Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 8, Issue 2, Pages 351-355Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.114.000697
Keywords
coronary disease; histidine; histidine ammonia-lyase
Funding
- National Heart, Lung, and Blood Institute [HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268 201100009C]
- National Human Genome Research Institute [U01HG004402]
- National Institutes of Health [HHSN268200625226C, R01DK081572, R01HL116720]
- National Genome Research Institute [HG004402]
- National Heart Lung and Blood Institute of the National Institute of Health [HL102419]
- National Human Genome Research Institute of the National Institute of Health [HG003273, HG006542]
- National Heart, Lung, and Blood Institute (NHLBI)
- Boston University [N01-HC-25195]
- NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL105756, HL103612, HL068986, HL120393]
- National Institute on Aging (NIA) [AG023629]
- National Center for Advancing Translational Sciences
- CTSI [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant [DK063491]
- Erasmus Medical Center
- Erasmus University, Rotterdam
- Netherlands Organization for the Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]
- Genetic Laboratory of the Department of Internal Medicine, Erasmus MC
- Netherlands Organization for Scientific Research (NWO) [184021007]
- Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL) [Rainbow Project (RP10]
- National Institute on Minority Health and Health Disparities
- NWO [916.12.154]
- EUR Fellowship
- National Heart, Lung, and Blood Institute. [R01HL59367, R01HL086694, HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201 300050C]
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Background-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. Methods and Results-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 (beta=0.26; P=1.2x10(-13)). The positive association with histidine levels was replicated by genotyping an independent sample of 718 ARIC African Americans (minor allele frequency=1%; P=1.2x10(-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=1.9x10(-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. Conclusions-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.
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