Effects of Vitamin D Dose and Genotype of the Binding Protein in Infants and Children

Vitamin D has recently been the subject of much attention. Advantages to the prevention of
vitamin D deficiency (VDD) in young children are obvious: acutely, hypocalcemic seizures may
occur in VDD, and rickets can result in long-term skeletal deformities. Previous research
has emphasized the importance of identifying optimal supplementation doses and appropriate
target thresholds for circulating 25-hydroxyvitamin D (25-OHD), the best described marker of
vitamin D status. The timely next step is to objectively establish effective doses for the
prevention of VDD, without creating risk from overzealous supplementation, in a population
representative of those most at risk for overt disease.

Although the primary role of vitamin D is considered to be its effect on intestinal calcium
absorption, enormous variability of fractional calcium absorption in relation to 25-OHD
levels exists. We provide evidence that a significant component of this variability is
genetic in nature and in particular, relates to vitamin D binding protein (DBP) genotype.

The aggregate data suggest that the critical mechanism for the development of nutritional
rickets is reduction in availability of calcium to the skeleton, which is largely determined
by vitamin D status and intestinal calcium absorption. Our proposal focuses on the
establishment of a workable definition of vitamin D deficiency in an underserved and highly
vulnerable population and to assess the impact of genetic variance in VDR and DBP as factors
to be considered in the recommendation of vitamin D status assessment, taking into account
the outcome of 25-OHD level, and in additional studies, potential functional consequences of
vitamin D related to both its classical and non-classical effects.

Inclusion Criteria:

- 6 months to 6 years of age

- healthy or free from any diseases or conditions that may affect nutritional status or
bone metabolism

- willingness of family to participate in a 6-month study of vitamin D supplementation

Exclusion Criteria:

- Chronic disease

- Prematurity < 32 weeks gestational age

- Liver disease such as hepatitis or renal/urologic disease (e.g., recurrent urinary
tract infection)

- Use of pharmacologic or prescription-level dosages of vitamin D or its metabolites.
We will exclude users of any systemic glucocorticoid preparation and users of inhaled
steroids that are considered greater than medium dose for age 4 yrs. Specifically,
this would exclude users of over 1 mg/day of budesonide, and over 352 mcg/day of
fluticasone.

- Current or recent (within 1 month) use of anticonvulsants or other medications known
to affect bone and mineral homeostasis or alkaline phosphatase levels.