title: A genomewide exploration suggests a new candidate gene at chromosome 11q23 as the major determinant of plasma homocysteine levels: results from the GAIT project.
abstract: Homocysteine (Hcy) plasma level is an independent risk marker for venous thrombosis, myocardial infarction, stroke, congestive heart failure, osteoporotic fractures, and Alzheimer disease. Hcy levels are determined by the interaction of genetic and environmental factors. The genetic basis is still poorly understood, since only the MTHFR 677 C-->T polymorphism has been consistently associated with plasma Hcy levels. We conducted a genomewide linkage scan for genes affecting variation in plasma Hcy levels in 398 subjects from 21 extended Spanish families. A variance-components linkage method was used to analyze the data. The strongest linkage signal (LOD score of 3.01; genomewide P = .035) was found on chromosome 11q23, near marker D11S908, where a candidate gene involved in the metabolism of Hcy (the nicotinamide N-methyltransferase gene [NNMT]) is mapped. Haplotype analyses of 10 single-nucleotide polymorphisms within this gene found one haplotype associated with plasma Hcy levels (P = .0003). Our results, to our knowledge, represent the first genomic scan for quantitative variation in Hcy plasma levels. They strongly suggest that the NNMT gene could be a major genetic determinant of plasma Hcy levels in Spanish families. Since this gene encodes an enzyme involved in Hcy synthesis, this finding would be consistent with known biochemical pathways. These data could be relevant in determining the relationships between Hcy level, cardiovascular disease, osteoporosis, and Alzheimer disease.
authors.affiliation: Unitat de Trombosi i Hemostàsia, Departament d' Hematologia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. jsouto@hsp.santpau.es
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Souto
authors.forename: Francisco
authors.initials: F
authors.lastname: Blanco-Vaca
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Soria
authors.forename: Alfonso
authors.initials: A
authors.lastname: Buil
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.forename: Jordi
authors.initials: J
authors.lastname: Ordoñez-Llanos
authors.forename: Jesús Ma
authors.initials: JM
authors.lastname: Martín-Campos
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: William
authors.initials: W
authors.lastname: Stone
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.forename: Jordi
authors.initials: J
authors.lastname: Fontcuberta
mesh_terms: D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D015971:Gene Expression Regulation, Enzymologic; D008040:Genetic Linkage; D005819:Genetic Markers / Q000235:genetics; D014644:Genetic Variation; D015894:Genome, Human; D006239:Haplotypes; D006579:Heterozygote; D006710:Homocysteine / Q000097:blood* / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008780:Methyltransferases / Q000235:genetics; D008954:Models, Biological; D050903:Nicotinamide N-Methyltransferase; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013030:Spain; D019851:Thrombophilia / Q000097:blood / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D006710:Homocysteine; D008780:Methyltransferases; C494406:NNMT protein, human; D050903:Nicotinamide N-Methyltransferase