Single Nucleotide Polymorphisms Upstream from the β-Carotene 15,15'-Monoxygenase Gene Influence Provitamin A Conversion Efficiency in Female Volunteers4

Abstract

β-Carotene, the most abundant provitamin A carotenoid in the diet, is converted to retinal by β-carotene 15,15'-monoxygenase (BCMO1). However, β-carotene absorption and conversion into retinal is extremely variable among individuals, with proportions of low responders to dietary β-carotene as high as 45%. Recently, 2 common nonsynonymous single nucleotide polymorphisms (SNPs) within the BCMO1 coding region (R267S; rs12934922 and A379V; rs7501331) revealed reduced catalytic activity, confirming that genetic variations contribute to the low responder phenotype. Because 4 SNPs 5' upstream from the BCMO1 gene were recently shown to affect circulating carotenoid concentrations, the current study aimed to investigate the effects of these SNPs on β-carotene conversion efficiency. Three of the 4 polymorphisms (rs6420424, rs11645428, and rs6564851) reduced the catalytic activity of BCMO1 in female volunteers by 59, 51, and 48%, respectively. The TG-rich lipoprotein fraction retinyl palmitate:β-carotene ratio was negatively correlated with the G allele of rs11645428 (r = -0.44; P = 0.018), whereas it was positively correlated with the G allele of rs6420424 (r = 0.53; P = 0.004) and the T allele of rs6564851 (r = 0.41; P = 0.028). Furthermore, large inter-ethnic variations in frequency of affected alleles were detected, with frequencies varying from 43 to 84% (rs6420424), 52 to 100% (rs11645428), and 19 to 67% (rs6564851). In summary, a range of SNPs can influence the effectiveness of using plant-based provitamin A carotenoids to increase vitamin A status in at-risk population groups and this effect may vary depending on ethnic origin.

β-Carotene 15,15′-monooxygenase 1 single nucleotide polymorphisms in relation to plasma carotenoid and retinol concentrations in women of European descent

“…Rs4889286 or rs56389940, in composite LD with rs6564851 and in the same upstream area, was selected for the b-carotene, a-carotene, and lutein/zeaxanthin gene scores. SNPs upstream of BCMO1, rs7501331 + rs12934922, and rs7501331 alone were previously reported to reduce BCMO1 activity and were associated with fasting plasma b-carotene (7,9). Here, the rs12934922 T allele was positively associated with plasma b-carotene, and either rs12934922 or rs4889293, in composite LD with rs12934922, was selected for the provitamin A carotene gene scores.…”

“…Additionally, through a genome-wide association study (GWAS), Ferrucci et al (8) identified 4 other SNPs in modest (r 2 = 0.22-0.55) linkage disequilibrium (LD) with each other near BCMO1 that were related to circulating carotenoid concentrations. Specifically, rs6564851 was associated with increased band a-carotene and decreased lutein, zeaxanthin, and lycopene (8); rs6564851 was recently reported to reduce BCMO1 activity by 48% in females (9).…”

Genetics and Diet Regulate Vitamin A Production via the Homeobox Transcription Factor ISX

“…A large genome-wide association study identified a SNP about 7 kb upstream of the BCMO1 gene that strongly correlates (p ϭ 1.6 ϫ 10 Ϫ24 ) with increased fasting BC levels in serum (13). A small intervention study with female volunteers revealed that carriers of this SNP evidence a reduced BC conversion rate by about 50% (14). These observations could be explained by altered intestinal BCMO1 activity, an assumption supported by the finding that a rare missense mutation in human BCMO1 as well as genetic disruption of BCMO1 in mice lead to highly elevated BC blood levels and hypovitaminosis A (32,33).…”

“…A genome-wide study has associated a single nucleotide polymorphism (SNP, rs6564851) 7-kb upstream of the BCMO1 gene with increased fasting BC serum levels (13). A small intervention study provided evidence that this SNP is associated with reduced intestinal BC conversion (14). Additionally, several lines of evidence indicate that conversion of BC is under negative feedback control of vitamin A (15)(16)(17).…”

High provitamin A carotenoid serum concentrations, elevated retinyl esters, and saturated retinol-binding protein in Zambian preschool children are consistent with the presence of high liver vitamin A stores

“…Polymorphisms in BCO1 are associated with elevated fasting b-carotene concentrations (42), and a lower conversion efficiency of b-carotene, albeit at pharmacologic doses (43). Although statistically significant, a polymorphism associated with a higher b-carotene concentration only explained 1.9% of the variance at the population level (42), and other variations in genes related to the absorption, transport, and cleavage of carotenoids are likely involved in the individual variation in response to dietary carotenoids (16) as well as their transcription factors (18).…”