Common variation in the beta-carotene 15,15'-monooxygenase 1 gene affects circulating levels of carotenoids: a genome-wide association study.
Low plasma levels of carotenoids and tocopherols are associated with increased risk of chronic disease and disability. Because dietary intake of these lipid-soluble antioxidant vitamins is only poorly correlated with plasma levels, we hypothesized that circulating carotenoids (vitamin A-related compounds) and tocopherols (vitamin E-related compounds) are affected by common genetic variation. By conducting a genome-wide association study in a sample of Italians (n = 1190), we identified novel common variants associated with circulating carotenoid levels and known lipid variants associated with alpha-tocopherol levels. Effects were replicated in the Women's Health and Aging Study (n = 615) and in the alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) study (n = 2136). In meta-analyses including all three studies, the G allele at rs6564851, near the beta-carotene 15,15'-monooxygenase 1 (BCMO1) gene, was associated with higher beta-carotene (p = 1.6 x 10(-24)) and alpha-carotene (p = 0.0001) levels and lower lycopene (0.003), zeaxanthin (p = 1.3 x 10(-5)), and lutein (p = 7.3 x 10(-15)) levels, with effect sizes ranging from 0.10-0.28 SDs per allele. Interestingly, this genetic variant had no significant effect on plasma retinol (p > 0.05). The SNP rs12272004, in linkage disequilibrium with the S19W variant in the APOA5 gene, was associated with alpha-tocopherol (meta-analysis p = 7.8 x 10(-10)) levels, and this association was substantially weaker when we adjusted for triglyceride levels (p = 0.002). Our findings might shed light on the controversial relationship between lipid-soluble anti-oxidant nutrients and human health.
Ferrucci
Luigi
L
Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, United States of America. ferruccilu@grc.nia.nih.gov
Perry
John R B
JR
Matteini
Amy
A
Perola
Markus
M
Tanaka
Toshiko
T
Silander
Kaisa
K
Rice
Neil
N
Melzer
David
D
Murray
Anna
A
Cluett
Christie
C
Fried
Linda P
LP
Albanes
Demetrius
D
Corsi
Anna-Maria
AM
Cherubini
Antonio
A
Guralnik
Jack
J
Bandinelli
Stefania
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Singleton
Andrew
A
Virtamo
Jarmo
J
Walston
Jeremy
J
Semba
Richard D
RD
Frayling
Timothy M
TM
D002338:Carotenoids / Q000097:blood*; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D007408:Intestinal Absorption; D020641:Polymorphism, Single Nucleotide; D024502:alpha-Tocopherol / Q000097:blood* / Q000378:metabolism; D019207:beta Carotene / Q000097:blood; D050559:beta-Carotene 15,15'-Monooxygenase / Q000235:genetics* / Q000378:metabolism
D019207:beta Carotene; D002338:Carotenoids; C493358:BCO1 protein, human; D050559:beta-Carotene 15,15'-Monooxygenase; D024502:alpha-Tocopherol