included in the study by a non-probability purposive sampling technique. Patients who showed a rise of >2 mg/dl in hemoglobin level and/or whose hemoglobin levels reached 9 gm/dl without blood transfusions were designated as excellent responders. Patients whose hemoglobin levels did not show an increment rise of >2 and/or whose hemoglobin levels did not rise above 5.9 gm/dl and needed blood transfusions to maintain optimal hemoglobin levels were designated as non-responders. DNA was extracted, and whole-exome sequencing was performed on an Illumina HiSeq System. Aligning and variant calling were done by the Sentieon software. Annotation was done by Annovar. RESULTS: The age of study participants ranged from 1-12 years, with a mean of 5.45 ± 3.81 years. There were 17 (85%) males and three (15%) females. A total of 222,180 germline variants were identified across 20 subjects, from which 24 candidate variants across 24 genes were identified. The three most common polymorphisms in the excellent responder group were found in the exon region of CHI3L1 (rs880633), NPNT (rs35132891), and ZNF 208 (rs10425763), which were found in 92%, 85%, and 71% cases, respectively. The commonest polymorphisms in the non-responder group were found in the PM20D1 gene (rs7518979), LGR6 (rs75658797), MYH15 (rs4299484), and RESF1 (rs3207618), each of which was found in 66.6% cases. CONCLUSION: This study shows a significant association of single-nucleotide polymorphisms rs880633, rs35132891, and rs10425763 with excellent response status, while rs7518979, rs75658797, rs4299484, and rs3207618 are associated with non-response status.