Common variation in the beta-carotene 15,15'-monooxygenase 1 gene affects circulating levels of carotenoids: a genome-wide association study

Abstract

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.

Figure 1

Associations between SNPs in and around the BCMO1 Gene and β-Carotene Levels Red triangles represent the –log10 p values from all SNPs passing QC in the GWAS InCHIANTI study. The stars represent the three-study meta-analysis p values of the four SNPs taken forward into the replication studies.

Figure 2

Molecular Structure of Carotenoids Measured in the Study β-carotene, α-carotene, and β-cryptoxanthin are considered potential vitamin A precursors because they contain at least one unsubstituted β-ionone ring and a polyene side chain attached to at least five conjugated double bonds. Note that the portion of the molecule shaded in gray is “equivalent” to retinol.

Figure 3

BCMO1-Catalyzed Central Cleavage of β-Carotene Forms Two Molecules of Retinal, Whereas the Cleavage of α-Carotene or β-cryptoxanthin Forms Only One Molecule of Retinal Within the enterocytes, retinal is transformed into retinol, and then retinyl-esters, before being packed into nascent chylomicrons and transported through the lymphatic system.