Donna K. Arnett
Summary of the American Heart Association’s Scientific Statement on the Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease
University of Alabama at Birmingham
homearteriosclerosis thrombosis vascular biologyvol 27 8summary american heart associations scientific statement relevance genetics genomics prevention treatment cardiovascular disease free accesseditorialpdfepubaboutview pdfview epubsections toolsadd favoritesdownload citationstrack citationspermissions shareshare onfacebooktwitterlinked inmendeleyreddit jump tofree accesseditorialpdfepubsummary american heart associations scientific statement relevance genetics genomics prevention treatment cardiovascular disease donna k arnett donna k arnettdonna k arnett department epidemiology dka university alabama birmingham department epidemiology dka university alabama birmingham writing group originally published1 aug 2007httpsdoiorg101161atvbaha107147207arteriosclerosis thrombosis vascular biology 20072716821686atherosclerotic cardiovascular disease cvd major health problem united states around world12 development cvd complex process evidence demonstrates family history associated cvd3 several mendelian disorders contribute cvd although mutations rare large relative risk common forms cvd however believed multifactorial result many genes small effect working alone combination modifier genes environmental factorssee circulation 200711528782901two main approaches used discover genetic influences cvd figure genomewide linkage gene association studies discovery new genes frequently used method genomewide linkage conducted using genetic phenotypic data families linkage analysis hypothesisgenerating method intended localize genomic regions might contain genes influencing trait likely regions discovered efforts shift identifying causative genes gene maps scrutinized candidate genes within regions interest identified based prior knowledge gene function candidate gene association studies designed compare genotype frequencies case control groups statistical difference frequencies cases controls offers evidence genotype associated trait download figuredownload powerpointfigure fundamentals techniques used discovery genetic basis cvd adapted permission arnett dk baird ae barkley ra basson ct boerwinkle e ganesh sk herrington dm hong jaquish c mcdermott da odonnell cj relevance genetics genomics prevention treatment cardiovascular disease scientific statement american heart association council epidemiology prevention stroke council functional genomics translational biology interdisciplinary working group circulation 200711528782901 copyright 2007 american heart associationthree examples genetically complex forms cvdmyocardial infarction atherosclerotic cvdalthough clear mendelian pattern inheritance myocardial infarction mi atherosclerotic cvd substantial evidence familial component diseases particularly early age onset46 evidence linkage observed chromosomes 1 2 3 13 14 16 x although strong replication single chromosomal region714 finescale linkage mapping identified potentially causal gene alox5ap implicated mi stroke12 although evidence linkage strong association variants alox5ap locus mi stroke replicated studies1516 linkage studies also conducted subclinical atherosclerotic cvd although studies reported1718 large number candidate gene association studies conducted mi atherosclerotic cvd however relatively gene associations replicated19 studies summarized recent reviews2021 variants apoe22pai123ace24 mthfr genes25 examined metaanalyses overall magnitude association common polymorphisms modesthypercholesterolemia lipid phenotypesmendelian forms hypercholesterolemia thoroughly studied number well documented example familial hypercholesterolemia fh common mendelian form hypercholesterolemia caused mutations ldlr fh causes elevated serum ldlc however prevalence monogenic disorders ranging 000002 02 monogenic forms account fraction observed hypercholesterolemia many linkage scans sought genes modest dyslipidemic effects several suggestive significant regions implicated however causal genes remain elusive data associations dozens gene variants lipid related traits reviewed26 many studies conducted consistent evidence apoe genehypertensiongenetic factors account approximately 30 population variability blood pressure27 several mendelian forms hypertension identified28 example liddle syndrome form hypertension increased activity amilioridesensitive epithelial sodium channel attributable mutations scnn1b gene29 blood pressure maintained intricate network physiological systems however multiple genes interactions likely contribute essential hypertension suggestive linkage evidence hypertension susceptibility genes spread across genome family blood pressure program conducted finescale linkage mapping identified slc4a5 gene important candidate hypertension30 candidate gene association studies served connect specific genes high blood pressure however 2 phenotypes almost every published positive result followed negative result31 luft32 turner boerwinkle33 kaplan et al34 published reviews candidate gene work related hypertension focused various renal sodium transport proteins members reninangiotensinaldosterone system raas34 however many complex interactions raas pathways systems yet elucidatedconclusions three examplesfinding genes influencing mi atherosclerotic cvd lipids blood pressure linkage candidate gene studies somewhat successful future efforts take advantage explosive growth genomic resources advanced statistical methods inconsistency findings observed across genetic genomic studies cvd likely indicative genetic heterogeneity complex traits genegene geneenvironment interactions exist negative results may stem genes whose relative phenotypic effects smaller presence specific genetic environmental backgroundscurrent areas focus genetics cvdgeneenvironment interactiongeneenvironment interaction occurs genotype produces different phenotype different environmental exposures age pharmacological treatment interventional studies identify geneenvironment interactions provide evidence translation findings clinical practice example blood pressure response lowsodium diet shown vary polymorphisms agt results dietary approaches stop hypertension dash study showed agt 6 aa genotype associated significant decrease blood pressure individuals dash diet35 similar approaches evaluating response dietary fat intake36 physical activity37 demonstrated variable efficacy according genotype although considerable amount work remains done elucidate genes optimal interventions address genetic riskpharmacogeneticspharmacogenetics study genetic determinants individual variation response drugs example cyp2d6 facilitates oxidative metabolism cvd drugs including flecainide propafenone blockers3840 depending population studied 1 10 subjects variant producing rapid extensive metabolizing phenotype examples documented41 however still lack research provides evidence justify incorporation pharmacogenetic testing routine clinical practice given large number cvd drugs available large number patients eligible receive drugs even small variations drug efficacy safety important implications clinical public health therefore make pharmacogenetic research potentially valuablewholegenome association resequencing expression profiling studiestechnological advances led development lowcost dense genotyping arrays 500000 singlenucleotide polymorphisms snps cover majority genome42 complex diseases wholegenome association studies type hundreds thousands variants provide excellent power markedly exceeding power linkage methodology identify genes modest effect43 example study 100000 snps led discovery variant nos1ap gene underlying qtinterval length ecg finding replicated cohorts44 studies provide proof principle potential wholegenome association studies discovery novel genetic determinants cvd rapidly growing number wholegenome association studies underway diseasebased casecontrol studies large populationswholegenome resequencing would resolve question regarding relative contribution rare common variants common cvd present wholegenome resequencing prohibitively expensive45 however several studies performed focused resequencing coding regions candidate genes4647 studies laying groundwork far extensive studies may provide fully personalized characterization individuals genome costs longer prohibitively highgene expression profiling creates snapshot rate genes expressed tissue sample gene expression changes pathological conditions gene expression profiling point genes may involved disease pathogenesis example acute stroke associated upregulation genes related white blood cell activation differentiation upregulation genes response altered cerebral microenvironment48 gene expression profiling potential application clinical practice specific molecular clinically meaningful cvd signatures developed49genetic counselingas dnabased testing moves toward risk assessment diagnosis clinic demand genetic counseling likely grow although counseling complex genetic diseases still hypothetical stage discipline draw experiences disorders familial hypercholesterolemia venous thromboembolism develop approaches genetically complex diseases guiding principles apposite testing counseling contextssuch restricting screening highrisk individuals concomitant assessment nongenetic factors appropriate consideration screening family memberswill also inform counseling practice complex cvdsrecommendations future practice researchwe conclude editorial set recommendations intended help incorporate knowledge clinical public health practice foster guide research prepare researchers practitioners changes likely occur molecular genetics moves laboratory clinic continue use family history tool identify susceptible individuals familiesdevelop research infrastructure includes following incentives researchers assemble multidisciplinary collaborative research teams incentives researchers currently conducting genetic research collect dna consent use specimens data future studies incentives researchers undertake translational research publicprivate partnerships expedite translation geneticgenomic findings clinical public health practiceprioritize following research agendas characterize genetic variants associated cvd across individuals communities populations evaluate behavioral environmental factors interact genes influence cvd risk develop new technologies cvd characterization risk assessment outcome prediction assess genedrug interaction impact findings intervention strategies drug development develop new methods analyze understand wealth breadth complexity genetic dataprepare proactively effective genetic screening programs establish prevalence criteria trigger screening programs atrisk populations create standards laboratory oversight mechanisms genetic testing facilities match appropriate treatment guidelines particular genetic susceptibility findings assess potential cost effectiveness genetic screening programseducate researchers clinicians public health professionals general public effective researchers must proficient genetic epidemiology computational biology statistical genetics clinicians become aware genetic tools disposal understand put use results genetic screening complex cvds graduate educational curricula include population biology genetics public health professionals must continue incorporate genetic knowledge understanding population risk cvds general public need basic genetic literacy understand technical negotiate ethical aspects molecular genetic screeningdisclosureswriting group disclosureswriting group memberemploymentresearch grantother research supportspeakers bureauhonorariaownership interestconsultantadvisory boardotherthis table represents relationships writing group members may perceived actual reasonably perceived conflicts interest reported disclosure questionnaire members writing group required complete submitdonna k arnettuniversity alabama school public healthnonenonenonenonenonenoneallison e bairdnational institute neurological disorders strokenonenonenonenonenonenoneruth barkleyuniversity texas health science center houstonnonenonenonenonenonenonecraig bassonweill medical college cornell universitynonereynolds foundationnonenonenonenoneeric boerwinkleuniversity texas health science center houstonnonenonenonenonecelere dxnonesanthi k ganeshnational heart lung blood institutenonenonenonenonenonenonedavid herringtonwake forest university school medicinenonenonenonenonenonenoneyuling hongamerican heart associationnonenonenonenonenonenonecashell jaquishnational institutes healthnational heart lung blood institutenonenonenonenonenonenonedeborah mcdermottweill medical college cornell universitynonenonenonenonenonenonechristopher j odonnellnational heart lung blood institutenonenonenonenonenonenonereviewer disclosuresrevieweremploymentresearch grantother research supportspeakers bureauhonorariaexpert witnessownership interestconsultantadvisory boardotherthis table represents relationships reviewers may perceived actual reasonably perceived conflicts interest reported disclosure questionnaire reviewers required complete submitdaniel oconnoruniversity california san diegononenonenonenonenonenonenonebruce psatyuniversity washingtonnonenonenonenonenonenonenonealan wederuniversity michigannonenonenonenonenonenonenonefootnotescorrespondence dr donna k arnett university alabama birmingham department epidemiology 1665 university blvd birmingham al 35294 email email protected references 1 thom haase n rosamond w howard vj rumsfeld j manolio zheng zj flegal k odonnell c kittner lloydjones goff dc jr hong adams r friday g furie k gorelick p kissela b marler j meigs j roger v sidney sorlie p steinberger j wasserthielsmoller wilson wolf p heart disease stroke statistics 2006 update report american heart association statistics committee stroke statistics subcommittee circulation 2006 113 e85e151linkgoogle scholar2 murray cj lopez ad global mortality disability contribution risk factors global burden disease 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