Association of Genetically Predicted Lipid Levels With the Extent of Coronary Atherosclerosis in Icelandic Adults.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadImportance: Genetic studies have evaluated the influence of blood lipid levels on the risk of coronary artery disease (CAD), but less is known about how they are associated with the extent of coronary atherosclerosis. Objective: To estimate the contributions of genetically predicted blood lipid levels on the extent of coronary atherosclerosis. Design, setting, and participants: This genetic study included Icelandic adults who had undergone coronary angiography or assessment of coronary artery calcium using cardiac computed tomography. The study incorporates data collected from January 1987 to December 2017 in Iceland in the Swedish Coronary Angiography and Angioplasty Registry and 2 registries of individuals who had undergone percutaneous coronary interventions and coronary artery bypass grafting. For each participant, genetic scores were calculated for levels of non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides, based on reported effect sizes of 345 independent, lipid-associated variants. The genetic scores' predictive ability for lipid levels was assessed in more than 87 000 Icelandic adults. A mendelian randomization approach was used to estimate the contribution of each lipid trait. Exposures: Genetic scores for levels of non-HDL-C, LDL-C, HDL-C, and triglycerides. Main outcomes and measures: The extent of angiographic CAD and coronary artery calcium quantity. Results: A total of 12 460 adults (mean [SD] age, 65.1 [10.7] years; 8383 men [67.3%]) underwent coronary angiography, and 4837 had coronary artery calcium assessed by computed tomography. A genetically predicted increase in non-HDL-C levels by 1 SD (38 mg/dL [to convert to millimoles per liter, multiply by 0.0259]) was associated with greater odds of obstructive CAD (odds ratio [OR], 1.83 [95% CI, 1.63-2.07]; P = 2.8 × 10-23). Among patients with obstructive CAD, there were significant associations with multivessel disease (OR, 1.26 [95% CI, 1.11-1.44]; P = 4.1 × 10-4) and 3-vessel disease (OR, 1.47 [95% CI, 1.26-1.72]; P = 9.2 × 10-7). There were also significant associations with the presence of coronary artery calcium (OR, 2.04 [95% CI, 1.70-2.44]; P = 5.3 × 10-15) and loge-transformed coronary artery calcium (effect, 0.70 [95% CI, 0.53-0.87]; P = 1.0 × 10-15). Genetically predicted levels of non-HDL-C remained associated with obstructive CAD and coronary artery calcium extent even after accounting for the association with LDL-C. Genetically predicted levels of HDL-C and triglycerides were associated individually with the extent of coronary atherosclerosis, but not after accounting for the association with non-HDL cholesterol. Conclusions and relevance: In this study, genetically predicted levels of non-HDL-C were associated with the extent of coronary atherosclerosis as estimated by 2 different methods. The association was stronger than for genetically predicted levels of LDL-C. These findings further support the notion that non-HDL-C may be a better marker of the overall burden of atherogenic lipoproteins than LDL-C.deCODE genetics/Amgen Inc

Rannsókn á tengslum erfðabreytileika í og við genin TTN/CCDC141 við hjartsláttartruflanir í gáttum

Inngangur: Víðtækar erfðamengisrannsóknir hafa fundið tengsl á milli 170 erfðabreytileika og gáttatifs en minna er vitað um erfðafræði annarra hjartsláttartruflana í gáttum. Nýlegar rannsóknir Íslenskrar erfðagreiningar hafa gefið vísbendingar um tengsl erfðabreytileika á svæðinu TTN/CCDC141 við ýmsar hjartsláttartruflanir í gáttum. Markmið þessarar rannsóknar var að meta betur þessi tengsl. Efni og aðferðir: Við safngreindum upplýsingar úr víðtækri erfðamengisleit fyrir hjartsláttartruflanir í gáttum frá Íslandi, UK Biobank og Copenhagen Hospital Biobank en afmörkuðum okkur við svæðið TTN/CCDC141. Við könnuðum tengsl 8366 erfðabreytileika á svæðinu við fjórar hjartsláttartruflanir og notuðum Bonferroni leiðréttingu til að fá marktækniþröskuldinn 6,0×10-6 . Einnig skoðuðum við tengsl erfðabreytileika sem tengdust hjartsláttartruflunum við hjartalínuritsmælingar frá Landspítala og rannsóknum Íslenskrar erfðagreiningar. Niðurstöður: Við fundum tengsl við fjórar hjartsláttartruflanir í gáttum. Erfðabreytileikinn rs2288327 tengdist gáttatifi (P = 2,8 × 10-29, OR (e. odds-ratio, gagnlíkindahlutfall) = 1,11), rs10660645 tengdist sjúkum sínushnúti (P = 6,8 × 10-9 , OR = 1,13), rs13031826 tengdist gáttasleglarofi (= 2,65 × 10-17, OR = 1,23), rs10497529 tengdist ofansleglahraðtakti (P = 1,7 × 10-11, OR = 1,23) og einnig tengdist rs1873164 ofansleglahraðtakti (P = 1,4 × 10-12, OR = 1,22). Allir þessir breytileikar sýndu minna marktæk tengsl við aðra hjartsláttartruflun í gáttum, eina eða fleiri. Skilyrt greining sýndi hins vegar að þau tengsl voru afleiðing tengslaójafnvægis. Allir erfðabreytileikarnir höfðu tengsl við ýmsar hjartalínuritsmælingar, en tengslamynstrið var mismunandi á milli breytileikanna. Engin marktæk tengsl fundust milli þessara erfðabreytileika og háþrýstings, hjartavöðvakvilla, hjartabilunar og kransæðasjúkdóms, sem bendir til þess að áhrif á rafleiðni hjartans miðli tengslum erfðabreytileikanna við hjartsláttartruflanirnar, fremur en aðrir hjartasjúkdómar. Ályktanir: Við sýndum að það eru fimm erfðabreytileikar á svæðinu TTN/CCDC141 sem tengjast mismunandi hjartsláttartruflunum í gáttum og einnig hjartalínuritsmælingum sem mæla rafleiðni í hjartanu. Engu öðru svæði í erfðamenginu hefur verið lýst með víðtækri erfðamengisrannsókn sem hefur áhrif á svona margar mismunandi hjartsláttartruflanir í gáttum. Þessar niðurstöður kalla á frekari rannsóknir til að skilja betur áhrif þessa svæðis á rafleiðni í hjarta