Background Plasma cholesterol is one of the strongest risk factors associated with the development of atherosclerotic cardiovascular disease (ASCVD) and myocardial infarction. Human studies suggest that elevated plasma β-carotene is associated with reductions in circulating cholesterol and the risk of myocardial infarction. The molecular mechanisms underlying these observations are unknown. Objective The objective of this study was to determine the impact of dietary β-carotene and the activity of β-carotene oxygenase 1 (BCO1), which is the enzyme responsible for the conversion of β-carotene to vitamin A, on circulating cholesterol concentration. Methods In our preclinical study, we compared the effects of a 10-d intervention with a diet containing 50 mg/kg of β-carotene on plasma cholesterol in 5-wk-old male and female C57 Black 6 wild-type and congenic BCO1-deficient mice. In our clinical study, we aimed to determine whether 5 common small nucleotide polymorphisms located in the BCO1 locus affected serum cholesterol concentrations in a population of young Mexican adults from the Universities of San Luis Potosí and Illinois: A Multidisciplinary Investigation on Genetics, Obesity, and Social-Environment (UP AMIGOS) cohort. Results Upon β-carotene feeding, Bco1−/− mice accumulated >20-fold greater plasma β-carotene and had ∼30 mg/dL increased circulating total cholesterol (P < 0.01) and non–HDL cholesterol (P < 0.01) than wild-type congenic mice. Our results in the UP AMIGOS cohort show that the rs6564851 allele of BCO1, which has been linked to BCO1 enzymatic activity, was associated with a reduction in 10 mg/dL total cholesterol concentrations (P = 0.009) when adjusted for vitamin A and carotenoid intakes. Non–HDL-cholesterol concentration was also reduced by 10 mg/dL when the data were adjusted for vitamin A and total carotenoid intakes (P = 0.002), or vitamin A and β-carotene intakes (P = 0.002). Conclusions Overall, our results in mice and young adults show that BCO1 activity impacts circulating cholesterol concentration, linking vitamin A formation with the risk of developing ASCVD.

Background: Circulating fetuin-A (FetA) inhibits insulin receptor signaling and activates the toll-like receptor 4 proinflammatory cascade; thus, it may contribute to metabolic syndrome. Polymorphisms in alpha-2-Heremans-Schmid glycoprotein (AHSG), the gene which codes FetA, may influence metabolic syndrome progression in higher-risk ethnic groups. We aimed to identify whether individual variation in AHSG influences biomarkers of metabolic disease and obesity in young Mexican adults. Methods: The participants were Mexican college applicants (18-25 years, n = 641). Dietary intake, anthropometric data, and blood for the analysis of biomarkers and genetics were collected. Single nucleotide polymorphisms (SNPs) in AHSG (rs2518136 and rs4917) were genotyped. Results: Neither AHSG SNP was associated with body mass index (BMI) or waist circumference. rs4917 C allele carriers had lower triglycerides (TG) than T allele homozygotes (98.85 ± 2.3 vs. 112.2 ± 5.2 mg/dL, p = 0.0113). BMI was strongly associated with TG (p < 0.0001) regardless of genotype. The relationship between circulating TG and dietary intake of carbohydrates and saturated fat was significant in rs4917 CT allele heterozygotes only (p = 0.03 and p = 0.02, respectively). Conclusions: rs4917 T allele carriers had higher TG. This relationship was exaggerated in individuals with overweight and obesity. Dietary intake was significantly associated with TG in only those with heterozygosity at rs4917, suggesting that these individuals may be more susceptible to dietary interventions.

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Retinoic acid and retinol are important mediators of a multitude of metabolic processes in the human body, including lipid metabolism. Major dietary precursors of retinoids include the pro‐vitamin A carotenoids. Beta‐carotene, which is cleaved by the enzyme BCMO1, can be a principle source of retinoic acid in the diet. Within the BCMO1 gene, single nucleotide polymorphisms (SNPs) (rs6564851 and rs10048138) have been found to affect activity of this enzyme. Previously, associations between these SNPs and plasma lipid levels have been observed in U.S. cohorts but have not been replicated in the Mexican population. Our objective was to examine the association between differences in genotype of BCMO1‐rs6564851 and rs10048138 and plasma lipid levels in a cohort of young Mexican adults (n=374). DNA was obtained from whole blood and was genotyped using the Taqman system. General linear models were used to systematically analyze associations. Both SNPs were in Hardy‐Weinberg Equilibrium with minor allele frequencies of 0.53 and 0.29, respectively. We found a genetic association between a haplotype constructed with these two SNPs and plasma HDL‐C levels. Regardless of BMI category and smoking status, minor allele carriers were associated with elevated plasma HDL‐C (p<0.02). These results suggest that the SNPs in the BCMO1 gene could confer changes in enzyme activity that could affect risk for dyslipidemia. Grant Funding Source: University of Illinois at Urbana‐Champaign Research Board grant 09070 (to F. Andrade)

Retinoids are key in facilitating many physiological functions, including lipid metabolism, and are typically formed from the cleavage of β,β‐carotene by BCMO1. Recently, an IGV in the BCMO1 gene (SNP, rs10048138) was associated with cholesterol levels in a U. S. cohort; however, there are no replicates in the Mexican population. Our objective was to examine the association of this BCMO1 marker with cholesterol levels, a risk factor for metabolic disease, in college‐age individuals from the UP‐AMIGOS cohort. UP‐AMIGOS is a multidisciplinary project on genetics, obesity, and social environment between the Universities of San Luis Potosi (San Luis Potosi, Mexico) and Illinois. For this cross‐sectional study genotype, health and nutrition data from 72 participants (aged 18–21 years) was analyzed. Homozygotes for the minor allele of BCMO1‐rs10048138 had lower cholesterol (137.4±9.8 mg/dL) compared to the other genotypes (158.1±2.7 and 157.6±4.0 mg/dL) adjusted for sex and age (p<0.04). Our analyses show that genetic variability in BCMO1 was associated with cholesterol levels and may prove to influence risk for metabolic disease; this association was strengthened (p<0.02) when considering smoking.Grant Funding Source: USDA/NIFA Hatch Project (#600108–793000‐793323 and #600109–698000‐698354)