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Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease.
Friday,2015-04-17 14:22 America/Los_Angeles — zdrager
| Title | Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease. |
| Publication Type | Journal Article |
| Year of Publication | 2015 |
| Authors | Yu, B, Li, AH, Muzny, D, Veeraraghavan, N, de Vries, PS, Bis, JC, Musani, SK, Alexander, D, Morrison, AC, Franco, OH, Uitterlinden, A, Hofman, A, Dehghan, A, Wilson, JG, Psaty, BM, Gibbs, R, Wei, P, Boerwinkle, E |
| Journal | Circ Cardiovasc Genet |
| Volume | 8 |
| Issue | 2 |
| Pagination | 351-5 |
| Date Published | 2015 Apr |
| ISSN | 1942-3268 |
| Keywords | Adult, African Americans, Alleles, Coronary Disease, European Continental Ancestry Group, Female, Histidine, Histidine Ammonia-Lyase, Humans, Male, Mutation |
| Abstract | <p><b>BACKGROUND: </b>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><p><b>METHODS AND RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>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.</p> |
| DOI | 10.1161/CIRCGENETICS.114.000697 |
| Alternate Journal | Circ Cardiovasc Genet |
| PubMed ID | 25575548 |
| PubMed Central ID | PMC4406800 |
| Grant List | AG023629 / AG / NIA NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States HG003273 / HG / NHGRI NIH HHS / United States HG004402 / HG / NHGRI NIH HHS / United States HG006542 / HG / NHGRI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States HHSN268201100005C / HL / NHLBI NIH HHS / United States HHSN268201100006C / HL / NHLBI NIH HHS / United States HHSN268201100007C / HL / NHLBI NIH HHS / United States HHSN268201100008C / HL / NHLBI NIH HHS / United States HHSN268201100009C / HL / NHLBI NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States HHSN268201100011C / HL / NHLBI NIH HHS / United States HHSN268201100012C / HL / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States HHSN268201300046C / HL / NHLBI NIH HHS / United States HHSN268201300047C / HL / NHLBI NIH HHS / United States HHSN268201300048C / HL / NHLBI NIH HHS / United States HHSN268201300049C / HL / NHLBI NIH HHS / United States HHSN268201300050C / HL / NHLBI NIH HHS / United States HL068986 / HL / NHLBI NIH HHS / United States HL080295 / HL / NHLBI NIH HHS / United States HL087652 / HL / NHLBI NIH HHS / United States HL102419 / HL / NHLBI NIH HHS / United States HL103612 / HL / NHLBI NIH HHS / United States HL105756 / HL / NHLBI NIH HHS / United States HL120393 / HL / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States N01HC55222 / HC / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N01HC85079 / HC / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01HC85080 / HC / NHLBI NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States N01HC85081 / HC / NHLBI NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States N01HC85082 / HC / NHLBI NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States N01HC85083 / HC / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States N01HC85086 / HC / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States R01 DK081572 / DK / NIDDK NIH HHS / United States R01 HL059367 / HL / NHLBI NIH HHS / United States R01 HL068986 / HL / NHLBI NIH HHS / United States R01 HL080295 / HL / NHLBI NIH HHS / United States R01 HL086694 / HL / NHLBI NIH HHS / United States R01 HL087641 / HL / NHLBI NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States R01 HL103612 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States R01 HL116720 / HL / NHLBI NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States R01DK081572 / DK / NIDDK NIH HHS / United States R01HL086694 / HL / NHLBI NIH HHS / United States R01HL087641 / HL / NHLBI NIH HHS / United States R01HL59367 / HL / NHLBI NIH HHS / United States RC2 HL102419 / HL / NHLBI NIH HHS / United States T32 HL007208 / HL / NHLBI NIH HHS / United States U01 HG004402 / HG / NHGRI NIH HHS / United States U01HG004402 / HG / NHGRI NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States U54 HG006542 / HG / NHGRI NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States UL1 TR000371 / TR / NCATS NIH HHS / United States UL1TR000124 / TR / NCATS NIH HHS / United States |