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Circ Cardiovasc Genet. 2015 Apr;8(2):351-5. doi: 10.1161/CIRCGENETICS.114.000697. Epub 2015 Jan 8.

Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease.

Author information

1
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.).
2
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.). Eric.Boerwinkle@uth.tmc.edu.

Abstract

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 (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.

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.

KEYWORDS:

coronary disease; histidine; histidine ammonia-lyase

PMID:
25575548
PMCID:
PMC4406800
DOI:
10.1161/CIRCGENETICS.114.000697
[Indexed for MEDLINE]
Free PMC Article

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