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.

Genetic polymorphisms in early-onset myocardial infarction in a sample of Iraqi patients: a pilot study.

OBJECTIVES: Early-onset myocardial infarction constitutes nearly one third of cases of myocardial infarction among Iraqis, which is rather higher than the proportions reported in many Western countries. Thus this study was initiated to investigate the role of some genetic polymorphisms, as well as acquired risk factors in this condition. RESULTS: A total of 102 Iraqi patients with first myocardial infarction aged 50 years, and 77 matched controls were enrolled. The DNAs of participants were screened for nine polymorphisms, namely: ß-Fibrinogen (- 455G > A), Factor XIII (V34L), Plasminogen Activator inhibitor-1 (PAI-1, 4G/5G), Human Platelet Antigen-1 (HPA1a/b), 5,10-Methylenetetrahydrofolate Reductase MTHFR (C677T) and MTHFR (A1298C), Angiotensin-Converting Enzyme (ACE) 287 bp insertion/deletion (I/D), Apolipoprotein-B (ApoB: R3500Q), and Apolipoprotein-E (Apo E: E2/E3/E4), using PCR and reverse hybridization technique. Among traditional risk factors, univariate analysis revealed that smoking (OR 2.86 [95%CI 1.53-5.34]), hyperlipidemia (OR 5.23 [95%CI 2.66-10.29]), and diabetes mellitus (OR 4.05 [95% CI 1.57-10.41]) were significantly higher among patients compared to controls (P<0.001, <0.001 and 0.002 respectively), while none of the nine genetic polymorphisms reached significance. Multivariate Logistic regression, however, revealed that only smoking and hyperlipidemia retained significance (P of < 0.001 each). The need to initiate further studies on larger cohorts is paramount to understand the higher than expected frequency of early-onset myocardial infarction in our population.

The association of HBG2, BCL11A, and HMIP polymorphisms with fetal hemoglobin and clinical phenotype in Iraqi Kurds with sickle cell disease.

INTRODUCTION: Fetal hemoglobin (HbF) is the major modifier for sickle cell disease (SCD) severity. HbF is modulated mainly by three major quantitative trait loci (QTL) on chromosomes 2, 6, and 11. METHODS: Five SNPs in the three QTLs (HBG2, rs7482144; BCL11A, rs1427407 and rs10189857; and HBS1L-MYB intergenic region, rs28384513 and rs9399137) were investigated by multiplex PCR and reverse hybridization, and their roles in HbF and clinical phenotype variability in Iraqi Kurds with SCD were assessed. RESULTS: HBG2 rs7482144 with minor allele frequency (MAF) of 0.133 was the most significant contributor to HbF variability, contributing 18.1%, followed by rs1427407 (MAF of 0.266) and rs9399137 (MAF of 0.137) at 14.3% and 8.8%, respectively. The other two SNPs were not significant contributors. Furthermore, when the cumulative numbers of minor alleles in the three contributing SNPs were assessed, HbF% and hemoglobin concentration increased with increasing number of minor alleles (P < 0.0005 and 0.001, respectively), while serum lactic dehydrogenase, reticulocytes, leukocytes, transfusion, and pain frequencies decreased (P = 0.003, 0.004, <0.0005, <0.0005, and 0.017, respectively). CONCLUSIONS: It was demonstrated that SNPs in all three major HbF QTLs contribute significantly to HbF and clinical variability in Iraqi Kurds with SCD and that the cumulative number of minor alleles at contributing SNPs may serve as a better predictor of such variability in this population.