Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma homocysteine in a healthy population: a genome-wide evaluation of 13 974 participants in the Women's Genome Health Study.
Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma homocysteine in a healthy population: a genome-wide evaluation of 13 974 participants in the Women's Genome Health Study.
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DOI：
10.1161/circgenetics.108.829804
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发表时间：
2009-04
期刊：
影响因子：
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通讯作者：
Ridker PM
中科院分区：
文献类型：
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作者：
Paré G;Chasman DI;Parker AN;Zee RR;Mälarstig A;Seedorf U;Collins R;Watkins H;Hamsten A;Miletich JP;Ridker PM
同型半胱氨酸是一种含硫氨基酸，在流行病学研究中，其血浆浓度与心血管疾病、神经管缺陷和认知功能丧失的风险有关。虽然已知MTHFR和CBS的遗传变异会影响同型半胱氨酸浓度，但同型半胱氨酸的共同遗传决定因素在很大程度上仍然未知。为了全面解决这一问题，我们进行了全基因组关联分析，在13,974名健康高加索女性中检测了336,469个snp。虽然我们证实了与MTHFR （1p36.22; rs1801133; p=8.1 × 10−35）和CBS （21q22.3; rs6586282; p=3.2 × 10−10）的关联，但我们发现了与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）和DPEP1 （16q24.3; rs1126464; p=1.2 × 10−12）的新关联。MTHFR、DPEP1和CBS的相关性在PROCARDIS研究的独立样本中得到了重复，而CPS1的相关性仅在女性中得到了重复。这些关联为同型半胱氨酸代谢的生化途径提供了新的见解，并为更好地描述同型半胱氨酸在健康和疾病中的作用提供了机会。
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. While genetic variants of MTHFR and CBS are known to influence homocysteine concentration, common genetic determinants of homocysteine remain largely unknown. To address this issue comprehensively, we performed a genome wide association analysis, testing 336,469 SNPs in 13,974 healthy Caucasian women. While 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. These associations offer new insights into the biochemical pathways involved in homocysteine metabolism and provide opportunities to better delineate the role of homocysteine in health and disease.