Genski polimorfizmi estrogenskog receptora alfa, androgenog receptora i aromataze u izoliranoj fibrilaciji atrija [Genetic polymorphisms of the estrogen receptor alpha, androgen recptor, and aromatase in lone atrial fibrillation]

Golubić, Karlo (2014) Genski polimorfizmi estrogenskog receptora alfa, androgenog receptora i aromataze u izoliranoj fibrilaciji atrija [Genetic polymorphisms of the estrogen receptor alpha, androgen recptor, and aromatase in lone atrial fibrillation]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Introduction: According to published data, there could be an association between polymorphisms of the estrogen receptor gene and lone atrial fibrillation. Considering their biological role and connection, it is possible that polymorphisms of other sex hormone receptors and enzymes involved in sex hormone metabolism could also be associated with lone atrial fibrillation. ----- Aim: To establish whether there is an association between the (TA)n ESR1, (CAG)n AR as well as (TTTA)n CYP19A1 polymorphisms and the prevalence of lone atrial fibrillation (AF). ----- Methods: We conducted a case-controlled study involving 117 patients with lone AF and 197 healthy controls. The main inclusion criterion for the lone AF group was an electrocardiographically (ECG) documented episode of AF, without known etiological factors (i.e. arterial hypertension, heart failure, valve disease, cardiomyopathy, congenital heart defects, coronary disease, thyroid disease, obesity, diabetes, chronic obstructive lung disease, sleep apnea and chronic renal disease). Patient with a history of smoking, alcohol and drug abuse were excluded from the study. The control group consisted of healthy employees of the university hospital center Zagreb who have undergone preemptive examination, as well as other healthy clients of the center (e.g. bone marrow donors) with healthy hearts and normal ECGs. All participants had 5 ml of blood drawn from a peripheral vein, and genomic DNA was extracted from their leukocytes. The genotype was determent by PCR with labeled forward and unlabeled reverse primers. After the amplification, the PCR products were run on a 6% polyacrylamide gel in an automated sequencer. Assignment of alleles was performed using computer software. The determination of genotype was performed by laboratory personnel blinded to participant status regarding AF. Mann–Whitney U test was conducted to compare the differences between cases and controls in continuous variables and χ2 test for categorical variables. All polymorphisms were analyzed at first separately, then according to groups of similar numbers of polynucleotide repeats, and at last as genotype combinations. To assess the association of genotype with AF, binary logistic regression models were built with AF as outcome for each polymorphism. For all analyses, a double-sided p<0.05 was considered statistically significant. ----- Results: After ranking by sex, and number of dinucleotide repeats, an increased frequency of "long" alleles ((TA)n>21) was registered in the AF group which was entirely driven by the male sex, 43.1% vs. 33%, p=0.012. Furthermore, there was an increased frequency of haplotypes with the combination of two "long" alleles in the AF group of men, 19.2% vs. 7.6%, p=0.021. There was also decreased frequency of the LL genotype ((CAGn<22)) in women with AF compared to the control group, albeit the result is not statistically significant. There were no differences in distribution of the (TTTA)n polymorphism of the CYP19A1 gene between the AF and the control group. According to the results of the binary logistic regression, carriers of the ESR1 LL genotype were twice as likely to develop AF compared to controls, OR=2.05, CI=1.06-3.95, p=0.032. When adjustment was made for age, sex, BMI, and blood pressure were added, the observed association remained statistically significant and its magnitude did not change. ----- Conclusions: There is a positive association between the number of (TA)n repeats of the ESR1 gene and lone AF in men. This association could indicate a role of estrogen and its receptors in the pathophysiology of AF. Large-scale studies conducted in different populations are required to more comprehensively and reliably assess the relationship of (TA)n length with the quantity and quality of ER-α transcripts, and the occurrence of AF, and perhaps use its curative potential.

Abstract in Croatian

Uvod: Prema do sada objavljenoj literaturi, postoje naznake da bi polimorfizmi estrogenskog receptora mogli biti povezani s izoliranom FA. S obzirom na njihovu biološku ulogu i povezanost, moguće je da i polimorfizmi drugih receptora odnosno enzima igraju ulogu u izoliranoj FA. ----- Cilj: Analizirati povezanost genotipa s obzirom na polimorfizme (TA)n ESR1, (CAG)n AR i (TTTA)n CYP19A1 s pojavom izolirane fibrilacije atrija u odnosu na kontrolnu skupinu. ----- Ispitanici i metode: U ovoj studiji parova sudjelovalo je 117 bolesnika s izoliranom FA i 197 zdravih ispitanika koji su služili kao kontrole. Glavni kriterij uključivanja u skupinu bolesnika s izoliranom FA bila je elektrokardiografski dokumentirana epizoda FA, bez poznatih etioloških čimbenika za FA (tj. arterijska hipertenzija, srčano popuštanje, bolest srčanih zalistaka, kardiomiopatija, kongenitalne srčane greške, koronarna bolest, bolest štitnjače, pretilost, šećerna bolest, kronična opstruktivna bolest pluća, apneja u spavanju i kronična bolest bubrega). Iz ispitivanja su isključeni bolesnici pušači te korisnici alkohola i droga. Kontrolnu su skupinu činili zdravi zaposlenici KBC-a Zagreb podvrgnuti sistematskom pregledu, kao i drugi zdravi korisnici usluga KBC-a Zagreb (npr. darivatelji koštane srži) sa zdravim srcima i normalnim elektrokardiogramima. Svim ispitanicima izvađeno je 5 ml krvi iz periferne vene te im je iz leukocita izolirana genomska DNA. Odrećivanje genotipa učinjeno je pomoću lančane reakcije polimeraze (PCR) sa obilježenim prednjim i neobilježenim reverznim primerima. Nakon amplifikacije, produkti PCR podvrgnuti su elektroforezi na gelu od 6% poliakrilamida u automatiziranom uređaju za sekvencioniranje. Određivanje alela učinjeno je pomoću računalnog programa. Genotipizacija je provedena od strane laboratorijskog osoblja kojima nije bio poznat status ispitanika s obzirom na izoliranu FA. Mann–Whitney U test korišten je za uspoređivanje razlika između bolesnika i kontrola za kontinuirane varijable, a za kategorijske varijable korišten je χ2 test. Svi polimorfizmi analizirani su isprva zasebno, prema broju ponavljanja polinukleotidnih sekvencija, a potom su razmatrani kao kombinacije alela. Povezanost pojedinih genotipova s FA, analizirana je pomoću binarne logističke regresije; načinjeni su modeli s FA kao ishodom za svaki pojedini gen. Za sve analize, p<0.05 (double-sided) smatran je signifikantnim. ----- Rezultati: Nakon rangiranja prema spolu, po broju dinukleotidnih ponavljanja, zamjetna je veća zastupljenost duljih alela ((TA)n>21) u skupini bolesnika s FA koja se nakon raščlanjivanja po spolu jasno može pripisati muškarcima s FA, 43.1% vs. 33%, p=0.012. Osim toga, potvrđena je i povećana učestalost haplotipova s kombinacijom dviju "dugih" alela u skupini muškaraca s FA, 19.2% vs. 7.6%, p=0.021. Prilikom analize haplotipova gena androgenog receptora, primjećen je manji udio LL genotipa ((CAGn<22)) kod žena s FA u odnosu na zdrave kontrole, rezultat međutim nije statistički značajan. Nije nađeno razlika u distribuciji (TTTA)n polimorfizma CYP19A1 gena između skupine s FA i kontrolne skupine. Prema rezultatima binarne logističke regresije, nosioci ESR1 LL genotipa izvrgnuti su dvostruko većem riziku FA od ostalih ispitanika, OR=2.05, CI=1.06-3.95, p=0.032. Nakon što su u modele su uključene i ostale varijable: krvni tlak (MAP u mmHg), starost ispitanika (u godinama), indeks tjelesne mase (BMI u kg/m2) te muški spol (1-da, 0-ne). ESR1 LL genotip ostao je signifikantan prediktor bez značajne promjene rizika. ----- Zaključak: Postoji pozitivna povezanost između broja dinukleotidnis ponavljanja (TA)n polimorfizma ESR1 gena s izoliranom FA kod muškaraca. Ta povezanost mogla bi upućivati na ulogu estrogena i njihovih receptora u patofiziologiji FA. Potrebna su daljnja istraživanja na većem broju ispitanika te istraživanja na molekularnoj razini kako bi se ta uloga razjasnila i iskoristila kao potencijalna metoda liječenja.

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