Marginal biotin deficiency causes birth defects in some animals including mammals, raising concern that biotin deficiency causes human birth defects. We seek funding for a definitive study of biotin status during normal human pregnancy. Previous studies suggest that during pregnancy about half of women become marginally biotin deficient. However, confidence in this conclusion is limited because the best validated index of biotin status (urinary 3-hydroxyisovaleric acid, 3HIA) depends on renal function, which is altered by pregnancy per se. We propose to quantitate activity of the biotin-dependent enzyme propionyl-CoA carboxylase (PCC) in peripheral blood lymphocytes. This validated indicator of biotin status will be used to test the overall hypothesis that a significant number of women develop marginal biotin deficiency during normal gestation. The study will be conducted in two phases. In the first phase (Qualifying Phase), PCC activity will be determined for 104 women in early pregnancy. Mean PCC activity of the pregnancy group will be compared to a control group of women who are not pregnant to test the hypothesis that PCC activity is significantly decreased in early pregnancy, reflecting reduced biotin status. The second phase (Intervention Phase) will use a randomized, placebo-controlled design to test the hypothesis that the reduced PCC activity identified in the Qualifying Phase does indeed reflect biotin deficiency, rather than an effect of pregnancy per se. Twenty-six pregnant women with low PCC activity will be randomized to either biotin supplementation (300 5g daily supplement for 3 weeks) or placebo. Activity of PCC will be determined immediately before and at the end of the supplement period. We expect that PCC activity will increase significantly in the biotin-supplemented group and not change significantly in the placebo group, providing strong evidence of biotin deficiency. Urinary 3HIA will be used as a secondary indicator of biotin status in both the Qualifying Phase and the Intervention Phase. The proposed studies will also address mechanism. We will 1) investigate the role of accelerated biotin degradation (as assessed by increased urinary excretion of biotin metabolites) in causing biotin deficiency, and 2) confirm that a limited biotin supply is the cellular mechanism for the observed decrease in PCC activity by quantitating PCC and holocarboxylase synthetase gene expression, apo- and holo-PCC mass, and PCC in vitro activation coefficient.

Public Health Relevance

We are concerned that marginal biotin deficiency causes human birth defects. Here we seek funding to demonstrate that marginal biotin deficiency is common in pregnancy. If so, then the next logical question would be """"""""Does marginal biotin deficiency cause a substantial number of human birth defects?"""""""" Large-scale epidemiologic correlation studies, a large-scale biotin intervention trial or both would be needed to answer that question. Given the expense of such trials, the smaller study proposed here is an essential prerequisite in a line of research with substantial healthcare implications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK079892-03
Application #
8136520
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$292,758
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Biochemistry
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Bogusiewicz, Anna; Horvath, Thomas D; Stratton, Shawna L et al. (2012) Measurement of acylcarnitine substrate to product ratios specific to biotin-dependent carboxylases offers a combination of indicators of biotin status in humans. J Nutr 142:1621-5
Horvath, Thomas D; Matthews, Nell I; Stratton, Shawna L et al. (2011) Measurement of 3-hydroxyisovaleric acid in urine from marginally biotin-deficient humans by UPLC-MS/MS. Anal Bioanal Chem 401:2805-10
Stratton, Shawna L; Horvath, Thomas D; Bogusiewicz, Anna et al. (2011) Urinary excretion of 3-hydroxyisovaleryl carnitine is an early and sensitive indicator of marginal biotin deficiency in humans. J Nutr 141:353-8
Stratton, Shawna L; Horvath, Thomas D; Bogusiewicz, Anna et al. (2010) Plasma concentration of 3-hydroxyisovaleryl carnitine is an early and sensitive indicator of marginal biotin deficiency in humans. Am J Clin Nutr 92:1399-405
Horvath, Thomas D; Stratton, Shawna L; Bogusiewicz, Anna et al. (2010) Quantitative measurement of urinary excretion of 3-hydroxyisovaleryl carnitine by LC-MS/MS as an indicator of biotin status in humans. Anal Chem 82:9543-8
Horvath, Thomas D; Stratton, Shawna L; Bogusiewicz, Anna et al. (2010) Quantitative measurement of plasma 3-hydroxyisovaleryl carnitine by LC-MS/MS as a novel biomarker of biotin status in humans. Anal Chem 82:4140-4