اسم المؤلف:
وسام جاسم محمد
اسم المشرف:
بسام موسى صادق الموسوي
المستخلص:
Ischemic heart disease (IHD) is a major cause of morbidity and mortality worldwide; its incidence is increasing in developing countries. It is estimated that 17.5 million individuals die from CVD each year, accounting for 31% of all deaths worldwide; more than 75% of these deaths occur in low to middle income population. Understanding the pathogenesis of IHD has been modified over the years and many new genetic risk factors have been recognized. Attention is now focused towards understanding the genetic basis of IHD. Enormous effort has been invested in understanding the genes and specific DNA sequence variations responsible for this heritability and genetic polymorphisms might be risk factors that predispose to IHD.Aim of Study : To analyze the genetic risk factors among Iraqi patients with acute IHD and to determine the frequency of each type of mutation / polymorphism.Patients, Materials & Methods : This is a cross sectional study that recruited 56 patients admitted to the Cardiac Care Unit (CCU) of Ibn Al - Nafees Teaching Hospital with a clinical diagnosis of acute ischemic heart disease (myocardial infarction and unstable angina) during a two - month period between December 8th, 2015 and February 8th, 2016. All cases <50 years with acute MI or angina were included, while those >50 years and those with documented hyperlipidemia were excluded.Demographic and clinical data of the enrolled patients were reported. Two - three ml of peripheral blood samples were aspirated from all recruited patients and collected in K2EDTA tube to be store at - 20oC for further DNA analysis. Molecular analysis to detect 12 commonIIImutations/ polymorphisms, namely : FV G1691A (Leiden), FV H1299R (R2), Prothrombin C20210A, Factor Xlll V34L, β - Fibrinogen - 455 G - A, PAI - 1 4G/5G, GPllla L33P (HPA - 1), MTHFR C677T, MTHFR A1298C, ACE l/D, Apo B R3500Q, and Apo E2/E3/E4 was performed by PCR amplification using biotinylated primers and hybridization of amplification products to a test strip containing allele - specific oligonucleotide probes immobilized as an array of parallel lines. The bound biotinylated sequences were detected using streptavidin - alkaline phosphatase and color substrates according to the manufacturers’ instructions.Results : The age range of patients was 18 - 50 years, with a mean ±SD of 40±7 years. The vast majority of enrolled cases were males (54/56 (96.4%). The traditional risk factors were frequently encountered in the current study (hypertension 21.4%, diabetes 26.8%, smoking 75%, family history of IHD 48.2%, and previous attack of ischemia 23.2%). Serum troponin was positive in 72.2% of cases. The study found that the genotype frequencies of 12 genetic mutations / polymorphisms were as follows : MTHFR A1298C and C677T were the highest reported mutations among the study group (62.5%) and (50%) respectively, followed by β - fibrinogen gene mutation detected in (46.5%), and PAI - 1 4G/5G polymorphism which was detected in (75%) of patients, while PAI - 1 4G/4G was detected in (16.1%) of patients. Homozygous ACE D/D polymorphism was present in 35.7% in our cases and heterozygous HPA - 1(a/b) polymorphisms was present in 28.6%. The E4 allele of Apo E gene was present in 7.1% of the studied cases.IV Heterozygous factor XIII (FXIII) V34L variant was detected in 21.4% patients, while homozygous state was detected in 3.6% patients, i.e. 25% of selected cases had Leu allele, Heterozygous FV R2 was detected in 12.5%, and factor V Leiden mutation was detected in 1.8%, while no abnormal homozygous alleles were detected. Prothrombin G20210A mutation were detected in 1(1.8%) patient. Neither heterozygous nor homozygous states for the mutant Apo B allele were detected in this study. The study showed no statistically significant difference between age group I (<40 years) and age group II (40 - 50 years), but the study showed higher frequency for some genes like PAI - 1(4G) and Apo E4 alleles in group I than group II (100% versus 85.3%) and (13.6% versus 2.9%) respectively, while HPA - 1 (a/b) polymorphism was higher frequent in group II than group I (35.3% versus18.2%).Subgroup analysis of the studied traditional risk factors (hypertension, diabetes mellitus, smoking, family history of ischemic heart disease) showed that β - Fibrinogen mutation had higher frequency in smoker patients than nonsmokers (50% versus 35.71%), the D allele of ACE gene was more frequent in hypertensive than in non - hypertensive patients (91.7% versus 79.5%), and higher frequency of HPA - 1b allele in diabetic than non - diabetic patients 46.7% versus 22%).Genetic risk score (0 - 16) was established according to the number of risky alleles detected in each case; the results showed that all patients had at least 2 genetic risk factors and none had more than 8; the study also showed that patients with 4 or more risky genes represented 82.14% of the studied patients, and that the risk of IHD increases in those who carry 4 or more genetic risk factors when associated with at least one traditional risk factor.
