A quantitative trait locus on chromosome 11 is the major genetic determinant of homocysteine plasma levels. Results from the GAIT Project

Abstract number: OC160

Souto^* J., Blanco-Vaca^* F., Soria^* J. M., Buil^* A., Ordoñez-Llanos^* J., Lathrop† M., Almasy‡ L., Stone§ W., Blangero‡ J., Fontcuberta^* J.

†Centre National de Genotypage, France; ^*Hospital de la Santa Creu i Sant Pau, Spain; §Hospital de la Santa Creu i Sant Pau, USA ‡South-west Foundation for Biomedical Research, USA;

Plasma levels of homocysteine (Hcy) are associated with the risk of prevalent diseases like venous thrombosis, myocardial infarction, stroke and Alzheimer's disease. The level of Hcy is a quantitative phenotype determined by the interaction of genetic and environmental factors. Previous results from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project indicated that the phenotypic variation in Hcy plasma levels is in part due to the additive effect of genes. The MTHFR C677T polymorphism has been associated with moderate hyperhomocysteinemia, but it explains only a small proportion of the genetic effect on Hcy plasma level. We measured Hcy in 398 individuals in 21 Spanish families participating in the GAIT study. Twelve of these families were recruited through a proband with idiopathic thrombosis and nine were ascertained without regard to phenotype. A genome scan was performed using highly informative microsatellite DNA markers spaced at approximately 10 cM intervals on the 22 autosomal chromosomes. After a log transformation of the Hcy values, a multipoint variance component linkage analysis was performed using the SOLAR program. The heritability of ln Hcy was 34% (P < 0.0001). From the genome scan, we identified one linkage signal with a LOD score of 3.01 (nominal P = 0.0001) on chromosome 11. Another region on chromosome 10 showed a suggestive linkage signal with a maximum LOD score of 1.68 (P = 0.003). The locus containing the MTHFR gene on chromosome 1p36 had a LOD score of 1.03 (P = 0.015), confirming that this locus plays a significant, but minor, role in the genetic determination of Hcy plasma levels. These results indicate that a gene on chromosome 11 is the major genetic determinant of Hcy plasma levels in Spanish population. Fine linkage mapping should be performed to narrow the pertinent region on chromosome 11 and to identify the candidate gene. Then, DNA resequencing should be done to determine DNA sequence variation within this candidate gene and to describe the allelic architecture and the functional variants determining Hcy levels. These functional variants (polymorphism) should be considered genetic risk factors for cardiovascular diseases and possibly for Alzheimer's disease.