Drug target gene discovery for diseases with cardiometabolic risk factors utilizing large-scale biobank data

Tutkimustuotos: OpinnäyteVäitöskirjaArtikkelikokoelma

Abstrakti

Cardiometabolic disorders are a huge and increasing financial and public health burden. Genome-wide association studies (GWASs) have been effective at uncovering genetic variants associated with numerous traits, including cardiometabolic ones. However, only a tiny fraction of these results have been translated into pharmaceutical preforms. Arguably the two most important reasons for this are, first, that the overwhelming majority of associated variants have small associated effects and, second, that ascertaining the biological mechanism of how associated variants influence traits has proven difficult. In the studies included in this dissertation, the aim was to boost the likelihood of finding links between gene function and cardiometabolic phenotypes by analyzing both endophenotypes of cardiometabolic disease endpoints and protein-coding variation. The added benefit of analyzing protein-coding variation is that its effects on gene function are readily interpretable. Therefore, we analyzed genetic population samples of Finns - an isolated population enriched for protein-coding variants. Some of the most significant and modifiable risk factors of coronary artery disease (CAD) are blood lipids whose genetic determinants can be studied to find mechanisms that affect CAD risk. In Publication I we set out to identify loss-of-function variants associated with both circulating lipids and cardiometabolic disorders in Finns. We uncovered two highly Finnish-enriched variants in ANGPTL4 and ANGPTL8 genes that were significantly associated with lower triglyceride levels and lower risks of cardiometabolic disorders. The loss-of-function variant in ANGPTL4 was associated with 30% lower odds of type 2 diabetes (T2D) and the odds of CAD were 47% lower per ANGPTL8 loss-of-function allele. Studying the genetics of disease endophenotypes can improve the likelihood for discovering biological mechanisms that affect disease pathology. In Publication II we curated novel endophenotypes for CAD from cardiometabolic medication purchase events to help uncover novel CAD genetics. We validated this approach by observing significant genetic correlations between the antihyperlipidemic, antihypertensive and T2D medication purchase counts and, first, their indicated cardiometabolic risk factors and, second, CAD. In the GWASs of the three cardiometabolic medication purchase count phenotypes we identified 298 unique and independent loci of which 32 had not previously been associated with CAD or its risk factors. Six of these potentially novel loci’s lead variants’ associated effects were correlated with those of CAD. These potentially novel genetic loci for CAD highlight the utility of CAD-preventing medication phenotypes in boosting the chances of identifying genetic factors of CAD. Varicose veins, whose genetics have not been studied extensively, is a comorbidity of cardiovascular diseases. In Publication III, we leveraged the protein-coding variant enrichment in Finns and uncovered 29 novel genetic loci for varicose veins including TGFB2 and GJD3 with protein-coding lead variants severely enriched in Finns. The missense variant in the novel GJD3 locus was associated with 38% lower odds of varicose veins and did not show any significant pleiotropic effects in our phenome-wide scan of 1,706 disease endpoints. These results as well as the fact that GJD3 is a member of the connexin gene family underlines the significance of GJD3 in a potential connexin-modulating therapeutic strategy for varicose veins. Our results demonstrate the utility of endophenotypes and protein-coding variants in large population samples for identifying links between gene function and cardiometabolic traits. Moreover, we present potential drug target genes for hyperlipidemia and varicose veins.
Alkuperäiskielienglanti
Valvoja/neuvonantaja
  • Ripatti, Samuli, Valvoja
  • Surakka, Ida, Valvoja, Ulkoinen henkilö
JulkaisupaikkaHelsinki
Kustantaja
Painoksen ISBN978-951-51-9542-5
Sähköinen ISBN978-951-51-9543-2
TilaJulkaistu - 2023
OKM-julkaisutyyppiG5 Tohtorinväitöskirja (artikkeli)

Lisätietoja

M1 - 94 s. + liitteet

Tieteenalat

  • 3111 Biolääketieteet
  • 1184 Genetiikka, kehitysbiologia, fysiologia

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