Effect of SNPs in the BCMO1 Enzyme (BETASNP2)

• ClinicalTrials.gov Identifier: NCT02276014
• Recruitment Status: Completed
• First Posted: October 27, 2014
• Last Update Posted: October 6, 2015
• Sponsor: Newcastle-upon-Tyne Hospitals NHS Trust
• Collaborators: Newcastle University; DSM Nutritional Products, Inc.
• Information provided by (Responsible Party): Newcastle-upon-Tyne Hospitals NHS Trust

Tracking Information

• First Submitted Date: October 21, 2014
• First Posted Date: October 27, 2014
• Last Update Posted Date: October 6, 2015
• Study Start Date: April 2012
• Actual Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 23, 2014)

• Area under the plasma concentration versus time curve (AUC) of beta-carotene [ Time Frame: Pharmacokinetic measures (0,1,4,36,46,57,60 days post-dose) ]
• Area under the plasma concentration versus time curve (AUC) of [13C]retinol [ Time Frame: Pharmacokinetic measures (0,1,2,3,4,8,10,22,36,46,57,58,59,60,64,66,78,92,113 days post-dose) ]

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effect of SNPs in the BCMO1 Enzyme
• Official Title: Effect of SNPs in the Beta-carotene 15, 15'-Monooxygenase (BCMO1) Enzyme on Retinol Formation and Beta-carotene Plasma Responses

Brief Summary

Summary:

Chronic intake of foods low in vitamin A (retinol) and provitamin A forming an unbalanced diet with little variety is common in young individuals in the United Kingdom (UK) population and can lead to subclinical micronutrient deficiency. Provitamin A sources such as β-carotene are cleaved centrally by the β-carotene 15,15'-monooxygenase (BCMO1) into retinal, the precursor of retinol. However, the amount of β-carotene and retinol produced after ingestion of β-carotene is highly variable between healthy individuals, with approximately 40% of the subjects being classified as low responders. Several stable isotope studies have shown a large disparity between the most efficient converters and the most inefficient converters of β-carotene with variations of up to 8-fold. It is possible that differences in β-carotene response may be due to single nucleotide polymorphisms (SNPs) in genes involved in aspects of β-carotene conversion. Previous work has shown that carriers of both, the 379V and 267S+379V BCMO1 variant alleles had a reduced ability to convert β-carotene. More importantly, 44% of the western population have the 379V haplotype. A high percentage of the Western population may therefore not be able to achieve adequate vitamin A intake if dietary β-carotene is a major source of their vitamin A intake. This is of particular relevance to vegetarians, to young individuals aged 19-24 years who have lower intakes of preformed retinol than any other age group, and to pregnant women. The aim of this study is to establish whether the maximum recommended dose for β-carotene of 7mg/day by the British Expert Committee on Vitamins and Minerals (EVM) can overcome the SNP effect in the BCMO1 enzyme.

Hypothesis:

The investigators hypothesize that the current maximum recommended intake of 7 mg of β-carotene per day cannot overcome the low convertor phenotype in BCMO1 to fulfill vitamin A requirements in these people.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Participant); Primary Purpose: Basic Science

Condition

• Beta-carotene Bioavailability
• Vitamin A Deficiency

• Intervention: Dietary Supplement: Beta-carotene

Study Arms

• Supplement A
  Beta-carotene 7mg formulation A
  Intervention: Dietary Supplement: Beta-carotene
• Supplement B
  Beta-carotene 7mg formulation B
  Intervention: Dietary Supplement: Beta-carotene
• Supplement C
  Beta-carotene 7mg formulation C
  Intervention: Dietary Supplement: Beta-carotene

Publications *

• Oxley A, Berry P, Taylor GA, Cowell J, Hall MJ, Hesketh J, Lietz G, Boddy AV. An LC/MS/MS method for stable isotope dilution studies of β-carotene bioavailability, bioconversion, and vitamin A status in humans. J Lipid Res. 2014 Feb;55(2):319-28. doi: 10.1194/jlr.D040204. Epub 2013 Oct 24.
• Lietz G, Oxley A, Leung W, Hesketh J. Single nucleotide polymorphisms upstream from the β-carotene 15,15'-monoxygenase gene influence provitamin A conversion efficiency in female volunteers. J Nutr. 2012 Jan;142(1):161S-5S. doi: 10.3945/jn.111.140756. Epub 2011 Nov 23.
• Grune T, Lietz G, Palou A, Ross AC, Stahl W, Tang G, Thurnham D, Yin SA, Biesalski HK. Beta-carotene is an important vitamin A source for humans. J Nutr. 2010 Dec;140(12):2268S-2285S. doi: 10.3945/jn.109.119024. Epub 2010 Oct 27.
• Leung WC, Hessel S, Méplan C, Flint J, Oberhauser V, Tourniaire F, Hesketh JE, von Lintig J, Lietz G. Two common single nucleotide polymorphisms in the gene encoding beta-carotene 15,15'-monoxygenase alter beta-carotene metabolism in female volunteers. FASEB J. 2009 Apr;23(4):1041-53. doi: 10.1096/fj.08-121962. Epub 2008 Dec 22.
• Furr HC, Green MH, Haskell M, Mokhtar N, Nestel P, Newton S, Ribaya-Mercado JD, Tang G, Tanumihardjo S, Wasantwisut E. Stable isotope dilution techniques for assessing vitamin A status and bioefficacy of provitamin A carotenoids in humans. Public Health Nutr. 2005 Sep;8(6):596-607. Review.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 23, 2014): 85
• Original Actual Enrollment: Same as current
• Actual Study Completion Date: September 2014
• Actual Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Healthy individual.
• Female.
• Between 18 and 45 years of age.
• Caucasian.
• BMI between 18 and 30 kg/m2.
• Subject willing and able to give written informed consent.

Exclusion Criteria:

• Smoking.
• Diabetes.
• Gastrointestinal diseases.
• Renal and hepatic diseases.
• Hyperlipidaemia.
• Preformed dietary retinol intake above 60% of reference nutrient intake (RNI) values.
• Recreational drug use.
• Multi-vitamin consumption.
• Pregnancy.
• Menopause.
• Allergy or sensitivity to study products or ingredients.
• Blood donation 3 months prior to screening.
• Participation in other clinical study 4 weeks prior to study start.
• Suspected inability or unwillingness to comply with study procedures.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 45 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT02276014
• Other Study ID Numbers: 2011-01-18-BETASNP2; REC 11/NE/0211 ( Other Identifier: National Research Ethics Service (NRES) )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Newcastle-upon-Tyne Hospitals NHS Trust
• Study Sponsor: Newcastle-upon-Tyne Hospitals NHS Trust

Collaborators

• Newcastle University
• DSM Nutritional Products, Inc.

Investigators

• Principal Investigator: Georg Lietz, PhD; Newcastle University

• PRS Account: Newcastle-upon-Tyne Hospitals NHS Trust
• Verification Date: October 2015