Associations between serum levels of calcium, parathyroid hormone and future risk of venous thromboembolism: the Tromsø study

Lerstad, Gunhild; Brodin, Ellen; Svartberg, Johan; Jorde, Rolf; Brox, Jan; Brækkan, Sigrid Kufaas; Hansen, John‐Bjarne

doi:10.1530/eje-16-1037

Cited by 6 publications

(5 citation statements)

References 42 publications

(53 reference statements)

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“…by SKAT analysis do not provide directionality, but the risks of embolism/ thrombosis and diastolic heart failure have been shown to be influenced by serum Ca concentrations; 32,33 likewise, neuropsychiatric disorders have been associated with serum Ca concentrations in small case-control studies. 34,35 CaSR is widely expressed in the cardiovascular 36,37 and nervous 38 systems, and it remains to be determined whether these disease associations result from elevated serum Ca concentrations, reduced CaSR function, or both.…”

Section: Discussionmentioning

confidence: 99%

Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population

Dershem

Gorvin

Metpally

et al. 2020

The American Journal of Human Genetics

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The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss-or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequence Kernel Association Test (SKAT) to identify rare variant-associated diseases. We identified predicted heterozygous loss-of-function CASR variants (6 different nonsense/frameshift variants and 12 different missense variants) in 38 unrelated individuals, 21 of whom were hypercalcemic. Missense CASR variants were identified in two unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemiaassociated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemiaassociated missense variants increased expression, plasma membrane targeting, and/or signaling. Thus, 38 individuals with a genetic diagnosis of FHH1 and two individuals with a genetic diagnosis of ADH1 were identified in the 51,289 cohort, giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1. SKAT combining all nonsense, frameshift, and missense loss-of-function variants revealed associations with cardiovascular, neurological, and other diseases. In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas ADH1 is a major cause of non-surgical hypoparathyroidism.

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Section: Discussionmentioning

confidence: 99%

Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population

Dershem

Gorvin

Metpally

et al. 2020

The American Journal of Human Genetics

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“…Thus, increased serum PTH concentrations due to vitamin D insufficiency might lead to low arterial compliance and high stiffness, resulting in increased CVD. High PTH was also associated with increased risk of heart failure and venous thromboembolism [ 39 , 40 ]. Clinical research has indicated that early treatment of parathyroid disorders may reverse cardiovascular remodeling and mitigate cardiac risk factors [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Association of serum vitamin D and parathyroid hormone with subclinical atherosclerotic phenotypes: The Dong-gu Study

et al. 2017

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BackgroundAlthough previous studies reported an association between serum vitamin D and parathyroid hormone (PTH) with carotid atherosclerosis or arterial stiffness, these were inconsistent. We examined the independent association between serum vitamin D and PTH with multiple subclinical markers of atherosclerosis.MethodsA total of 8,217 subjects who participated in the Dong-gu Study in Korea were included in the final analysis. The carotid artery structure, including intima-media thickness (IMT), plaques, and luminal diameter, was evaluated using a high-resolution B-mode ultrasound. The brachial-ankle pulse wave velocity (baPWV) was determined using an automatic waveform analysis device, and the mean of the left and right baPWV was used.ResultsThe PTH concentration was positively associated with carotid luminal diameter and baPWV, but not with carotid IMT and plaques. The mean carotid luminal diameter of individuals with PTH levels in the second, third, and fourth quartiles was significantly larger compared with those in the first quartile (P-trend < 0.01). The mean baPWV of individuals with PTH levels in the fourth quartile was significantly greater than those with PTH levels in the first quartile (P-trend = 0.01). However, there was no significant association between vitamin D and any atherosclerotic phenotypes, including carotid IMT, plaques, luminal diameter, and baPWV.ConclusionThis suggests that PTH might affect the development of atherosclerosis by altering vascular compliance.

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“…Furthermore, among 27,685 subjects (25-87 years) participating in Tromsø 4 (1994Tromsø 4 ( -1995 and 8547 individuals participating in Tromsø 5 (2001Tromsø 5 ( -2002 surveys, where total calcium and PTH were measured, 712 cases of venous thromboembolism (VTE) were documented during a median follow-up of 15 years. Subjects with high serum levels of both calcium and PTH (calcium ≥2.45 mmol/L and PTH ≥4.0 pmol/L) had an increased risk of VTE compared to that in subjects with normal calcium and PTH values (multivariable HR: 1.78, 95% CI: 1.12-2.84) [16]. These studies support a correlation between calcium levels and enhanced activation of the coagulation system.…”

Section: Discussionmentioning

confidence: 58%

Calcium Prevents Enhanced Degradation of Factor VIII in the Condition of Motion

Cohen,

Keren-Politansky,

Crispel

et al. 2023

Biology

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Background: Hemophilia A and B induce recurrent bleeding episodes, mainly in skeletal muscles and joints that are in intermittent motion. We have previously demonstrated that intermittent motion contributes to increased degradation of factors VIII and IX. Objectives: Given that calcium ions are known to enhance factor VIII–von Willebrand factor (vWF) interaction, the present study has investigated the role of these ions on factors VIII and IX in the condition of motion. Methods: The effects of calcium ions were assessed using purified proteins via Western blot, factor VIII activity, immunocytochemistry, and in Institute of Cancer Research (ICR) mice with no specific genetic background. Results: Calcium was found to prevent degradation of plasma-derived factor VIII but not that of factor IX, during intermittent motion. Calcium levels in the microcirculation of mouse striated muscles were elevated following movement, enabling prevention of factor VIII degradation in normal physiology. Calcium supplementation in drinking water increased factor VIII levels in blood and striated muscles of ICR mice during movement. Conclusions: calcium ions decrease factor VIII degradation in the condition of motion. Further research on the impact of calcium salt oral supplementation on hemophilia patients is warranted.

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Associations between serum levels of calcium, parathyroid hormone and future risk of venous thromboembolism: the Tromsø study

Abstract: Serum levels of calcium and PTH separately were not associated with future risk of VTE, but subjects with high levels of both calcium and PTH had increased risk of VTE compared to those in subjects with normal levels.

Cited by 6 publications

References 42 publications

Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population

Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population

Association of serum vitamin D and parathyroid hormone with subclinical atherosclerotic phenotypes: The Dong-gu Study

Calcium Prevents Enhanced Degradation of Factor VIII in the Condition of Motion

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