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Observational studies have shown that vitamin D binding protein (DBP) levels, a key determinant of 25-hydroxy-vitamin D (25OHD) levels, and 25OHD levels themselves both associate with risk of disease. If 25OHD levels have a causal influence on disease, and DBP lies in this causal pathway, then DBP levels should likewise be causally associated with disease. We undertook a Mendelian randomization study to determine whether DBP levels have causal effects on common calcemic and cardiometabolic disease. We measured DBP and 25OHD levels in 2,254 individuals, followed for up to 10 y, in the Canadian Multicentre Osteoporosis Study (CaMos). Using the single nucleotide polymorphism rs2282679 as an instrumental variable, we applied Mendelian randomization methods to determine the causal effect of DBP on calcemic (osteoporosis and hyperparathyroidism) and cardiometabolic diseases (hypertension, type 2 diabetes, coronary artery disease, and stroke) and related traits, first in CaMos and then in large-scale genome-wide association study consortia. The effect allele was associated with an age- and sex-adjusted decrease in DBP level of 27.4 mg/l (95% CI 24.7, 30.0; n = 2,254). DBP had a strong observational and causal association with 25OHD levels (p = 3.2 × 10(-19)). While DBP levels were observationally associated with calcium and body mass index (BMI), these associations were not supported by causal analyses. Despite well-powered sample sizes from consortia, there were no associations of rs2282679 with any other traits and diseases: fasting glucose (0.00 mmol/l [95% CI -0.01, 0.01]; p = 1.00; n = 46,186); fasting insulin (0.01 pmol/l [95% CI -0.00, 0.01,]; p = 0.22; n = 46,186); BMI (0.00 kg/m(2) [95% CI -0.01, 0.01]; p = 0.80; n = 127,587); bone mineral density (0.01 g/cm(2) [95% CI -0.01, 0.03]; p = 0.36; n = 32,961); mean arterial pressure (-0.06 mm Hg [95% CI -0.19, 0.07]); p = 0.36; n = 28,775); ischemic stroke (odds ratio [OR]  = 1.00 [95% CI 0.97, 1.04]; p = 0.92; n = 12,389/62,004 cases/controls); coronary artery disease (OR = 1.02 [95% CI 0.99, 1.05]; p = 0.31; n = 22,233/64,762); or type 2 diabetes (OR = 1.01 [95% CI 0.97, 1.05]; p = 0.76; n = 9,580/53,810). DBP has no demonstrable causal effect on any of the diseases or traits investigated here, except 25OHD levels. It remains to be determined whether 25OHD has a causal effect on these outcomes independent of DBP. Please see later in the article for the Editors' Summary.

After synthesis in the skin or dietary ingestion, vitamin D is removed from the bloodstream into various tissues, including the liver, adipose tissue and muscle. Its biologic half-life is about 60 days,4 and it is eventually converted to 25-hydroxy - vitamin D in the hepatocytes.4,5 Vitamin D3 (cholecalciferol) is the molecule synthesized in the skin in response to ultraviolet B radiation, whereas vitamin D2 (ergocalciferol) is derived from irradiation of certain fungi. Both vitamin D2 and vitamin D3 create 1,25-dihydroxyvitamin D, the active form, although there is some evidence that vitamin D2 may not be used in the body as efficiently as vitamin D3.6 In Canada, most vitamin D supplements consist of vitamin D3, but high-dose preparations, available by prescription, are vitamin D2. In this paper we use the term \"vitamin D\" to refer to both forms, unless a distinction is warranted. There has been a marked increase in the clinical use of 25- hydroxyvitamin D assays.11 However, serum 25-hydroxyvitamin D should be measured only if deficiency is suspected or would affect the person's response to therapy (e.g., in cases of impaired intestinal absorption, such as celiac disease, or osteoporosis requiring pharmacologic therapy). In treating deficiency, serum 25-hydroxyvitamin D will indicate the effectiveness of vitamin D therapy. The half-life of 25- hydroxyvitamin D in the body is 15-20 days.4 With standarddose supplementation, serum 25-hydroxyvitamin D plateaus after three to four months.12 Therefore, serum 25-hydroxyvitamin D should be checked no sooner than three months after standard-dose treatment is initiated (level 2 evidence, grade B recommendation). After high-dose oral or parenteral vitamin D replacement is administered (e.g., 500 000 IU), the peak 25-hydroxyvitamin D level may be achieved in one month.13 Patients taking daily doses above Health Canada's \"tolerable upper intake level\" (currently set at 50 µg [2000 IU]) should undergo monitoring of serum 25-hydroxyvitamin D (level 4 evidence, grade D recommendation). For healthy Canadians, the dose recommendations for routine supplementation in this paper should result in adequate blood levels. Monitoring of routine supplement use and routine testing of otherwise healthy individuals as a screening procedure are not indicated (grade D recommendation). When supplements are used to treat vitamin D insufficiency, the amount should be great enough to increase 25- hydroxyvitamin D to desirable levels. Daily doses over 50 µg (2000 IU) can safely be administered under medical supervision. 2 Assuming that the patient can absorb an orally administered dose, severe deficiency (rickets or osteomalacia) requires doses as high as 1250 µg (50 000 IU) daily for two to four weeks, then weekly or biweekly, with monitoring of serum 25-hydroxyvitamin D at one month and three months. Less severe deficiency can be managed with lower doses.5 A clinically useful estimate is 1 nmol/L for each microgram of vitamin D;12,37,38 for example, vitamin D3 1 µg (40 IU) daily raises serum 25-hydroxyvitamin D by 0.7-2.0 nmol/L. If diet and a background of moderate sun exposure during summer is assumed to achieve a mean serum 25-hydroxyvitamin D level of 50 nmol/L, then a further 25 µg (1000 IU) per day of dietary vitamin D3 may be needed to exceed 75 nmol/L. Some individuals, particularly those deprived of sunlight and those who are elderly, may need greater intake (level 2 evidence).

Abstract Context Recent studies have reported elevated urinary vitamin D binding protein (uVDBP) concentrations in patients with diabetic kidney disease, although the utility of uVDBP to predict deterioration of kidney function over time has not been examined. Objective Our objective was to assess the association of uVDBP with longitudinal changes in kidney function. Methods Adults at-risk for type 2 diabetes from the Prospective Metabolism and Islet Cell Evaluation (PROMISE) study had 3 assessments over 6 years (n = 727). Urinary albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were used as measures of kidney function. Measurements of uVDBP were performed with enzyme-linked immunosorbent assay and normalized to urine creatinine (uVDBP:cr). Generalized estimating equations (GEEs) evaluated longitudinal associations of uVDBP and uVDBP:cr with measures of kidney function, adjusting for covariates. Results Renal uVDBP loss increased with ACR severity at baseline. Individuals with normoalbuminuria, microalbuminuria, and macroalbuminuria had median log uVDBP:cr concentrations of 1.62 μg/mmol, 2.63 μg/mmol, and 2.48 μg/mmol, respectively, and ACR positively correlated with uVDBP concentrations (r = 0.37; P < .001). There was no significant association between uVDBP and eGFR at baseline. Adjusted longitudinal GEE models indicated that each SD increase both in baseline and longitudinal uVDBP:cr was significantly associated with higher ACR over 6 years (β = 30.67 and β = 32.91, respectively). Conversely, neither baseline nor longitudinal uVDBP:cr measures showed a significant association with changes in eGFR over time. These results suggest that loss of uVDBP:cr over time may be a useful marker for predicting renal tubular damage in individuals at risk for diabetes.

Inactivating mutations of the multiple endocrine neoplasia 1 (MEN1) gene cause MEN1 syndrome, characterized by primary hyperparathyroidism (pHPT), and parathyroid and gastro-entero-pancreatic pituitary tumors. At present, only 14 cases of malignant parathyroid tumor have been associated with the syndrome, with 6 cases carrying an inactivating mutation of the MEN1 gene. The present study presents the case of a 48-year-old female who presented with multigland pHPT and multiple pancreatic lesions. The patient underwent surgery several times for the excision of parathyroid hyperplasia, carcinoma and adenoma. The MEN1 gene was screened, revealing three variants (in cis) at the intron/exon 3 boundary (IVS2-3G>C, c.497A>T and c.499G>T) detected on the DNA of the proband, not shared by her relatives. RNA sequencing revealed that the IVS2-3C>G variant caused the skipping of the exon 3. Therefore, the present study reports on a novel rare association of MEN1 syndrome and parathyroid carcinoma. The reported splicing mutation was previously identified in subjects who always developed malignant lesions; thus, a possible genotype-phenotype association may be considered.

Familial hypocalciuric hypercalcemia (FHH) is caused by heterozygous loss‐of‐function mutations in the calcium‐sensing receptor (CASR), in which the lifelong hypercalcemia is generally asymptomatic. Homozygous loss‐of‐function CASR mutations manifest as neonatal severe hyperparathyroidism (NSHPT), a rare disorder characterized by extreme hypercalcemia and the bony changes of hyperparathyroidism, which occur in infancy. Activating mutations in the CASR gene have been identified in several families with autosomal dominant hypocalcemia (ADH), autosomal dominant hypoparathyroidism, or hypocalcemic hypercalciuria. Individuals with ADH may have mild hypocalcemia and relatively few symptoms. However, in some cases seizures can occur, especially in younger patients, and these often happen during febrile episodes due to intercurrent infection. Thus far, 112 naturally‐occurring mutations in the human CASR gene have been reported, of which 80 are unique and 32 are recurrent. To better understand the mutations causing defects in the CASR gene and to define specific regions relevant for ligand‐receptor interaction and other receptor functions, the data on mutations were collected and the information was centralized in the CASRdb (www.casrdb.mcgill.ca), which is easily and quickly accessible by search engines for retrieval of specific information. The information can be searched by mutation, genotype–phenotype, clinical data, in vitro analyses, and authors of publications describing the mutations. CASRdb is regularly updated for new mutations and it also provides a mutation submission form to ensure up‐to‐date information. The home page of this database provides links to different web pages that are relevant to the CASR, as well as disease clinical pages, sequence of the CASR gene exons, and position of mutations in the CASR. The CASRdb will help researchers to better understand and analyze the mutations, and aid in structure–function analyses. Hum Mutat 24:107–111, 2004. © 2004 Wiley‐Liss, Inc.

The calcium‐sensing receptor (CASR) is a plasma membrane G protein coupled receptor that is expressed in the parathyroid hormone (PTH) producing chief cells of the parathyroid gland and the cells lining the kidney tubule. By virtue of its ability to sense small changes in circulating calcium concentration ([Ca2+]o) and to couple this information to intracellular signaling pathways that modify PTH secretion or renal cation handling, the CASR plays an essential role in maintaining mineral ion homeostasis. Inherited abnormalities of the CASR gene located on chromosome 3p13.3‐21 can cause either hypercalcemia or hypocalcemia depending upon whether they are inactivating or activating, respectively. Heterozygous loss‐of‐function mutations give rise to familial (benign) hypocalciuric hypercalcemia (FHH) in which the lifelong hypercalcemia is asymptomatic. The homozygous condition manifests itself as neonatal severe hyperparathyroidism (NSHPT), a rare disorder characterized by extreme hypercalcemia and the bony changes of hyperparathyroidism which occur in infancy. The disorder autosomal dominant hypocalcemia (ADH) is due to gain‐of‐function mutations in the CASR gene. ADH may be asymptomatic or present with neonatal or childhood seizures. A common polymorphism in the intracellular tail of the CASR, Ala to Ser at position 986, has a modest effect on the serum calcium concentration in healthy individuals. Hum Mutat 16:281–296, 2000. © 2000 Wiley‐Liss, Inc.

Following publication of the original article [1], the authors identified the following errors in the scientific content: p.4, para. 3: “(1 tablet/10 mL RIPA)” should read “(1 tablet/10 mL RIPA buffer)”. p.4, para. 4: “II-1” should read “II-2”. Minor mistakes were also identified in the table on page 6, and in the Abbreviations section on page 7. The original article has been corrected.

A sequencing study comparing ancient and contemporary genomes reveals that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, ancient north Eurasians (related to Upper Palaeolithic Siberians) and early European farmers of mainly Near Eastern origin. The genetics of European prehistory By sequencing and comparing the genomes of nine ancient Europeans that bridge the transition to agriculture in Europe between 8,000 and 7,000 years ago, David Reich and colleagues show that most present-day Europeans derive from at least three highly differentiated populations — west European hunter-gatherers, ancient north Eurasians (related to Upper Palaeolithic Siberians) and early European farmers of mainly Near Eastern origin. They further propose that early European farmers had about 44% ancestry from a 'basal Eurasian' population that split before the diversification of other non-African lineages. These results raise interesting new questions, for instance that of where and when the Near Eastern farmers mixed with European hunter-gatherers to produce the early European farmers. We sequenced the genomes of a ∼7,000-year-old farmer from Germany and eight ∼8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes 1 , 2 , 3 , 4 with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians 3 , who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations’ deep relationships and show that early European farmers had ∼44% ancestry from a ‘basal Eurasian’ population that split before the diversification of other non-African lineages.

Bone metastases are a common problem for breast cancer patients, causing significant disease-related morbidity and mortality. Bisphosphonates and other cancer therapies can assist in managing these patients. However, assessing treatment efficacy in bone metastases is hampered by the inability to accurately measure disease response within a clinically desirable time frame. Bone-specific biochemical markers, notably type I collagen telopeptide cross-link by-products such as N-telopeptide (NTx) and C-telopeptide (CTx), have been shown to be effective tools for assessing the severity and extent of bone metastases, and the response to bisphosphonates. Elevated NTx levels correlate with adverse clinical outcomes. Normalization of NTx and CTx excretion rates are associated with relief of symptoms and a reduced incidence of skeletal-related events (SRE). This review discusses the expanding role of these bone markers in guiding treatment of bone metastases from breast cancer.