ABSTRACT
To assess the roles of genetic modifiers in Iraqi ß-thalassemia patients, and determine whether a genotype-based scoring system could be used to predict phenotype, a total of 224 Iraqi patients with molecularly characterized homozygous or compound heterozygous ß-thalassemia were further investigated for α-thalassemia deletions as well as five polymorphisms namely: rs7482144 C > T at HBG2, rs1427407 G > T and rs10189857 A > G at BCL11A, and rs28384513 A > C and rs9399137 T > C at HMIP. The enrolled patients had a median age of 14 years, with 96 males and 128 females. They included 144 thalassemia major, and 80 thalassemia intermedia patients. Multivariate logistic regression analysis revealed that a model including sex and four of these genetic modifiers, namely: ß+ alleles, HBG2 rs7482144, α-thalassemia deletions, and BCL11A rs1427407 could significantly predict phenotype (major versus intermedia) with an overall accuracy of 83.9%. Furthermore, a log odds genetic score based on these significant predictors had a highly significant area under curve of 0.917 (95% CI 0.882-0.953). This study underscores the notion that genetic scoring systems should be tailored to populations in question, since genetic modifiers (and/or their relative weight) vary between populations. The population-oriented genetic scoring system created by the current study to predict ß-thalassemia phenotype among Iraqis may pave the way to personalized medicine in this patient's group.
Subject(s)
Phenotype , Polymorphism, Single Nucleotide , Precision Medicine , Repressor Proteins , beta-Thalassemia , Humans , beta-Thalassemia/genetics , beta-Thalassemia/diagnosis , Male , Female , Iraq , Adolescent , Child , Genotype , Alleles , Adult , Young Adult , Child, Preschool , alpha-Thalassemia/genetics , alpha-Thalassemia/diagnosisABSTRACT
ß-thalassemia is a prevalent inherited red cell disorder in the Kurdistan region of Iraq. To determine the chromosomal background of the frequent ß-thalassemia mutations in the latter region, we investigated the ß-globin gene cluster haplotypes in 202 ß-thalassemia chromosomes. Haplotypes analysis utilized restriction fragment length polymorphism-PCR of seven restriction sites through the ß-globin gene cluster. It was observed that IVS-II-1 (G > A) was mainly associated with haplotype III (68.8%), IVS-1-110 (G > A), codon 8/9 (+G) and codon 44 (-C) with haplotype I (in 90.0%, 100%, and 62.5% respectively), IVS-1-6 (T > C) with haplotype VI (97.4%), codon 8 (-AA) with haplotype IV (75%), codon 5(-CT) and IVS1.1 (G > A) with haplotype V (55.6% and 58.3% respectively), while codon 39 (C > T) and IVS1.5 (G > C) were mainly associated with haplotype VII (85.7% and 75% respectively). These observations support the notion that while some mutations may have originated in the Kurdistan region, others were more likely brought in by gene flow from neighboring countries or the Indian subcontinent. The association of some ß-thalassemia defects with more than one haplotype may be due to mutations or recombination events.
Subject(s)
beta-Thalassemia , Humans , Haplotypes , beta-Thalassemia/epidemiology , beta-Thalassemia/genetics , Iraq/epidemiology , Mutation , Codon , beta-Globins/genetics , Multigene FamilyABSTRACT
Tyrosine Kinase inhibitors (TKIs) have dramatically changed the prospects for patients with chronic myeloid leukemia (CML); however, information on CML and response to TKIs from Asia are limited, particularly from West Asia, including Iraq. To address the latter issue we evaluated and monitored a cohort of 108 Iraqi patients diagnosed as chronic phase-CML, enrolled in a government-sponsored national program. The patients were all treated initially by imatinib mesylate. Ninety-two percent of patients had a complete hematological response, 38% had a major molecular response, while 79% had a major cytogenetic response after a median follow-up of 35.7 months. The 3-year Event-Free, Progression-Free, and Overall survival rates were 79.6, 87 and 98.1%, respectively. A total of 26 patients (24.1%) were shifted to an alternative TKI (Nilotinib). After one year of therapy in seventeen of the latter patients, 24% had major molecular response. In conclusion, our results compare favorably with those reported from the West and some Asian countries, and have demonstrated the importance of molecular as well as cytogenetic monitoring, and confirmed the relative success of the national CML program in our country.
