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Prezgodnje rojstvo (ang. PreTerm Birth, PTB) je pogosto in multifaktorsko stanje, ki je opredeljeno kot rojstvo pred dokončanim 37 tednom nosečnosti. V povprečju prizadene kar 11% nosečnosti po vsem svetu in je glavni vzrok smrti pri otrocih mlajših od 5 let. V nosečnosti se pojavijo številne fiziološke spremembe, ki prispevajo k spremembam tudi v lipidnem profilu zdravih nosečnic. Določena raven lipidov v materi je potrebna za normalen razvoj ploda, spremembe v fiziologiji lipidov med nosečnostjo pa lahko po drugi strani odražajo povečano odpornost na inzulin pri materah. Kar nekaj raziskav je pokazalo, da so pretirane spremembe ravni lipidov v krvi mater povezane s povečanim tveganjem za PTB, vendar še vedno ni popolnoma jasno, kako te spremembe vplivajo na PTB. Deregulacija cirkadianega sistema, zaradi genetskih mutacij ali okoljskih dejavnikov, lahko pri ljudeh in živalih privede do razvoja različnih patologij. Z uporabo različnih modelnih organizmov so pokazali, da je reprodukcijska fiziologija (estrogeni cikel, prezgodnji porod, itd.) pod kontrolo cirkadiane ure. Prav genetski dejavniki predstavljajo razlog za od 25 do 40% primerov, zato je koristno iskati potencialne genetske povezave med PTB in polimorfizmi posameznih nukleotidov (ang. Single Nucleotide Polymorphism, SNP) v genih cirkadianega ritma. Kljub zavedanju, da sta cirkadiana ura in lipidni metabolizem ključna procesa pri različnih reprodukcijskih vprašanjih, tudi PTB, do sedaj ni bilo veliko študij, ki bi raziskale vlogo cirkadiane genetike in lipidnega metabolizma med nosečnostjo in njihovo povezanost s PTB. V okviru doktorskega dela smo analizirali genetsko variabilnost s SNP iz genov cirkadiane ure in lipidnega metabolizma v povezavi z lipidi drugega trimesečja in PTB. S tem smo želeli ugotoviti, ali lahko SNP v genih osrednje cirkadiane ure in lipidnega metabolizma vplivajo na raven lipidov v krvi mater v drugem trimesečju in ali je to lahko povezano s povečanim tveganjem za PTB. S pomočjo sistematičnega pregleda literature smo izbrali 72 kandidatnih SNP iz genov cirkadiane ure in lipidnega metabolizma, ki so bili v predhodnih študijah povezani s presnovnimi fenotipi, vključno z dislipidemijo, debelostjo, diabetesom tipa 2, indeksom telesne mase (ang. Body Mass Index, BMI), nealkoholno bolznijo jeter ali reproduktivnimi fenotipi, kot je PTB. Na populaciji Kalifornijskih mater smo preverili povezanost z ravnjo lipidov v drugem trimesečju in nazadnje še s prezgodnjim rojstvom. Od 72 SNP v 40 genih je bilo kar 45 SNP značilno povezanih z najmanj enim lipidom. Po Bonferroni popravku je ostalo statistično značilnih pet SNP iz štitih genov lipidnega metabolizma in cirkadiane ure (APOE, CELSR2, PNPLA3, PER3). Šest SNP iz genov cirkadiane ure (CLOCK in PER3) in dva SNP iz genov lipidnega metabolizma (LIPC in ABCA1) je po popravku doseglo mejno signifikanco z najmnaj enim lipidom v krvi nosečnic. SNP, ki so bili statistično značilno povezani z lipidi so bili ovrednotili še za povezavo s PTB. Edina povezava, ki je ostala statistično značilna je bila pri SNP rs228669 v cirkadianem genu PER3. Vsak dodatni alel A je bil statistično značilno povezan z višjimi koncentracijami trigliceridov (ang. Tryglicerides, TG). Genotip AA je bil značilno povezan s povečanim tveganjem za spontani PTB (ang. Spontaneous PTB, SPTB) in PTB. V nadaljevanu smo preverili tudi ali ima morda SNP rs228669 vpliv na učinek v razmerju med TG in PTB. Za ta namen smo naredili stratifikacijo po genotipu in pokazali, da je nižja koncentracija TG povezana s PTB pri posameznicah z genotipom AA, medtem ko so bile višje koncentracije TG povezane s PTB pri posameznicah z genotipom GA. Nobene statistično značilne povezave med TG in PTB nismo opazili pri nosečnicah z genotipom GG. Kot nam je znano, je to prva študija, kjer so bile ovrednotene povezave med SNP iz genov cirkadiane ure in lipidnega metabolizma z lipidi v drugem trimesečju in PTB. Vsekakor je potrebnih še več raziskav, da bi v celoti lahko preučili vpliv cirkadiane genetike na PTB in povezanost z ravnjo lipidov med nosečnostjo. Preterm birth (PTB) is a common and multifactorial condition defined as delivery prior to 37 weeks’ completed gestation. It affects an average of 11% of pregnancies worldwide and is the leading cause of death in children under age 5. The level of maternal blood lipids is important for maintaining a healthy pregnancy with normal fetal development. In pregnancy, multiple physiological changes occur that contribute to the alterations in lipid profiles of healthy, gestating women. The changes in lipid physiology throughout the course of pregnancy allow for proper nutrients for the fetus and reflect increasing insulin resistance in the mother. Several studies showed that excessive changes in lipid levels are associated with increased risk for PTB. It is still unclear whether the lipid levels directly affect PTB or if PTB is influenced indirectly through changes in lipid levels that are a result of the pregnancy. Deregulation of the circadian system in humans and animals can lead to the development of various pathologies due to genetic mutations or environmental factors. With the use of various model organisms, it has been shown that various aspects of reproductive physiology (estrous cycle, parturition) are regulated by the circadian clock. Genetic factors account for 25 to 40% of the variation in the timing of birth. Thus, it is valuable to explore potential genetic associations between PTB and single nucleotide polymorphisms (SNPs) in genes playing an important role in the circadian rhythm pathway. Despite the importance of the circadian clock and lipid metabolism in regulating birth timing, few studies have examined the relationship between circadian genetics with lipid levels during pregnancy and their relationship with PTB. Within the PhD work, genetic variability in the form of SNPs from circadian clock and lipid genes was analyzed for association with 2nd trimester lipids and preterm birth. We aimed to determine if SNPs in genes from the circadian clock and lipid metabolism influence 2nd trimester maternal lipid levels and if this is associated with an increased risk for PTB. Systematical review of the literature was performed and 72 candidate SNP from circadian and lipid metabolism genes were selected. SNPs were previously associated with metabolic-related phenotypes including dyslipidemia, obesity, type 2 diabetes, body mass index (BMI), non-alcoholic fatty liver disease, or reproductive complications such as PTB. We examined the population of Californian mothers and selected SNPs were further tested for associations with lipid levels and PTB. Of the 72 candidate SNPs across 40 genes 45 SNPs were associated with one or more lipid levels. After the Bonferroni correction for multiple testing, five SNPs in four genes were associated with one or more 2nd trimester lipid levels. Six additional SNPs from circadian clock genes (5 SNPs in CLOCK and 1 in PER3) and two SNPs from lipid genes (1 SNP in LIPC and 1 SNP in ABCA1) nearly met Bonferroni correction with one or more lipid levels. SNPs that were statistically significantly associated with lipids were further evaluated for association with PTB. The only association that remained statistically significant was observed with SNP rs228669 in the PER3 gene. Each additional A allele was significantly associated with higher levels of triglycerides (TG). The AA genotype of rs228669 within the PER3 gene was marginally associated with an increased risk for spontaneous PTB (SPTB) and PTB. This association remained significant when limiting the sample to only spontaneous PTB. It was shown that association between SNPs from circadian, circadian related genes and lipids exists and is significant. Furthermore, we investigated whether rs228669 is an effect modifier of the relationship between TG and PTB. When stratifying data by genotype, lower TG levels were associated with PTB in individuals with the AA genotype, whereas higher TG levels were associated with PTB in individuals with the GA genotype. There was no association between TG levels and PTB in individuals with the GG genotype. To our knowledge this is the first study that focuses on the associations between SNPs in circadian clock and lipid metabolism genes with 2nd trimester lipid levels and PTB. More studies are needed to fully examine the influence of circadian clock genetics on PTB and the relationship with lipid levels during pregnancy. |
