Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine. (April 2015)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Circulation. Volume 8:Number 2(2015)
• Publication Date: 2015-04
• Subjects: Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.1042
• DOI: 10.1161/CIRCGENETICS.114.000697
• Languages: English
• ISSNs: 1942-325X

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>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.</p> </sec> <sec> <title>Methods and Results—</title> <p>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 <italic>HAL</italic>, a gene that encodes histidine ammonia-lyase in the first step of histidine catabolism. These LoF variants had large effects on blood histidine levels (<italic>β</italic>=0.26; <italic>P</italic>=1.2×10<sup>−13</sup>). The positive association with histidine levels was replicated by genotyping an independent sample of 718 ARIC African Americans (minor allele frequency=1%; <italic>P</italic>=1.2×10<sup>−4</sup>). 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; <italic>P</italic>=1.9×10<sup>−4</sup>). This finding was validated in an independent sample of European Americans from the Framingham Heart Study (FHS) Offspring Cohort. However, LoF variants in <italic>HAL</italic> were not directly significantly associated with incident CHD after meta-analyzing results from the CHARGE Consortium.</p> </sec> <sec> <title>Conclusions—</title> <p>Three LoF mutations in <italic>HAL</italic> 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 <italic>HAL</italic> gene variation and CHD are warranted.</p> </sec> </abstract>