A Genomewide Exploration Suggests a New Candidate Gene at Chromosome 11q23 as the Major Determinant of Plasma Homocysteine Levels: Results from the GAIT Project
| Autor: | Jordi Fontcuberta, Laura Almasy, John Blangero, Jordi Ordóñez-Llanos, Alfonso Buil, W. H. Stone, Jesús M. Martín-Campos, Juan Carlos Souto, José Manuel Soria, Francisco Blanco-Vaca, Mark Lathrop |
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| Rok vydání: | 2005 |
| Předmět: |
Genetic Markers
Heterozygote Candidate gene Homocysteine Genetic Linkage 030204 cardiovascular system & hematology Models Biological Polymorphism Single Nucleotide Gene Expression Regulation Enzymologic Genetic determinism 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Risk Factors Genetic linkage Genetic variation Nicotinamide N-Methyltransferase Genetics Humans Thrombophilia Genetics(clinical) Genetics (clinical) 030304 developmental biology 0303 health sciences biology Genome Human Chromosomes Human Pair 11 Haplotype Chromosome Mapping Genetic Variation Methyltransferases Articles 3. Good health Haplotypes chemistry Spain Genetic marker Methylenetetrahydrofolate reductase biology.protein Lod Score |
| Zdroj: | The American Journal of Human Genetics. 76:925-933 |
| ISSN: | 0002-9297 |
| DOI: | 10.1086/430409 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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