A Population-Oriented Genetic Scoring System to Predict Phenotype: A Pathway to Personalized Medicine in Iraqis With ß-Thalassemia.

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.

Updated Molecular Spectrum of ß-Thalassemia Mutations in Duhok Province, Northern Iraq: Ethnic Variation and the Impact of Immigration.

Immigration impact on genetic epidemiology of thalassemia worldwide is well-recognized. Over the past decade, the Duhok Province of Northern Iraq attracted a large number of immigrants. To assess whether immigration had contributed to changes in the mutation spectrum of ß-thalassemia (ß-thal) in the region, we recruited 218 registered patients with symptomatic ß-thal. The recruited patients included 50 (22.9%) from resettled migrant families. A total of 431 ß-thal alleles were fully characterized, with 20 different thalassemia mutations, the most frequent being IVS-II-1 (G>A) (HBB: c.315 + 1G>A), IVS-I-6 (T>C) (HBB: c.92 + 6T>C), codon 5 (-CT) (HBB: c.17_18delCT), IVS-I-110 (G>A) (HBB: c.93-21G>A), codon 44 (-C) (HBB: c.135delC), codon 8 (-AA) (HBB: c.25_26delAA) and IVS-I-1 (G>A) (HBB: c.92 + 1G>A) constituting 72.8% of the total. Some differences in mutation spectrum were observed compared to earlier studies from this same province, the most notable of which were the higher frequencies of IVS-I-110 and codon 8. Interestingly, the highest proportions of alleles related to immigrants were encountered in these two allele groups. Ethnic variation was also documented, so that while Muslim Kurds had IVS-II-1, IVS-I-6, IVS-I-110, codon 5 and codon 44 as their most frequent mutations, the most frequent among Kurdish Yazidis, were codon 5, codon 44, codon 8 and IVS-I-6. These ethnic variations and changes in mutation spectrums are important and should be taken in consideration to ensure effective implementation of the thalassemia preventive program.

A Novel ß0-Thalassemia Mutation, HBB: c.356_357delTT [Codon 118 (-TT)] in an Iraqi Kurd.

We report a novel frameshift ß-thalassemia (ß-thal) mutation due to a two-nucleotide deletion at codon 118 of the ß-globin gene (HBB: c.356_357delTT) in a 4-year-old Iraqi Kurd female presenting as transfusion-dependent ß-thal. This frameshift mutation, unlike many others involving the third exon, behaved as a recessive ß0 defect and not as dominant ß-thal mutation.

Complications and Challenges in the Management of Iraqi Patients with ß-Thalassemia Major: A Single-center Experience.

OBJECTIVES: We sought to assess the complications and challenges facing the management of ß-thalassemia major (ß-TM) in Iraq. METHODS: A total of 150 consecutive patients with ß-TM who were registered at a main thalassemia center in Northern Iraq were enrolled in the study. The patients had their records reviewed, were clinically evaluated, and investigated for various complications. RESULTS: Our patient cohort had a median age of 13 years (range: 1-35 years) and a male to female ratio of 1:1.2. Their median serum ferritin was 2762 µg/L, all were on regular transfusions, 94.7% were on chelation therapy, and 38.0% were splenectomized. Pre-transfusion hemoglobin levels were 3 9.0 g/dL in 38.7% of the patients. Short stature was encountered in 33.9% of those aged ≤ 20 years, and skeletal changes were noted in 50.7%. Iron overload associated complications, including hypogonadism, hypothyroidism, hypoparathyroidism, diabetes mellitus, and heart failure, were encountered in 52.8%, 7.3%, 3.3%, 3.3%, and 2.7%, respectively. Hepatitis C virus (HCV) antibodies were detectable in 35.3%, while HIV antibodies and hepatitis B surface antigen were not detectable in any. Patients with diabetes mellitus, heart failure, HCV antibodies, and hypoparathyroidism were significantly older than those without these complications. Hypogonadism was the only complication associated with significantly higher serum ferritin levels. Hypogonadism, heart failure, HCV antibodies, and diabetes were significantly more frequent among the splenectomized patients. CONCLUSIONS: The management of ß-TM in this cohort of Iraqi patients is still suboptimal, and the need to ensure timely transfusions and optimize chelation, as well as a more robust iron overload assessment, should be underscored.

Molecular Characterization of ß-Thalassemia in Nineveh Province Illustrates the Relative Heterogeneity of Mutation Distributions in Northern Iraq.

Beta thalassemia is an important health problem in Nineveh province, a large province in Northwestern Iraq. No previous study of significance had focused on the spectrum of ß-thalassemia mutations in this part of the country. A total of 94 unrelated ß-thalassemia minor subjects from the latter province were recruited. Their carrier status was confirmed by full blood count, Hb A2 and F estimation. Thereafter their DNA was subjected to multiplex polymerase chain reaction and reverse hybridization to detect 20 ß-thalassemia mutations. A total of eleven different ß-thalassemia mutations were documented. The most frequent mutation was IVS-I-110 (G>A) documented in 34 %, followed by IVS-I-6 (T>C) in 9.6 %, IVS-I-5(G>C) in 8.5 %, codon 39 (C>T) and codon 44 (-C) in 7.4 % each, while IVS-I-1(G>A) and IVS-II-1(G>A) were encountered in 6.4 % each. Other mutations were less frequent including codon 8 (-AA), IVS-I-130 (G>C), codon 5 (-CT) and IVS-II-745(C>G). The current study revealed notable differences in the relative frequencies of several ß-thalassemia mutations in Nineveh province as compared to other parts of Northern Iraq. Such an observation may be reflective of different ethnic backgrounds and varying historical population interactions. It is believed that these findings complement those of earlier studies on ß-thalassemia mutations from the country, and are quite essential in the setting of a proposed national preventive program.