Vitamin D binding protein gene polymorphisms are associated with lower plasma 25-hydroxy-cholecalciferol concentrations in Ethiopian lactating women.

Ethiopian women have been reported to have low plasma 25-hydroxy-cholecalciferol (25(OH)D) concentrations despite an abundance of sunshine. Low dietary vitamin D intake, limited skin exposure to sun, and genetics are among factors suggested to affect vitamin D status in this population. In this study (Clinical Trial NCT02210884), we hypothesized that polymorphisms in the vitamin D binding protein (VDBP) gene (rs7041, rs4588) are associated with reduced plasma 25(OH)D concentrations in Ethiopian women. Lactating Ethiopian women (n = 110) were randomly assigned to weekly administration of vitamin D3 (15,000 IU) or a placebo. Plasma 25(OH)D was measured at baseline (within 2 weeks of delivery, before supplementation) and at 3, 6, and 12 months after delivery. Associations between VDBP polymorphism status for rs7041 and rs4588 and plasma 25(OH)D were determined by analysis of variance and multiple linear and logistic regressions. Multiple linear regression with maternal age as a covariate revealed that rs7041 is associated with reduced plasma 25(OH)D (P = .021) and more risk alleles at rs7041 and rs4588 are associated with reduced plasma 25(OH)D (P = .017). Logistic regression models for vitamin D insufficiency showed that additional risk alleles for rs7041 and rs4588 are associated with increased odds ratios (OR = 1.66; 95% CI, 1.10-2.62; P = .019) for plasma 25(OH)D below 40 nmol/L. Supplementation increased plasma 25(OH)D at 3 months in women with fewer risk alleles and across all genotypes at 6 and 12 months. VDBP polymorphisms may contribute to vitamin D insufficiency in Ethiopian lactating women. Furthermore, VDBP polymorphisms may blunt short-term responses to vitamin D supplementation and require longer periods of intervention.

A role for zinc transporter gene SLC39A12 in the nervous system and beyond.

The SLC39A12 gene encodes the zinc transporter protein ZIP12, which is expressed across many tissues and is highly abundant in the vertebrate nervous system. As a zinc transporter, ZIP12 functions to transport zinc across cellular membranes, including cellular zinc influx across the plasma membrane. Genome-wide association and exome sequencing studies have shown that brain susceptibility-weighted magnetic resonance imaging (MRI) intensity is associated with ZIP12 polymorphisms and rare mutations. ZIP12 is required for neural tube closure and embryonic development in Xenopus tropicalis. Frog embryos depleted of ZIP12 by antisense morpholinos develop an anterior neural tube defect and lack viability. ZIP12 is also necessary for neurite outgrowth and mitochondrial function in mouse neural cells. ZIP12 mRNA is increased in brain regions of schizophrenic patients. Outside of the nervous system, hypoxia induces ZIP12 expression in multiple mammalian species, including humans, which leads to endothelial and smooth muscle thickening in the lung and contributes towards pulmonary hypertension. Other studies have associated ZIP12 with other diseases such as cancer. Given that ZIP12 is highly expressed in the brain and that susceptibility-weighted MRI is associated with brain metal content, ZIP12 may affect neurological diseases and psychiatric illnesses such as Parkinson's disease, Alzheimer's disease, and schizophrenia. Furthermore, the induction of ZIP12 and resultant zinc uptake under pathophysiological conditions may be a critical component of disease pathology, such as in pulmonary hypertension. Drug compounds that bind metals like zinc may be able to treat diseases associated with impaired zinc homeostasis and altered ZIP12 function.

Role of zinc transporter ZIP12 in susceptibility-weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function.

Brain zinc dysregulation is linked to many neurological disorders. However, the mechanisms regulating brain zinc homeostasis are poorly understood. We performed secondary analyses of brain MRI GWAS and exome sequencing data from adults in the UK Biobank. Coding ZIP12 polymorphisms in zinc transporter ZIP12 (SLC39A12) were associated with altered brain susceptibility weighted MRI (swMRI). Conditional and joint association analyses revealed independent GWAS signals in linkage disequilibrium with 2 missense ZIP12 polymorphisms, rs10764176 and rs72778328, with reduced zinc transport activity. ZIP12 rare coding variants predicted to be deleterious were associated with similar impacts on brain swMRI. In Neuro-2a cells, ZIP12 deficiency by short hairpin RNA (shRNA) depletion or CRISPR/Cas9 genome editing resulted in impaired mitochondrial function, increased superoxide presence, and detectable protein carbonylation. Inhibition of Complexes I and IV of the electron transport chain reduced neurite outgrowth in ZIP12 deficient cells. Transcriptional coactivator PGC-1α, mitochondrial superoxide dismutase (SOD2), and chemical antioxidants α-tocopherol, MitoTEMPO, and MitoQ restored neurite extension impaired by ZIP12 deficiency. Mutant forms of α-synuclein and tau linked to familial Parkinson's disease and frontotemporal dementia, respectively, reduced neurite outgrowth in cells deficient in ZIP12. Zinc and ZIP12 may confer resilience against neurological diseases or premature aging of the brain.

Genetic and Genomic Advances in Developmental Models: Applications for Nutrition Research.

There is increasing appreciation that dietary components influence and interact with genes important to metabolism. How such influences impact developmental regulation and programming or risks of chronic diseases remains unclear. Nutrition is recognized to affect development and chronic diseases, but our understanding about how genes essential to nutrient metabolism regulate development and impact risks of these diseases remains unclear. Historically, mammalian models, especially rodents such as rats and mice, have been the primary models used for nutrition and developmental nutrition science, although their complexity and relatively slow rate of development often compromise rapid progress in resolving fundamental, genetic-related questions. Accordingly, the objective of this review is to highlight the opportunities for developmental models in the context of uncovering the function of gene products that are relevant to human nutrition and provide the scientific bases for these opportunities. We present recent studies in zebrafish related to obesity as applications of developmental models in nutritional science. Although the control of external factors and dependent variables, such as nutrition, can be a challenge, suggestions for standardizations related to diet are made to improve consistency in findings between laboratories. The review also highlights the need for standardized diets across different developmental models, which could improve consistency in findings across laboratories. Alternative and developmental animal models have advantages and largely untapped potential for the advancement of nutrigenomics and nutritionally relevant research areas.