The association of megalin and cubilin genetic variants with serum levels of 25-hydroxvitamin D and the incidence of acute coronary syndrome in Egyptians: A case control study

Elsabbagh, Raghda A.; Rahman, Mohamed F. Abdel; Hassanein, Sally I.; Hanafi, Rasha S.; Assal, R.A.; Shaban, Gamal M.

doi:10.1016/j.jare.2019.09.006

Cited by 8 publications

(9 citation statements)

References 41 publications

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“…This strongly suggests that this SNP might be related to vitD deficiency and emphasizes the need for additional studies on the association between vitD status and SNPs in LRP2. To our knowledge, there is only one report in the literature and this opposes our finding, with polymorphism rs4667591 in LRP2 not found to be associated with total 25(OH)D ( Elsabbagh et al, 2020 ).…”

Section: Discussioncontrasting

confidence: 99%

“…Our WES study in families having vitD deficiency revealed various variants in genes related to vitD; however, the majority of these variants including the ones in GC (rs9016), CUBN (rs1801222), CASR (rs1801726), and LRP2 (rs4667591) coexisted in both the vitD-deficient families and the non-affected control group (with GC and CASR SNPs having the highest frequency), suggesting no association between these SNPs and 25(OH)D levels. In agreement with our findings, a case–control study in Egyptians ( n = 328) also found that CUBN (rs1801222) was not associated with total 25(OH)D levels Harding et al (2006) and Elsabbagh et al (2020) found no association between 25(OH)D and CASR (rs1801726). With regard to GC (rs9016) and LRP2 (rs4667591), no reports exist in the literature about their relationship with vitD.…”

Section: Discussionsupporting

confidence: 91%

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Whole-Exome Sequencing for Identification of Genetic Variants Involved in Vitamin D Metabolic Pathways in Families With Vitamin D Deficiency in Saudi Arabia

et al. 2021

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BackgroundNumerous research studies have found an association between vitamin D (vitD) status and single-nucleotide polymorphisms (SNPs) in genes involved in vitD metabolism. It is notable that the influence of these SNPs on 25-hydroxyvitamin D [25(OH)D] levels might vary in different populations. In this study, we aimed to explore for genetic variants in genes related to vitD metabolism in families with vitD deficiency in Saudi Arabia using whole-exome sequencing (WES).MethodsThis family-based WES study was conducted for 21 families with vitD deficiency (n = 39) in Saudi Arabia. WES was performed for DNA samples, then resulting WES data was filtered and a number of variants were prioritized and validated by Sanger DNA sequencing.ResultsSeveral missense variants in vitD-related genes were detected in families. We determined two variants in low-density lipoprotein 2 gene (LRP2) with one variant (rs2075252) observed in six individuals, while the other LRP2 variant (rs4667591) was detected in 13 subjects. Single variants in 7-dehydrocholesterol reductase (DHCR7) (rs143587828) and melanocortin-1 receptor (MC1R) (rs1805005) genes were observed in two subjects from two different families. Other variants in group-specific component (GC), cubilin (CUBN), and calcium-sensing receptor (CASR) gene were found in index cases and controls. Polymorphisms in GC (rs9016) and CASR (rs1801726) were found in the majority of family cases (94 and 88%), respectively.ConclusionIn vitD-deficient families in Saudi Arabia, we were able to detect a number of missense exonic variants including variants in GC (rs9016), CUBN (rs1801222), CASR (rs1801726), and LRP2 (rs4667591). However, the existence of these variants was not different between affected family members and non-affected controls. Additionally, we were able to find a mutation in DHCR7 (rs143587828) and a polymorphism in LRP2 (rs2075252), which may affect vitD levels and influence vitD status. Further studies are now required to confirm the association of these variants with vitD deficiency.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 91%

Whole-Exome Sequencing for Identification of Genetic Variants Involved in Vitamin D Metabolic Pathways in Families With Vitamin D Deficiency in Saudi Arabia

et al. 2021

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“…This internalization occurs in specific cells, such as renal tubular, fat, and muscle cells, enabling active transportation. This transpires via the megalin with its co-receptor, cubilin [ 79 ]. In addition, vitamin D influences mitochondrial functions directly and indirectly, including fusion, energy production, modulation of mitochondrial membrane potential, regulation of ion channels, and apoptosis [ 78 ].…”

Section: Vitamin D Generation—genomic and Non-genomic Actionsmentioning

confidence: 99%

Physiological Basis for Using Vitamin D to Improve Health

Wimalawansa

2023

Biomedicines

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Vitamin D is essential for life—its sufficiency improves metabolism, hormonal release, immune functions, and maintaining health. Vitamin D deficiency increases the vulnerability and severity of type 2 diabetes, metabolic syndrome, cancer, obesity, and infections. The active enzyme that generates vitamin D [calcitriol: 1,25(OH)2D], CYP27B1 (1a-hydoxylase), and its receptors (VDRs) are distributed ubiquitously in cells. Once calcitriol binds with VDRs, the complexes are translocated to the nucleus and interact with responsive elements, up- or down-regulating the expression of over 1200 genes and modulating metabolic and physiological functions. Administration of vitamin D3 or correct metabolites at proper doses and frequency for longer periods would achieve the intended benefits. While various tissues have different thresholds for 25(OH)D concentrations, levels above 50 ng/mL are necessary to mitigate conditions such as infections/sepsis, cancer, and reduce premature deaths. Cholecalciferol (D3) (not its metabolites) should be used to correct vitamin D deficiency and raise serum 25(OH)D to the target concentration. In contrast, calcifediol [25(OH)D] raises serum 25(OH)D concentrations rapidly and is the agent of choice in emergencies such as infections, for those who are in ICUs, and for insufficient hepatic 25-hydroxylase (CYP2R1) activity. In contrast, calcitriol is necessary to maintain serum-ionized calcium concentration in persons with advanced renal failure and hypoparathyroidism. Calcitriol is, however, ineffective in most other conditions, including infections, and as vitamin D replacement therapy. Considering the high costs and higher incidence of adverse effects due to narrow therapeutic margins (ED50), 1α-vitamin D analogs, such as 1α-(OH)D and 1,25(OH)2D, should not be used for other conditions. Calcifediol analogs cost 20 times more than D3—thus, they are not indicated as a routine vitamin D supplement for hypovitaminosis D, osteoporosis, or renal failure. Healthcare workers should resist accepting inappropriate promotions, such as calcifediol for chronic renal failure and calcitriol for osteoporosis or infections—there is no physiological rationale for doing so. Maintaining the population’s vitamin D sufficiency (above 40 ng/mL) with vitamin D3 supplements and/or daily sun exposure is the most cost-effective way to reduce chronic diseases and sepsis, overcome viral epidemics and pandemics, and reduce healthcare costs. Furthermore, vitamin D sufficiency improves overall health (hence reducing absenteeism), reduces the severity of chronic diseases such as metabolic and cardiovascular diseases and cancer, decreases all-cause mortality, and minimizes infection-related complications such as sepsis and COVID-19-related hospitalizations and deaths. Properly using vitamin D is the most cost-effective way to reduce chronic illnesses and healthcare costs: thus, it should be a part of routine clinical care.

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“…[17] LRP2 gene polymorphisms in humans have been linked to neural tube defects and cognitive impairment, elevated uric acid and gout, hypercholesterolemia, central adiposity, diabetic nephropathy, hypovitaminosis D and acute coronary syndrome, decreased Abeta amyloid clearance through the choroid plexus in Alzheimer's disease, susceptibility to Alzheimer's disease in Caucasians and ethnic Chinese Han, relapse rate of multiple sclerosis, and gallstone disease. [18][19][20][21][22][23][24][25][26][27] A study of African Americans found a unique missense megalin mutation that protected from end-stage kidney disease in patients with type 2-diabetes mellitus. [28]…”

Section: Megalin Is Essential For Brain Development and Normal Physio...mentioning

confidence: 99%

Megalin Facilitates the Regulation of Mitochondrial Function by Extracellular Cues

Li,

Sheikh-Hamad

2023

Integr Med Nephrol Androl

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Megalin (also known as low density lipoprotein-receptor related protein 2 [LRP2]) is a multi-ligand cell-surface endocytic receptor expressed widely; it is important for the uptake of vitamins, nutrients and hormones. We recently reported the discovery of LRP2/megalin in the mitochondria of many cells and organs. Importantly, megalin traffics the mitochondrial intracrines stanniocalcin-1, TGF-β and angiotensin II from the extracellular milieu to the mitochondria. This transport parallels the retrograde early endosome to Golgi pathway and requires the Rab GTPase Rab32 in the mitochondria, megalin associates with sirtuin family of class III histone deacetylases (Sirt3) and stanniocalcin-1 (Stc1), which are important for anti-oxidant defenses. Deletion of megalin impairs mitochondrial respiration and glycolysis. The interaction between stanniocalcin-1 and megalin is mediated by leucines within the signal peptides of the proteins; and this interaction is essential to the stimulation of mitochondrial respiration and glycolysis by stanniocalcin-1. Our findings suggest that megalin facilitates the regulation of mitochondrial function by extracellular cues.

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The association of megalin and cubilin genetic variants with serum levels of 25-hydroxvitamin D and the incidence of acute coronary syndrome in Egyptians: A case control study

Abstract: Graphical abstract

Cited by 8 publications

References 41 publications

Whole-Exome Sequencing for Identification of Genetic Variants Involved in Vitamin D Metabolic Pathways in Families With Vitamin D Deficiency in Saudi Arabia

Whole-Exome Sequencing for Identification of Genetic Variants Involved in Vitamin D Metabolic Pathways in Families With Vitamin D Deficiency in Saudi Arabia

Physiological Basis for Using Vitamin D to Improve Health

Megalin Facilitates the Regulation of Mitochondrial Function by Extracellular Cues

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