Novel Associations of CPS1, MUT, NOX4, and DPEP1 With Plasma Homocysteine in a Healthy Population
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abstract
Background—
Homocysteine is a sulfur amino acid whose plasma concentration has been associated with the risk of cardiovascular diseases, neural tube defects, and loss of cognitive function in epidemiological studies. Although genetic variants of
MTHFR
and
CBS
are known to influence homocysteine concentration, common genetic determinants of homocysteine remain largely unknown.
Methods and Results—
To address this issue comprehensively, we performed a genome-wide association analysis, testing 336 469 single-nucleotide polymorphisms in 13 974 healthy white women. Although we confirm association with
MTHFR
(1p36.22; rs1801133;
P
=8.1�10
−35
) and
CBS
(21q22.3; rs6586282;
P
=3.2�10
−10
), we found novel associations with
CPS1
(2q34; rs7422339;
P
=1.9�10
−11
),
MUT
(6p12.3; rs4267943;
P
=2.0�10
−9
),
NOX4
(11q14.3; rs11018628;
P
=9.6�10
−12
), and
DPEP1
(16q24.3; rs1126464;
P
=1.2�10
−12
). The associations at
MTHFR
,
DPEP1
, and
CBS
were replicated in an independent sample from the PROCARDIS study, whereas the association at
CPS1
was only replicated among the women.
Conclusions—
These associations offer new insight into the biochemical pathways involved in homocysteine metabolism and provide opportunities to better delineate the role of homocysteine in health and disease.
