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An Association Between Rs7635818 Polymorphism Located on Chromosome 3P12.3 and the Presence of Abdominal Aortic Aneurysm

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An Association Between Rs7635818 Polymorphism Located on Chromosome 3P12.3 and the Presence of Abdominal Aortic Aneurysm Physiol. Res. 70: 193-201, 2021 https://doi.org/10.33549/physiolres.934624 An Association Between rs7635818 Polymorphism Located on Chromosome 3p12.3 and the Presence of Abdominal Aortic Aneurysm Mária RAŠIOVÁ1,2, Viera HABALOVÁ3, Jozef ŽIDZIK3, Martin KOŠČO1, Ľudmila FARKAŠOVÁ1, Matej MOŠČOVIČ1, Marek HUDÁK1, Martin JAVORSKÝ2, Ivan TKÁČ2 1Faculty of Medicine, Department of Angiology, East Slovak Institute of Cardiovascular Diseases, Šafárik University, Košice, Slovakia, 2Faculty of Medicine, Department of Internal Medicine 4, Šafárik University, Košice, Slovakia, 3Faculty of Medicine, Department of Medicine Biology, Šafárik University, Košice, Slovakia Received November 27, 2020 Accepted January 28, 2021 Epub Ahead of Print March 8, 2021 Summary G-allele carriers (GC/GG) (42.5±22.0 mm vs 36.6±21.0 mm; The association between gene variant rs7635818 located on p=0.04) in univariate analysis. C-allele variant in rs7635818 G>C chromosome 3p12.3 and abdominal aortic aneurysm (AAA) was polymorphism is associated with a higher probability of not unambiguously determined by the results of genome-wide developing AAA in the Slovak population. association studies. The aim of our study was to examine this possible association in the Slovak population, with respect to the Key words presence and severity of AAA. A cross-sectional study was Abdominal aortic aneurysm • Polymorphism • Contactin-3 conducted between August 2016 and March 2020. The study included 329 participans, 166 AAA patients and a control group Corresponding author of 163 subjects without confirmed AAA with comparable Mária Rašiová, Faculty of Medicine, Department of Angiology, distribution of genders. The anteroposterior diameter of the East Slovak Institute of Cardiovascular Diseases, Šafárik abdominal aorta was determined by duplex ultrasonography. AAA University, 040 11 Košice, Slovakia. E-mail: [email protected] was defined as subrenal aortic diameter ≥ 30 mm. DNA samples were genotyped using real-time polymerase chain reaction and Introduction subsequent high-resolution melting analysis in presence of unlabelled probe. Genetic models studying the possible Abdominal aortic aneurysm (AAA), association were adjusted to age, sex, smoking, arterial a potentially lethal disease, can be defined as hypertension, diabetes mellitus, creatinine and body mass index an abdominal aortic diameter of 30 mm and more, or (BMI) in multivariate analysis. In the additive model, presence of when maximum diameter is ≥ 50 % greater than the each C-allele of rs7635818 polymorphism was associated with an suprarenal aortic diameter. The prevalence of AAA is almost 50 % increase in probability of developing AAA (OR 1.49; from 1.3 % to 3.3 % in male population of 65-years and 95 % CI 1.06‒2.08; p=0.020). Compared to GG homozygotes, older, however, there is no data documenting real CC homozygotes had more than two times higher risk of prevalence of AAA in Slovak population (Svensjö et al. developing AAA (OR 2.23; 95 % CI 1.14‒4.39; p=0.020). The 2011, Jacomelli et al. 2016, Grondal et al. 2015). risk of AAA was also in the recessive model higher for Although there is still a lack of knowledge CC homozygotes compared to G-allele carriers (GC/GG) (OR regarding factors initiating AAA formation, an imbalance 1.79; 95 %CI 1.01‒3.19; p=0.047). The abdominal aortic between synthesis and degradation of extracellular diameter in CC homozygotes of the rs7635818 polymorphism was matrix, smooth muscle cell apoptosis, neovascularization 7.66 mm greater compared to GG homozygotes (42.5±22.0 mm and chronic aortic wall inflammation has been implicated vs 34.8±21.3 mm; p=0.022) and 5.88 mm greater compared to in the AAA pathogenesis. There is an effort to identify PHYSIOLOGICAL RESEARCH • ISSN 1802-9973 (online) 2021 Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres 194 Rašiová et al. Vol. 70 an optimal biomarker that would reflect the AAA size diameter were performed by duplex ultrasonography and rupture risk. Animal models for AAA research are (Philips HD 15) in the axial view using curved array also used (Patelis et al. 2017). transducer in B-mode. Control patients were selected The absence of effective medical therapy that from patients older than 60 years who were hospitalised slows AAA progression highlights the need for better at our institute and who needed ultrasonograhic understanding the factors influencing AAA pathogenesis. examination of peripheral arteries (carotid arteries, limb AAA shares several risk factors with atherosclerosis such arteries, renal arteries, right/left internal mammary as old age, smoking, male sex and family history of the arteries), and/or veins at our angiology outpatient clinic. disease. Chronic inflammatory and reparative processes Patients with confirmed carotid artery stenosis ≥ 50 %, in arterial wall are present in atherosclerosis as well deep vein thrombosis, critical limb ischaemia were not (Slíva et al. 2019). Although the role of hypertension is included in the control group. Since international still controversial, it is currently considered a risk factor consensus concerning which boundaries to use during for AAA (Wanhainen et al. 2019, Altobelli et al. 2018). measurements of abdominal aortic diameter had not been Several studies have shown decreased risk of AAA in reached by the beginning of the study, outer to outer patients with diabetes mellitus, the reasons for which are measurement was used in order to prevent unexplained (Raffort et al. 2018, Cosentino et al. 2020). underestimation: the calipers were placed from the outer It is possible that metformin, the world's most commonly anterior aortic wall to the outer posterior aortic wall prescribed oral hypoglycemic agent, might be the AAA (Wanhainen et al. 2019). In AAA patients, measurements protective factor (Itoga et al. 2019). were performed in area of maximum subrenal abdominal There is a strong genetic component to AAA, aortic diameter. In control patients, aortic diameter with first-degree relatives having a 2-times higher risk of measurements were performed below the level of the developing the disease (Larsson et al. 2009). It is renal artery origin, 10‒20 mm above the aortic generally assumed that most AAAs have a polygenetic bifurcation and a greater diameter was chosen. The background where the small effect gene variants cause definitive result was the mean of three measurements of predisposition to the disease development. Differences in maximum abdominal aortic diameter performed in gene expression in the aneurysmal tissue and in the systole. All diameters were measured by the biopsy of healthy aortic tissue of the same patient were same experienced sonographer (MM). AAA patients also found (Prucha et al 2019). were defined as patients with subrenal aortic Genetic association between rs7635818 gene dilatation ≥ 30 mm. The control group of patients variant located on the short arm of chromosome 3 and consisted of patients with aortic diameter < 25 mm. AAA is not clear. It was reported in an early genome- Patients with known active malignancy, chronic wide association study (GWAS) of Elmore et al. (2009) inflammatory diseases, severe liver disease, chronic but not replicated in the further two GWAS conducted by kidney disease stage 3‒5, thoracic, iliac, femoral, Gretarsdottir et al. (2010) and Jones et al. (2009). The popliteal aneurysm, history of aortic reconstructive diverse results regarding this polymorphism association surgery were excluded from the study. with AAA suggest importance for further study in this Patients’ anthropometric data was collected from field (Smelser et al. 2010). their medical records. All patients were asked to complete The aim of the present study was to examine the a standardized health questionnaire on smoking habits association between the gene variant rs7635818 and AAA and medical history. The history of chronic diseases risk in the Central European Caucasian population of among subjects was self-reported. Hypertension was Slovakia, and to evaluate the association between this defined as systolic blood pressure ≥ 140 mm Hg and/or polymorphism and the severity of AAA expressed by the diastolic blood pressure ≥ 90 mmHg, and/or current diameter of abdominal aorta. antihypertensive medication. Diabetes mellitus (DM) determination was based on self-reported usage of anti- Methods diabetes medication, fasting glucose levels ≥ 7.0 mmol/l and/or postprandial glucose levels ≥ 11.1 mmol/l. AAA patients enrolled in this study were Dyslipidemia was defined by the use of hypolipidemic outpatients and/or hospitalized patients at the Department medication, and/or by lipid levels out of range of of Angiology between August 2016 and March 2020. The recommended treatment goals (Catapano et al. 2016). antero-posterior measurements of abdominal aortic Patients were classified as active smokers, ex-smokers 2021 Gene Variant rs7635818 and Abdominal Aortic Aneurysm 195 and never smokers. genetic model compares C-allele carriers (GC/CC) to Blood samples for biochemical, hematological GG homozygotes. The recessive genetic model compares analyzes and for genomic DNA extraction were taken in CC homozygotes to G-allele carriers (GG/GC). The the morning after 12 hours of fasting from the cubital co-dominant model compares CC homozygotes and vein. Whole blood for DNA analysis was collected into GC heterozygotes to GG homozygotes separately. The an evacuated tube containing K2EDTA. DNA was adjustments in multivariate analyses were performed for extracted with a Wizard Genomic DNA Isolation kit AAA risk factors (age, hypertension, sex, smoking habit), (Promega, Co, Ltd, USA) according to the AAA protective factor (diabetes mellitus), creatinine, and manufacturer´s instructions and resolved in DNA body mass index (BMI) due to their different distribution Rehydration Solution (10mM Tris, 1mM EDTA) from at univariate level (p<0.1). Differences were regarded as the kit. Spectrophotometer Nanodrop 2000 (Thermo statistically significant at two-tailed p-values p<0.05, Scientific) was used to quantify and assess the purity of since this was a replication genetic study.
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