Yu Bing, Li Alexander H, Muzny Donna, Veeraraghavan Narayanan, de Vries Paul S, Bis Joshua C, Musani Solomon K, Alexander Danny, Morrison Alanna C, Franco Oscar H, Uitterlinden André, Hofman Albert, Dehghan Abbas, Wilson James G, Psaty Bruce M, Gibbs Richard, Wei Peng, Boerwinkle Eric
From the Human Genetics Center (B.Y., A.H.L., A.C.M., P.W., E.B.) and Division of Biostatistics (P.W.), School of Public Health, University of Texas Health Science Center at Houston; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX (D.M., N.V., R.G., E.B.); Department of Epidemiology (P.S.d.V., O.H.F., A.U., A.H., A.D.) and Department of Internal Medicine (A.U.), Erasmus MC, Rotterdam, the Netherlands; Cardiovascular Health Research Unit (J.C.B., B.M.P.), Department of Epidemiology (B.M.P.), and Department of Health Services (B.M.P.), University of Washington, Seattle; Jackson Heart Study (S.K.M.) and Department of Physiology and Biophysics (J.G.W.), University of Mississippi Medical Center Jackson, Metabolon, Inc., Durham, NC (D.A.); and Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.).
Circ Cardiovasc Genet. 2015 Apr;8(2):351-5. doi: 10.1161/CIRCGENETICS.114.000697. Epub 2015 Jan 8.
Histidine is a semiessential amino acid with antioxidant and anti-inflammatory properties. Few data are available on the associations between genetic variants, histidine levels, and incident coronary heart disease (CHD) in a population-based sample.
By conducting whole exome sequencing on 1152 African Americans in the Atherosclerosis Risk in Communities (ARIC) study and focusing on loss-of-function (LoF) variants, we identified 3 novel rare LoF variants in HAL, a gene that encodes histidine ammonia-lyase in the first step of histidine catabolism. These LoF variants had large effects on blood histidine levels (β=0.26; P=1.2×10(-13)). The positive association with histidine levels was replicated by genotyping an independent sample of 718 ARIC African Americans (minor allele frequency=1%; P=1.2×10(-4)). In addition, high blood histidine levels were associated with reduced risk of developing incident CHD with an average of 21.5 years of follow-up among African Americans (hazard ratio=0.18; P=1.9×10(-4)). This finding was validated in an independent sample of European Americans from the Framingham Heart Study (FHS) Offspring Cohort. However, LoF variants in HAL were not directly significantly associated with incident CHD after meta-analyzing results from the CHARGE Consortium.
Three LoF mutations in HAL were associated with increased histidine levels, which in turn were shown to be inversely related to the risk of CHD among both African Americans and European Americans. Future investigations on the association between HAL gene variation and CHD are warranted.
组氨酸是一种具有抗氧化和抗炎特性的半必需氨基酸。在基于人群的样本中，关于基因变异、组氨酸水平与冠心病（CHD）发病之间关联的数据较少。
通过对社区动脉粥样硬化风险（ARIC）研究中的1152名非裔美国人进行全外显子组测序，并聚焦于功能丧失（LoF）变异，我们在HAL基因中鉴定出3个新的罕见LoF变异，HAL基因在组氨酸分解代谢的第一步中编码组氨酸解氨酶。这些LoF变异对血液组氨酸水平有很大影响（β=0.26；P=1.2×10⁻¹³）。通过对718名ARIC非裔美国人的独立样本进行基因分型，复制了与组氨酸水平的正相关关系（次要等位基因频率=1%；P=1.2×10⁻⁴）。此外，在非裔美国人平均21.5年的随访中，高血液组氨酸水平与冠心病发病风险降低相关（风险比=0.18；P=1.9×10⁻⁴）。这一发现在美国弗明汉心脏研究（FHS）子代队列的欧洲裔美国人独立样本中得到验证。然而，在对CHARGE联盟的结果进行荟萃分析后，HAL基因中的LoF变异与冠心病发病没有直接显著关联。
HAL基因中的3个LoF突变与组氨酸水平升高相关，而组氨酸水平升高又被证明与非裔美国人和欧洲裔美国人的冠心病风险呈负相关。未来有必要对HAL基因变异与冠心病之间的关联进行进一步研究。
