A genomewide exploration suggests a new candidate gene at chromosome 11q23 as the major determinant of plasma homocysteine levels: Results from the GAIT project

Juan Carlos Souto, Francisco Blanco-Vaca, José Manuel Soria, Alfonso Buil, Laura Almasy, Jordi Ordoñez-Llanos, Jesús Ma Martín-Campos, Mark Lathrop, William Stone, John Blangero, Jordi Fontcuberta

    Research output: Contribution to journalArticle

    85 Scopus citations

    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 Hey 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 Hey plasma levels. They strongly suggest that the NNMT gene could be a major genetic determinant of plasma Hey 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.

    Original languageEnglish (US)
    Pages (from-to)925-933
    Number of pages9
    JournalAmerican Journal of Human Genetics
    Volume76
    Issue number6
    DOIs
    StatePublished - Jun 2005

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)

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    Souto, J. C., Blanco-Vaca, F., Soria, J. M., Buil, A., Almasy, L., Ordoñez-Llanos, J., Martín-Campos, J. M., Lathrop, M., Stone, W., Blangero, J., & Fontcuberta, J. (2005). A genomewide exploration suggests a new candidate gene at chromosome 11q23 as the major determinant of plasma homocysteine levels: Results from the GAIT project. American Journal of Human Genetics, 76(6), 925-933. https://doi.org/10.1086/430409