Lipīdu vielmaiņu regulējošo gēnu polimorfismu asociācija ar koronāro sirds slimību un lipīdu līmeņiem

Abstract

Ievads. Identificējot ģenētiskos lipīdu fenotipu variantus, varētu veidot jaunu izpratni par slimību un veicināt terapijas principu izmaiņas dislipidēmijas ārstēšanā un KVS riska līmeņa noteikšanā primārās prevencijas ietvaros. Ģenētiskā riska noteikšana kopā ar klasiskajām riska noteikšanas metodēm uzlabotu augsta riska grupu skrīninga iespējas. Mērķis ir noskaidrot, vai lipīdu vielmaiņu ietekmējošo kandidātgēnu viena nukleotīda polimorfismi ietekmē lipīdu līmeņus un paaugstina koronārās sirds slimības risku Latvijā atlasītā personu paraugā. Metodes: Veselā kontroles grupa (n=95) tika nejaušinātā veidā atlasīta no Latvijas populācijas šķērsgriezuma pētījuma no indivīdiem kam nav bijusi KVS anamnēzē. Pacienti (n=96) tika atlasīti no LKC un LBMC datubāzes starp tiem, kuriem iepriekš ir angiogrāfiski apstiprināta KSS. Tika ievērots vecuma atlases kritērijs zem 70 gadiem. Genomiskās DNS iegūšana no asins paraugiem un genotipēšana tika veikta LBMC ar Illumina BeadExpress system (Illumina Golden Gate genotyping assay) balstoties uz ražotāja lietošanas instrukcijām. Datu statistiskā apstrāde veikta ar SPSS programmas 19.0 versiju. Rezultāti. Statistiski ticami biežāk slimības grupā pierādīta piecu polimorfismu reto alēļu sastopamība: APOA1 A/G rs480878, APOB A/G rs10495712, LPL C/T rs2410630, DOCK7 A/C rs1167998, APOA1 C/T rs4938303(p<0.05). Veselo kontroles grupā statistiski ticami biežāk sastopami sešu polimorfismu retās alēles: TOMM40 A/G rs157580, LPL C/T rs10096633, TOMM40 A/G rs2075650, CELSR2 C/T rs4970834, TOMM40 A/G rs6859, APOA1 A/C rs12272004 (p<0.05). Statististiski ticamas lipīdu līmeņu atšķirības pierāda 27 polimorfismu genotipi deviņos gēnos, viens no tiem slimības grupā asociēts ar KSS (ABOB A/G rs10495712), 12 no tiem asociācijā ar ABL-H līmeni, seši ar TG līmeni, pieci ar KH un četri ar ZBL-H līmeni. Literatūrā asociācijā ar KSS sakrīt viens polimorfisms (APOA1 C/T rs4938303), ar lipīdiem - 12 polimorfismi, no kuriem astoņi ar ABL-H līmeni (CETP A/C rs1800775, LPL A/G rs6993414, CETP C/T rs708272, CETP A/C rs1800775, CETP G/T rs3764261, CETP C/T rs173539, CETP A/G rs7205804, LPL C/G rs7016880) divi ar TG līmeni (LDLR G/T rs6511720, TRIB1 A/G rs17321515, TRIB A/T rs2954029) un viens ar KH līmeni (TRIB1 A/T rs2954029). Secinājumi. Ar paaugstinātu koronārās sirds slimības risku asociāciētas piecu lipīdu vielmaiņu ietekmējošo gēnu polimorfismu retās alēles: APOA1 A/G rs480878, APOB A/G rs10495712, LPL C/T rs2410630, DOCK7 A/C rs1167998, APOA1 C/T rs4938303. Ar koronārās sirds slimības protektīvo efektu asociētas sešu lipīdu vielmaiņu ietekmējošo gēnu polimorfismu retās alēles: TOMM40 A/G rs157580, LPL C/T rs10096633, TOMM40 A/G rs2075650, CELSR2 C/T rs4970834, TOMM40 A/G rs6859, APOA1 A/C rs12272004. Atrastas asociācijas 12 polimorfismiem ar ABLH, sešiem ar TG, pieciem ar KH un četriem ar ZBLH. Literatūrā atrodamajos datos mūsu pētījuma rezultātos esošā pozitīvā asociācijā ar KSS ir viens no pieciem polimorfismiem (APOA1 C/T rs4938303), ar lipīdiem - 27 polimorfismi, no kuriem astoņi no 12 ar ABL-H līmeni (CETP A/C rs1800775, LPL A/G rs6993414, CETP C/T rs708272, CETP A/C rs1800775, CETP G/T rs3764261, CETP C/T rs173539, CETP A/G rs7205804, LPL C/G rs7016880), trīs no sešiem ar TG līmeni (LDLR G/T rs6511720, TRIB1 A/G rs17321515, TRIB A/T rs2954029), viens no pieciem ar KH līmeni (TRIB1 A/T rs2954029) un neviens no četriem ar ZBL-H līmeni. Atslēgvārdi: Risks, koronārā sirds slimība, lipīdi, viena nukleotīda polimorfismi.

Lipid Metabolism Regulating Gene Polymorphisms in Association with Coronary Heart Disease and Lipid Levels Author: Lina Dreiberga, 6th year student, Faculty of Medicine, University of Latvia, Supervisor: Gustavs Latkovskis, Associated Professor, MD, Pauls Stradins Clinical University Hospital, University of Latvia. Background. Identification of the genetic variants of lipid phenotype could provide a new understanding of the disease, promote the change in principles of treatment of dyslipidemia and CVD and change in risk level determination within the framework of primary prevention. Genetic risk evaluation, together with conventional risk measurement techniques would improve screening options for high-risk population groups. Objective is to find out whether candidate gene single nucleotide polymorphisms increase the risk of coronary heart disease and affects lipid levels in Latvia selected individuals. Methods. Healthy control group (n=95) is selected in randomized manner from the Latvian population cross-sectional study of individuals who had no history of CVD. Patients (n=96) were selected from the LCC and LBMC databases among those with previously angiographically confirmed CHD. The criterion for selection under the age of 70 years was respected. Genomic DNA from blood samples was obtained and genotyping with the Illumina LBMC BeadExpress system (Illumina Golden Gate genotyping assay) based on the manufacturer's operating instructions. Statistical data processing with SPSS version 19.0 was performed. Results. Five polymorphism rare alleles in disease group demonstrated statistically significant higher frequency rate: APOA1 A/G rs480878, APOB A/G rs10495712, LPL C/T rs2410630, DOCK7 A/C rs1167998, APOA1 C/T rs4938303 (p<0.05). Six polymorphism rare alleles in healthy control group demonstrated statistically significant higher frequency rate: TOMM40 A/G rs157580, LPL C/T rs10096633, TOMM40 A/G rs2075650, CELSR2 C/T rs4970834, TOMM40 A/G rs6859, APOA1 A/C rs12272004 (p<0.05). 27 polymorphism genotypes in nine genes showed statististically reliable differences in lipid levels in healthy group, including one in a group of diseases which was associated with CHD (APOB A/G rs10495712), 12 in association with levels of HDL-C, six with levels of TG, five with levels of TC and four with levels of LDL–C. There is a match in our study with literature data in association with CHD (APOA1 C/T rs4938303), in association with HDL-H (CETP A/C rs1800775, LPL A/G rs6993414, CETP C/T rs708272, CETP A/C rs1800775, CETP G/T rs3764261, CETP C/T rs173539, CETP A/G rs7205804, LPL C/G rs7016880), in association with TG (LDLR G/T rs6511720, TRIB1 A/G rs17321515, TRIB A/T rs2954029), and in assocation with TC (TRIB1 A/T rs2954029). Conclusions. Five rare alleles of lipid metabolism regulating gene polymorphisms in association with CHD were found: APOA1 A/G rs480878, APOB A/G rs10495712, LPL C/T rs2410630, DOCK7 A/C rs1167998, APOA1 C/T rs4938303. Association with protective effect regarding rare alleles in six polymorphisms was found: TOMM40 A/G rs157580, LPL C/T rs10096633, TOMM40 A/G rs2075650, CELSR2 C/T rs4970834, TOMM40 A/G rs6859, APOA1 A/C rs12272004. There were found 12 polymorphisms in association with HDL-H, six in association with TG, five with TC, four with LDL-H. Regarding literature data there is one match in positive association with CHD in one polymorphism (APOA1 C/T rs4938303), eight out of 12 with levels of HDL-H (CETP A/C rs1800775, LPL A/G rs6993414, CETP C/T rs708272, CETP A/C rs1800775, CETP G/T rs3764261, CETP C/T rs173539, CETP A/G rs7205804, LPL C/G rs7016880), three out of six with levels of TG (LDLR G/T rs6511720, TRIB1 A/G rs17321515, TRIB A/T rs2954029), one out of five with levels of TC (TRIB1 A/T rs2954029) and none out of four with levels of LDL-H. Key words: risk, coronary heart disease, lipids, single nucleotide polymorphisms.