An investigation on the circulating transcriptome signatures in peripheral artery disease and the homocysteine pathway genomic signatures in coronary artery disease

Abstract

It is now ..... ell r«ognizcd that in vastllW discast. patients, c:oronary utery diseOlSC and paiphefll anay disease ol\cn coexiSL Due to poIy,mie inheritantt pauem, many ICnctic and enylronmental effects have cumillall~e effects in a particular yl$Cu!.ar discue phenotype. The aims of the present studin we~ to delineale aU the Kt'1lC$, ItId the variants in homocysteine pathway, that aWJ(:j,.tc witlt the peripltc1al ancry disease and coronary artery disease re$p«li~ely. De$pite the flCt lhat both IfC' sulxypn of cardi(l\'IS(;uiar di1cuc )-et the underlying ccnclic and rn~ironmenl.ll effeclJ an different and result in ~arying phenotypes. The rust pan of the scudy WIS carried OUI 111 Mayo Clinic Rochescet Minnesota. USA and focused on insight into the genetics ofperip/lo:fli astery di~a.sc: . WlIok IflUISCripl microarray 1«ltnoloaY was emplo)'ed for the cenetic anal)"Sis in 1'1'0 differenl groups of pmphml utery dl5C&S( eases and controls without diJca5c. ]n the firsl group nine cases UId nille control wbjects. .... hel'UJ in the 5Cl:0I\d group len CIlK5 and nine control subjects IOI"tl'e studied. This scudy rtpOrt5 for the fil'S! lime: the use of peripheral blood mononuckar cells for the ex~ profiling in peripltcfll arwy di~. The RNA _ a<lIKted from mononuclear cell, and was hybridized 10 AIT)lTletti)( expression ...... )'1. Tho: analysis of results. following stringent Sll.tistical analysis. re\'ealed a groupin, of thirty differentially regula1ed ~ne .... nscript, in both patient groups. Ooit of the thirty differentially regu'-tC(l transcripts, t ..... enl)' IWO tnln!iC:ripU were llpit'euJated.. se~en transcriptS were doWTIK&lIlated and one: trtlIllCripl .... as ul'lllnllOUllcd. te$pCCli\'Cly. £)(eludin& the gern: transcripts wilh kno .... n associations. this study proYides willt a IIOYCI set of fOlU'letrl uprtgulatcd genes and si~ dMl'Ilregulatw aenes wilh no previous knolOlTl association .... ilh the peripheral utei)' di5elSl!. The modulated pathways and the disease PIIthoIo&Y mediated by the implitaled genes include; immunil), aod inflammation, gene transcription, cell 8J'O"1h. eeltular mc:tabolism and sign.allinc, and cell dcathllpOptOSis. The highlighted genes and the pIIth"'ays moolll.1ed by these aenes lilly mhancc: the undcrslanding of disease causation and scntc as tar~ for earl)' di~ase $I1Itifltation in high risk indiyidlllls. The _and part ofthc scudy examined association ofhomocy Sleine pathwa), gene Yariant$ with coronary artery disease through the use of tetra primer AJU..1SPCR genot)'ping. Elevated blood homocysteine levels is. known coronary artery disease risk factor, and pol)'morphisms in homocysteine genes ~su1t in ele~atcd homocysteine Ie~els and high risk ofvllSCular disease. The srudy .. 'as perfonned in the Ph)'SioIoc labom«y, IXputmc:nl or BioIogicf,] Sciences Quaid-i-Alam University. Islamabad. Fi~ single nuclectick polymorphisms. in four homocysteinc pathw.y genes and 0IIIl pol)1T1orpllism in ACE Sene were studied bcause of their prior. known. association with CAD in world popu]"ions. A tOla] oflJO partkipanl5 were recruited from the tertiary can: hospiu.ls in Rawalpindi and IsllIlUIbad. These included 129 panicipillllS with coronary artery disease and 101 subjects without disease. Peripheral blood was obtained for DNA isolation and for analyses of Ktum pBnllllClCI'S. Tetra primer ARMS-PCR "115 used for allelk dis<:rimiNlion as it is a re:iatively new. rapid. re:lillble method and is mote lime. elTOI1 and COS! elTecd~ allele discrimination method as compared 10 con~mional approaches. Thc results of the sludy re:ve,].ed lluit two OUt of five single nuclCOlidc polymorph isms in homocysteine pathway genes and the variant in ACE gene were Issociated with risk of COfOIIIII')' artery diseue in the Pakistani population. Another sisniflcaru findinS was thaI senegene interaction I1C'Iworts.. in the studio:<! polymorph isms. were: addition,] modulators of coronary artery disease. This study is the first to report the usc of tetra primer ARMS-PCR for allele discrimination in homocysleillC pathway smes. and 10 rqIOrI the imponanec of these genes as risk flClOfS for COIOI\II)' artery disease in local population. The peripheral artery disease a.uociat~-d genes and implicaled pathways.. and the allelic variants in IIomocystcinc pathway may provide with insights inlo lhe progression ofcardiovascutar disease. add to the diaSOOS'ic tools and aid in designins management Sltatelics.