Short Report Single nucleotide polymorphism in CTH associated with variation in plasma homocysteine concentration J Wang a , AM Huff a , JD Spence b and RA Hegele a a Blackburn Cardiovascular Genetics Laboratory, and b Stroke Prevention and Atherosclerosis Research Center, Robarts Research Institute, London, Ontario, Canada Key words: atherosclerosis – complex trait – cystathioninuria – risk factor – trans-sulfuration Corresponding author: Robert A Hegele, MD, FRCPC, FACP, 406-100 Perth Drive, London, Ontario, Canada N6A 5K8. Tel.: þ1 519 663 3461; fax: þ1 519 663 3037; e-mail: hegele@robarts.ca Received 14 January 2004, revised and accepted for publication 23 February 2004 WangJ,HuffAM,SpenceJD,HegeleRA.Singlenucleotide polymorphism in CTH associatedwithvariationinplasma homocysteine concentration. ClinGenet2004:65:483–486 # Blackwell Munksgaard, 2004 Plasma total homocysteine (tHcy) concentration, an independent risk factorofatherosclerosis,hasnumerousgeneticandenvironmental determinants. While the thermolabile polymorphism in MTHFR encodingmethylenetetrahydrofolatereductaseisthebest-studiedgenetic factorassociatedwithvariationinplasmatHCy,othercandidategenes arebeingevaluated.Recently,wediscoveredthatcystathioninuriawas causedbymutationsinthe CTH geneencodingcystathionine g-lyase,an enzymethatconvertscystathioninetocysteineinthetrans-sulfuration pathway.Wealsoidentifiedacommonsinglenucleotidepolymorphism (SNP),namelyc.1364G>T(S403I)inexon12of CTH.Inthecurrent analysis,westudiedtheassociationofgenotypesofthisSNPwith plasmatHcyconcentrationsin496Caucasiansubjects. CTH 1364T/T homozygotes had significantly higher mean plasma tHcy concentration thansubjectswithothergenotypes,andtheeffectsizesof CTH and MTHFR genotypesweresimilar.Thefindingssuggestthatcommon variationin CTH maybeadeterminantofplasmatHcyconcentrations. Atherosclerosis is a complex process with many determinants (1), including elevated plasma concentrations of total homocysteine (tHcy) (2). Homocysteine is an intermediate metabolite in the trans-sulfuration pathway that converts methioninetocysteine.Theadditiontohomocys- teine of serine by the pyridoxal phosphate- dependentenzymecystathionine b-synthase(CBS) producescystathionine,whichinturnisconverted into cysteine by cystathionine g-lyase (CTH) (3). Homocysteinecaneitherberemethylatedbackto methionine by the enzyme methionine synthase (MTH) or can undergo trans-sulfuration to produce cystathionine (3). Thus, many enzymes can affect plasma tHcy concentrations and each enzyme identifies a potential candidate gene for evaluation of genetic determinants of plasma tHcy. Rare mutations in CBS and MTH cause hyperhomocysteinemia (4, 5). Among common geneticvariants,the677C>Tthermolabilevariant in MTHFR encoding methylenetetrahydrofolate has been relatively consistently associated with increased plasma tHcy (6). In addition, common variants in the genes encoding betaine-homo- cysteinemethyltransferase, methionine synthase, methionine synthase, glutamate carboxypeptidase andtranscobalaminarebeginningtobestudiedfor theirassociationwithplasmatHcy(7–10). Wediscoveredthatraremutationsin CTH cause cystathioninuria (11). In the course of that work, we identified a common non-synonymous single nucleotide polymorphism (SNP) in exon 12 of CTH, namely c.1364G>T (trivial name S403I) (11). Because plasma tHcy and cystathionine are sometimes increased together (12–14), we hypo- thesized that genotypes of CTH c.1364G>T wouldbeassociatedwithvariationinplasmatHcy. Materials and methods Study subjects Samplesof496predominantlyCaucasiansubjects who previously had plasma tHcy determinations Clin Genet 2004: 65: 483–486 Copyright # Blackwell Munksgaard 2004 Printed in Denmark. All rights reserved CLINICAL GENETICS doi: 10.1111/j.1399-0004.2004.00250.x 483