A Genome-Wide Linkage Scan for Homocysteine Levels Identifies Three Regions of Interest

Abstract number: OR127

Vermeulen¹ HHM, van der Vleuten² GM, de Graaf² J, Blom³ HJ, Hermus¹ AR, Stalenhoef² AF, den Heijer^1,4 M

^1,41Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands ¹¹Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands ²²Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands ³³Laboratory of Pediatrics and Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

A high homocysteine level is a risk factor for many clinical conditions, including venous thrombosis. Homocysteine levels are under control of genetic and environmental factors. Extensive candidate gene studies have identified genetic variants that influence homocysteine levels, including the MTHFR677C > T polymorphism, but so far only a part of the genetic variation in homocysteine can be explained. In order to identify chromosomal regions that influence the plasma homocysteine level without the necessity of advanced knowledge of candidate genes, a genome wide linkage analysis was conducted. A datafile consisting of 13 pedigrees and 469 subjects with plasma homocysteine measurements was available. A set of 377 markers covering the genome was genotyped in 275 subjects. Heritability was estimated and twopoint and multipoint linkage analyses were performed using the variance component linkage method (SOLAR version 2.1.3). The heritability of the age and sex adjusted homocysteine levels was 44% (P= 7.7 × 10^-11). One region with suggestive linkage with homocysteine levels was identified on chromosome 16 (LOD score 1.76; nominal P= 0.0024). Further, indications of linkage with regions on chromosome 12 (LOD score 1.57; nominal P= 0.0036) and chromosome 13 (LOD score 1.52; nominal P= 0.0041) were found.

The homocysteine level in our dataset was highly heritable. The genetic linkage analysis identified three regions that show suggestive evidence of linkage with plasma homocysteine levels.