Genetic, Dietary and Environmental Influences on Vitamin D Metabolism
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 412
- 试验地点
- 2
- 主要终点
- Serum concentrations of 24,25(OH)2D3
研究概览
简要总结
Determine differences in serum vitamin D metabolism by genetic ancestry.
详细描述
Vitamin D metabolites are well-recognized to stop cancer cell growth in culture. However, a clear definition of a sufficient level of serum vitamin D (currently measured as 25(OH)D) for disease prevention has been hampered by inconsistent results from both observational studies and randomized clinical trials. Observational cancer studies report both increased and reduced risks of cancer in subjects with higher serum levels of 25(OH)D, while large randomized trials report no significant benefit of vitamin D supplementation for breast cancer (incidence), colon cancer (incidence and mortality), lung cancer (mortality), or benign proliferative breast disease.
The 25(OH)D metabolite of vitamin D (comprised of 25(OH)D3 and 25(OH)D2), is the principal hydroxylated metabolite in serum and is considered a reasonable functional biomarker of vitamin D status. This is because, although subject to seasonal variation, multiple measurements in the same individual are relatively consistent over time. The most biologically active vitamin D metabolite is 1,25(OH)2D3, and may therefore be the most relevant to long-term health outcomes. Nonetheless, 1,25(OH)2D3 is not frequently used as a biomarker in epidemiologic studies as it displays diurnal variation and has a short in vivo half life.
Notably, in vivo treatment with 1,25(OH)2D3 is associated with increased metabolic clearance of 25(OH)D3, decreased serum 25(OH)D3 levels, and a higher 25(OH)D3 to 24,25(OH)2D3 conversion rate in humans and animals. This suggests that use of 25(OH)D as single biomarker of vitamin D status does not fully capture the entire picture. Paradoxically, one individual may be classified with 'low' 25(OH)D as a consequence of low dietary intake and little sun exposure while yet another individual classified with 'low' 25(OH)D may actually have a higher concentration of the 1,25(OH)2D3 metabolite-possibly due to genetic differences in enzymes that metabolize vitamin D (CYP2R1, CYP27B1, and CYP24A1).
Genome-wide and candidate gene association studies of serum 25(OH)D levels have suggested a role of single nucleotide polymorphisms (SNPs) near the vitamin D binding protein (GC) and CYP2R1. However, the investigators and others have shown that serum 25(OH)D levels are also associated with genetic ancestry. Because existing studies do not adjust for genetic ancestry and the function of these SNPs have yet to be established, it is not known whether these SNPs actually play a role or whether these may be spurious associations due to ancestral background (i.e., population stratification), correlations with truly causal SNPs, or to random chance. In addition, because of the number of SNPs that must be distinguished, genome-wide studies do not capture regions with high homology or sequence repeats, such as the promoter region of CYP24A1 which has a higher guanine-cytosine content. Improved classification of 'low' 25(OH)D levels within the context of a particular genetic background through identification of "rapid" versus "slow" vitamin D metabolizers will likely have important implications for cancer risk.
It is well-recognized that individuals with African Ancestry have substantially lower (~2-fold) serum 25(OH)D levels compared with other racial/ethnic groups. These differences have been attributed primarily to skin pigmentation. However, the relation between serum 25(OH)D levels and health outcomes is complex and involves a number of variables including diet, sun exposure and hormone status. For example, despite lower average dietary intake of both calcium and vitamin D, and lower serum 25(OH)D levels, African Americans have higher bone mineral density and a 3-fold lower risk of hip fracture relative to European Americans. There are some lines of evidence which suggest that African Americans may have comparatively higher circulating levels of 1,25(OH)2D3, although most studies are small and do not account for age and/or diurnal variation, and this may explain why other studies report no difference.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Triple (Participant, Care Provider, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 35 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy African American and Caucasian adult volunteers
- •Aged 18 to 35
- •At least 50% African American or at least 50% Caucasian
- •Willing to take a vitamin D supplement for two months
- •Willing to attend monthly visits to the clinic for blood draw and vital check
- •Willing to refrain from taking other dietary supplements including herbal supplements, multi-vitamins and vitamin D supplements other than the supplements provided in the trial.
- •Willing to avoid tanning bed use during the above mentioned period.
- •Willing to avoid extensive use of analgesics and have the consumption of the following drugs recorded: Acetaminophen, Celecoxib, Codeine, Fentanyl, any antibiotics, and Hormonal IUD.
排除标准
- •Participants with a fever (100 degrees F or higher) at the time of the visit
- •Participants with severe chronic disease (i.e., chronic kidney disease, cirrhosis of the liver, heart attack, HIV/AIDS, alcoholism, hemophilia, sickle cell disease, or other serious underlying illness that prevents blood donation),
- •Participants that have received radiation therapy or chemotherapy within the past 4 weeks,
- •Participants with any of the following on the upper right arm: rashes, a cast, swelling, paralysis, open sores or wounds.
- •Individuals with blindness and/or deafness
- •Pregnant participants will be excluded from the study.
- •Participants taking any of the following medications will be excluded from the study:
- •Long-term antibiotic use: Clarithromycin, Ciprofloxacin, Erythromycin, Telithromycin, Nafcillin
- •Chemotherapy for cancer
- •Prescription vitamin supplement
- •Anti-convulsants: Carbamazepine, Pentobarbital, Phenobarbital, Phenytoin, Primidone, Fosphenytoin
- •Erectile dysfunction drugs: sildenafil, vardenafil, tadalafil
- •Immunosuppressants: Tacrolimus, Cyclosporine A, Sirolimus, Mycophenolate, Glucocorticoids (like Dexamethasone)
- •Proton-pump inhibitors: omeprazole lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, and esomeprazole
- •Calcium Channel Blockers: nifedipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, amlodipine, lacidipine, Verapamil, diltiazem
- •Diuretics : furosemide, bumetanide, torsemide, ethacrynic acid, amiloride, triamterene, spironolactone, eplerenone,
- •Statins: lovastatin, simvastatin, atorvastatin, Pravastatin, fluvastatin, rosuvastatin, pitavastatin, Orlistat (Xenical, Alli),
- •Anti-fungal: Itraconazole, Ketoconazole, Posaconazole, Voriconazole, Fluconazole, Isavuconazole (isavuconazonium sulfate) Clotrimazole
- •HIV protease inhibitors and other anti-retrovirals : Atazanavir, Boceprevir, Darunavir, Indinavir, Lopinavir, Nelfinavir, Ombitasvirparitaprevirritonavir, Ombitasvirparitaprevirritonavir plus dasabuvir, Ritonavir and ritonavir containing coformulations, Saquinavir, Telaprevir
- •TB medications: Rifabutin, Rifampin (rifampicin), Rifapentine
- •As well as CYP3A4 inhibitors including: Ceritinib, Cobicistat and cobicistat containing coformulations, Idelalisib, Nefazodone, Amiodarone, Aprepitant, Cimetidine, Conivaptan, Crizotinib, Delavirdine, Desipramine, Dronedarone, Fosaprepitant Mifepristone, Netupitant, Nilotinib, and Tibolone
- •As well as CYP3A4 inducers including: Dexamethasone, Enzalutamide, Lumacaftor, Mitotane, St. John's wort, Bexarotene, Bosentan, Dabrafenib, Efavirenz, Eslicarbazepine, Etravirine, Modafinil
- •Other drugs that will cause a participant to be excluded include: Cholestyramine, Ferric carboxymaltose (treatment of iron deficiency anemia), Dapsone, Metformin
结局指标
主要结局
Serum concentrations of 24,25(OH)2D3
时间窗: Three month change
Differences in the increase in fasting serum levels of vitamin D metabolite 24,25(OH)D3 between African American and European American ancestry pairs will be determined at 0, 1 and 2 months.
Serum concentrations of 25(OH)D3
时间窗: Three month change
Differences in the increase in fasting serum levels of vitamin D metabolite 25(OH)D3 between African American and European American ancestry pairs will be determined at 0, 1 and 2 months.
Serum concentrations of 1,25(OH)2D3
时间窗: Three month change
Differences in the increase in fasting serum levels of vitamin D metabolite 1,25(OH)D3 between African American and European American ancestry pairs will be determined at 0, 1 and 2 months.
Metabolite Ratio
时间窗: Three months
Difference in the upstream to downstream vitamin D metabolite ratios (24,25(OH)2D3 to 25(OH)D3 and 1,25(OH)2D3 to 25(OH)D3) between African American and European American ancestry pairs will be determined at 0, 1 and 2 months.
次要结局
未报告次要终点
研究者
Robin Taylor Wilson
Associate Professor of Public Health Sciences
Milton S. Hershey Medical Center