6533b856fe1ef96bd12b3275
RESEARCH PRODUCT
Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
John F. ThompsonMarju Orho-melanderMary Susan BurnettJürgen SchrezenmeirNour Eddine El MokhtariChristopher J. O'donnellChristopher J. O'donnellPhilipp S. WildChristina WillenborgStacey GabrielYvonne T. Van Der SchouwMaja BarbalićAlistair S. HallChristopher Newton-chehMichael BoehnkeSonia S. AnandDiederick E. GrobbeeAndreas ZieglerAsif RasheedBruna GiganteAnne Tybjærg-hansenHeribert SchunkertKiran MusunuruKiran MusunuruJaume MarrugatVincent MooserMarkku S. NieminenPascal P. MckeownNicola MartinelliOlaf H. KlungelGeorge HindyCristen J. WillerAnthonius De BoerLi ChenDiego ArdissinoMarja-liisa LokkiRon DoKaren L. MohlkeElena GonzalezJohn F. PedenShaun PurcellShaun PurcellDiether LambrechtsRuth Frikke-schmidtMark J. DalyMark J. DalyIda SurakkaAarti SurtiFrans Van De WerfGina M. PelosoGina M. PelosoSerkalem DemissieSerkalem DemissieJolanda M. A. BoerGonçalo R. AbecasisAki S. HavulinnaW. M. Monique VerschurenHugh WatkinsDanish SaleheenBas J M PetersNilesh J. SamaniNilesh J. SamaniInke R. KönigDomenico GirelliMarkus PerolaPaul I.w. De BakkerJuha SinisaloJames C. EngertAlexandre F.r. StewartUnnur ThorsteinsdottirUnnur ThorsteinsdottirKeith A.a. FoxStefan BlankenbergMuredach P. ReillyJoseph M. DevaneyAnke-hilse Maitland-van Der ZeeKlaus BergerEric BoerwinkleMarcus FischerGudmundur ThorgeirssonJohn A. SpertusClara C. ElbersDaniel J. RaderStefan SchreiberArne SchäferTanja ZellerErik IngelssonArne SchillertJemma C. HopewellJohn DaneshIan BuysschaertToby JohnsonSamuli RipattiDavid S. SiscovickEric B. RimmJeanette ErdmannSekar KathiresanChristian HengstenbergOlle MelanderMingyao LiGudmar ThorleifssonRoberto ElosuaHilma HolmVera H.m. DeneerRuth McphersonBenjamin F. VoightBenjamin F. VoightBenjamin F. VoightCandace GuiducciN. Charlotte Onland-moretPhilippe M. FrossardJames P. PirruccelloJames P. PirruccelloCisca WijmengaMajken K. JensenLeena PeltonenLeena PeltonenUlf De FaireChristopher PattersonDiana RubinDavid AltshulerJose M. OrdovasJose M. OrdovasEric L. DingThomas M. MorganPieter W. KamphuisenNoël P. BurttPatrick DiemertRobert RobertsPier Mannuccio MannucciStephen E. EpsteinStephen M. SchwartzKim OvervadMonika StollVeikko SalomaaRobert ClarkeKari StefanssonKari StefanssonMarten H. HofkerL. Adrienne CupplesL. Adrienne Cupplessubject
LOCIMyocardial Infarction030204 cardiovascular system & hematologychemistry.chemical_compound0302 clinical medicineHigh-density lipoproteinGene Frequencyplasma HDL cholesterol ; mendelian randomisation ; MIHDL cholesterolsingle nucleotide polymorphismRisk FactorsGENETIC-VARIANTSARTERY-DISEASEProspective StudiesMyocardial infarction0303 health sciencesHDL cholesterol; myocardial infarction; single nucleotide polymorphismISCHEMIC CARDIOVASCULAR-DISEASEGeneral Medicine3. Good healthCardiologylipids (amino acids peptides and proteins)medicine.medical_specialtyDalcetrapibSingle-nucleotide polymorphismPolymorphism Single Nucleotide03 medical and health sciencesInternal medicinemedicineHumansCORONARY-HEART-DISEASEGenetic Predisposition to DiseaseMETAANALYSIS030304 developmental biologyBLOOD CHOLESTEROLbusiness.industryCholesterolCholesterol HDLCase-control studyCholesterol LDLLipaseOdds ratioMendelian Randomization Analysismedicine.diseaseENDOTHELIAL LIPASEATHEROSCLEROSISchemistryCase-Control StudiesbusinessHIGH-DENSITY-LIPOPROTEINBiomarkersEvacetrapibdescription
BACKGROUND: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. METHODS: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. FINDINGS: Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)). INTERPRETATION: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. FUNDING: US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-08-11 | The Lancet |