​Izbrani polimorfizmi genov poti PPARɣ-LXR-ABCA1 in miokardni infarkt pri bolnikih s sladkorno boleznijo tipa 2

Boh, Jakob (avtor), Petrovič, Danijel (mentor), Mankoč Ramuš, Sara (komentor)

Uvod: Miokardni infarkt (MI) je še vedno eden vodilnih vzrokov obolevnosti in umrljivosti v Sloveniji in po svetu. Bolniki s sladkorno boleznijo tipa 2 (SBT2) imajo 2- do 4-krat večje tveganje za koronarno arterijsko bolezen (KB) zaradi več mehanizmov, med katerimi je eden najpomembnejših aterogena lipidna modifikacija. Eden od procesov, ki to preprečuje, je povratni transport holesterola. Aktiven povratni transport holesterola primarno poteka s pomočjo transporterja ABCA1 (angl. ATP-binding cassette transporter A1). V regulacijo izražanja ABCA1 je vključenih več molekul, ki tvorijo metabolno pot PPAR?-LXR-ABCA1. Cilj študije je bil določiti povezavo izbranih polimorfizmov v genih, ki uravnavajo pot PPAR?-LXR-ABCA1, z MI pri osebah s SBT2. Material in metode: V študijo je bilo vključenih 1590 slovenskih oseb kavkaškega porekla, ki niso v sorodu in imajo SBT2 vsaj 10 let. 484 oseb je prebolelo MI, 1106 pa je bilo brez anamneze MI (kontrolna skupina). Izvedli smo genetsko analizo izbranih polimorfizmov v genih ABCA1, NR1H3, PPARG, PPARGC1A, HDAC9 in PARP1. Za testiranje povezav alelov in haplotipov z MI in KB smo izvedli statistično analizo, vključno z multivariatno logistično regresijo. V zadnji fazi raziskave smo z imunohistokemičnim barvanjem določili ravni proteinov ABCA1 in HD9 v steni koronarnih arterij pri bolnikih z in brez MI. Rezultati: Alel G polimorfizma rs1800977 (OR 1,21; CI 1,02 - 1,43, p = 0,026), alel T polimorfizma rs2230806 (OR 1,28; CI 1,08 - 1,52, p = 0,005) – oba v genu ABCA1 – in alel G polimorfizma rs12221497 v genu NR1H3 (OR 1,27; CI 1,02 - 1,6; p = 0,046) so bili povezani z višjim tveganjem za MI pri osebah s SBT2. Rizični haplotipi v genih ABCA1 in HDAC9 so prav tako pomembno povečali tveganje za MI pri osebah s SBT2. Poleg tega sta bila rizična alela polimorfizma rs3856806 v genu PPARG in polimorfizma rs8192678 v genu PPARGC1A povezana z višjo stopnjo KB, merjeno z odstotkom maksimalne stenoze na kateri koli koronarni arteriji. Zaključek: Ugotovili smo povezave večih polimorfizmov v genih, ki uravnavajo pot PPAR?-LXR-ABCA1, z MI in KB pri osebah s SBT2. Nekatere povezave so ugotovljene prvič v katerikoli človeški populaciji. Ugotovitve naše študije lahko prispevajo k razvoju učinkovitih poligenskih točkovnikov za oceno ogroženosti za MI in KB pri visoko rizični populaciji bolnikov s SBT2. Prav tako bi lahko spodbudile iskanje novih terapevtskih tarč za preprečevanje MI in KB.

• Jezik: Slovenski jezik
• Ključne besede: miokardni infarkt, genetika, koronarna bolezen, sladkorna bolezen, ateroskleroza, metabolizem holesterola
• Vrsta gradiva: Doktorsko delo/naloga
• Organizacija: MF - Medicinska fakulteta
• Leto izida: 2025
• PID: 20.500.12556/RUL-168415
• Datum objave v RUL: 12.04.2025

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Selected polymorphisms in genes related to PPARɣ-LXR-ABCA1 pathway and myocardial infarction in patients with type 2 diabetes

Izvleček

Background: Myocardial infarction (MI) is still one of the leading causes of morbidity and mortality in Slovenia and around the world. Patients with diabetes mellitus (DM) have a 2- to 4-fold increased risk for coronary artery disease (CAD) due to multiple mechanisms, one of most significant being atherogenic lipid modification. One of the processes that reduces atherogenic lipid modification is cholesterol efflux. The active efflux mechanisms are primarily mediated by ATP-binding cassette transporter A1 (ABCA1). Several molecules are involved into regulation of ABCA1 expression forming PPARɣ-LXR-ABCA1 pathway. The objective of the study was to determine the association of selected SNPs in genes regulating PPARɣ-LXR-ABCA1 pathway with MI in T2DM subjects. Materials and Methods: 1590 unrelated Slovenian subjects with Caucasian origin who have had T2DM for at least 10 years were included in the study. 484 subjects had history of MI and 1106 subjects in control group were without history of MI. We performed genetic analysis of selected polymorphisms in ABCA1, NR1H3, PPARG, PPARGC1A, HDAC9 and PARP1 genes. Statistical analysis including multivariable logistic regression was performed to test for associations of alleles and haplotypes with MI and CAD. Finally, levels of ABCA1 and HD9 proteins in the vessel wall by immunohistochemistry staining were determined in patients with and without MI. Results: G allele at the rs1800977 (OR 1.21; CI 1.02 - 1.43, p = 0.026), T allele at the rs2230806 (OR 1.28; CI 1.08 - 1.52, p = 0.005) – both in ABCA1 gene - and G allele at rs12221497 in NR1H3 gene (OR 1.27; CI 1.02 - 1.6; p = 0.046) were found to increase risk for MI among T2DM subjects. Risk haplotypes in ABCA1 and HDAC9 also significantly increased risk for MI in T2DM subjects. Furthermore, risk alleles at rs3856806 in PPARG and at rs8192678 in PPARGC1A gene were associated with higher degree of CAD measured by percent of maximal stenosis of any coronary artery. Conclusion: We found associations of several SNPs in genes regulating PPARɣ-LXR-ABCA1 cholesterol efflux pathway with MI and CAD in T2DM subjects. Some of the associations were found for the first time in any human population. The findings of our study could contribute to developing efficient polygenic risk scores to asses CAD and MI risk in a vulnerable population of T2DM patients. It could also encourage research for new therapeutic targets in preventing CAD and MI.

• Ključne besede: myocardial infarction, genetics, coronary artery disease, diabetes mellitus, atherosclerosis, cholesterol efflux