A genome-wide linkage scan for homocysteine levels suggests three regions of interest.
BACKGROUND
An elevated plasma total homocysteine (tHcy) level is a risk factor for many clinical conditions, including vascular disease and venous thrombosis. The tHcy levels are partly determined by genetic factors. Extensive candidate gene studies have identified several genetic variants, including the MTHFR 677C>T, that influence tHcy levels, but so far only part of the genetic variation in tHcy can be explained.


OBJECTIVE
In order to identify chromosomal regions that influence tHcy levels, a genome-wide linkage analysis was conducted.


METHODS
Our study population consisted of 13 pedigrees and 469 subjects with data on fasting plasma tHcy levels. A set of 377 markers covering the genome was genotyped in 275 subjects. The variance component linkage method (SOLAR version 2.1.3) was used for the two-point and multipoint linkage analyses.


RESULTS
The heritability of the age- and sex-adjusted homocysteine levels was 44%. The multipoint linkage analysis identified one region with suggestive linkage on chromosome 16q (LOD score 1.76; nominal P = 0.0024). Weaker evidence of linkage was found for regions on chromosome 12q (LOD score 1.57; nominal P = 0.0036) and chromosome 13q (LOD score 1.52; nominal P = 0.0041).


CONCLUSIONS
In our families the plasma tHcy level was highly heritable. The multipoint linkage analysis identified three regions that showed weak to suggestive linkage to tHcy levels.
Vermeulen
S H H M
SH
Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands. h.vermeulen@endo.umcn.nl
van der Vleuten
G M
GM
de Graaf
J
J
Hermus
A R
AR
Blom
H J
HJ
Stalenhoef
A F H
AF
den Heijer
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human; D005838:Genotype; D006710:Homocysteine / Q000097:blood / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D010375:Pedigree; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci
D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)