Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.
Jonas Bille NielsenOren RomIda SurakkaSarah E GrahamWei ZhouTanmoy RoychowdhuryLars G FritscheSarah A Gagliano TaliunCarlo SidoreYuhao LiuMaiken E GabrielsenAnne Heidi SkogholtBrooke N WolfordWilliam OvertonYing ZhaoJin ChenHe ZhangWhitney E HornsbyAkua AcheampongAusten GroomsAmanda SchaeferGregory J M ZajacLuis VillacortaJifeng ZhangBen Michael BrumptonMari LøsetVivek RaiPia Rengtved LundegaardMorten Salling OlesenKent D TaylorNicholette D D AllredYii-Der ChenSeung H ChoiSteven A LubitzPatrick T EllinorKathleen C BarnesMichelle DayaNicholas RafaelsScott T WeissJessica Lasky-SuRussell P TracyRamachandran S VasanL Adrienne CupplesRasika A MathiasLisa R YanekLewis C BeckerPatricia A PeyserLawrence F BielakJennifer A SmithStella AslibekyanBertha A HidalgoDonna K ArnettMarguerite R IrvinJames G WilsonSolomon K MusaniAdolfo CorreaStephen S RichXiuqing GuoJerome I RotterBarbara A KonkleJill M JohnsenAllison Elizabeth Ashley-KochMarilyn J TelenVivien A SheehanJohn E BlangeroJoanne E CurranJuan M PeraltaCourtney MontgomeryWayne H-H SheuRen-Hua ChungKaren SchwanderSeyed M NouraieVictor R GordeukYingze ZhangCharles KooperbergAlexander P ReinerRebecca D JacksonEugene R BleeckerDeborah A MeyersXingnan LiSayantan DasKetian YuJonathon LeFaiveAlbert Vernon SmithTom BlackwellDaniel TaliunSebastian ZollnerLukas ForerSebastian SchoenherrChristian FuchsbergerAnita PanditMatthew ZawistowskiSachin KheterpalChad M BrummettPradeep NatarajanDavid SchlessingerSeunggeun LeeHyun Min KangFrancesco CuccaOddgeir L HolmenBjørn Olav ÅsvoldMichael BoehnkeSekar KathiresanGonçalo R AbecasisYuqing Eugene ChenCristen J WillerKristian HveemPublished in: Nature communications (2020)
Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10-8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
Keyphrases
- low density lipoprotein
- copy number
- genome wide
- cardiovascular disease
- blood glucose
- induced apoptosis
- dna methylation
- cell cycle arrest
- protein protein
- binding protein
- type diabetes
- endothelial cells
- drug induced
- signaling pathway
- glycemic control
- insulin resistance
- cardiovascular risk factors
- cell death
- oxidative stress
- cell proliferation
- endoplasmic reticulum stress
- blood pressure
- induced pluripotent stem cells
- gene expression
- climate change
- pi k akt
- drug delivery
- pluripotent stem cells
- fatty acid
- electronic health record
- human health