Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Science Center at Houston, Houston, Texas.
Genet Epidemiol. 2013 Dec;37(8):840-5. doi: 10.1002/gepi.21752. Epub 2013 Aug 11.
Both the prevalence and incidence of heart failure (HF) are increasing, especially among African Americans, but no large-scale, genome-wide association study (GWAS) of HF-related metabolites has been reported. We sought to identify novel genetic variants that are associated with metabolites previously reported to relate to HF incidence. GWASs of three metabolites identified previously as risk factors for incident HF (pyroglutamine, dihydroxy docosatrienoic acid, and X-11787, being either hydroxy-leucine or hydroxy-isoleucine) were performed in 1,260 African Americans free of HF at the baseline examination of the Atherosclerosis Risk in Communities (ARIC) study. A significant association on chromosome 5q33 (rs10463316, MAF = 0.358, P-value = 1.92 × 10(-10) ) was identified for pyroglutamine. One region on chromosome 2p13 contained a nonsynonymous substitution in N-acetyltransferase 8 (NAT8) was associated with X-11787 (rs13538, MAF = 0.481, P-value = 1.71 × 10(-23) ). The smallest P-value for dihydroxy docosatrienoic acid was rs4006531 on chromosome 8q24 (MAF = 0.400, P-value = 6.98 × 10(-7) ). None of the above SNPs were individually associated with incident HF, but a genetic risk score (GRS) created by summing the most significant risk alleles from each metabolite detected 11% greater risk of HF per allele. In summary, we identified three loci associated with previously reported HF-related metabolites. Further use of metabolomics technology will facilitate replication of these findings in independent samples.
心力衰竭（HF）的患病率和发病率都在增加，尤其是在非裔美国人中，但尚未有大规模的全基因组关联研究（GWAS）报道与 HF 相关的代谢物。我们试图确定与之前报道与 HF 发生率相关的代谢物相关的新遗传变异。在 ARIC 研究的基线检查中，对 1260 名无 HF 的非裔美国人进行了先前确定的三种代谢物（焦谷氨酸盐、二羟基二十二碳三烯酸和 X-11787，为羟基亮氨酸或羟基异亮氨酸）的 GWAS。在染色体 5q33 上发现了焦谷氨酸盐的显著关联（rs10463316，MAF = 0.358，P 值 = 1.92×10(-10)）。在染色体 2p13 上的一个区域包含 N-乙酰转移酶 8（NAT8）的非同义替换，与 X-11787 相关（rs13538，MAF = 0.481，P 值 = 1.71×10(-23)）。二羟基二十二碳三烯酸的最小 P 值是染色体 8q24 上的 rs4006531（MAF = 0.400，P 值 = 6.98×10(-7)）。上述 SNP 均未单独与 HF 的发生相关，但每个代谢物中最显著的风险等位基因相加的遗传风险评分（GRS）显示，每个等位基因 HF 的风险增加了 11%。总之，我们确定了三个与先前报道的 HF 相关代谢物相关的基因座。进一步使用代谢组学技术将有助于在独立样本中复制这些发现。
