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| Name | Class |
|---|---|
| Maastricht University | OTHER |
| Biofortis Mérieux NutriSciences | OTHER |
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This study aims to demonstrate a potential association between gut microbiota composition, plasma levels of various forms of vitamin K, and severity of clinical manifestations of Pseudoxanthoma Elasticum (PXE).
Vitamin K deficiency contributes to pathological calcification which underlies the clinical picture of pseudoxanthoma elasticum (PXE), an inherited autosomal recessive disease. A substantial proportion of vitamin K, namely the K2 form (menaquinones), is produced by gut microbiota. In healthy volunteers fecal levels of the major menaquinone producers, Escherichia coli and Bacteroides species, are approximately 5 and 9 log10 CFU/g dry weight respectively. There is however a lack of data on gut microbiota in PXE patients. The objective of our project is to demonstrate a potential association between gut microbiota composition, plasma levels of various forms of vitamin K and severity of clinical manifestations in PXE patients.
This study will be performed as Research surrounding bio collection "Clinical and biological exploration of PXE patients" kept at the Center of Biological Resources of Angers University Hospital (bio collection n° DC 20116-14-67, authorization to transfer n° 2016-27-99). Fecal samples, plasma samples and clinical data will be collected from patients diagnosed with PXE who will be monitored at the Angers University Hospital Referral Center (France) in 2019-2020. Clinical severity of PXE will be assessed using modified Phenodex score. Gut microbiota will be analyzed using metagenomic sequencing. Plasma Vitamin K species and fecal excretion of menaquinones will be assessed using HPLC. Plasma dp-ucMGP (circulating biomarker of vitamin K status) and serum PIVKA-II (protein induced by vitamin K absence-II) will be assessed using immunoassay. Results will be compared to healthy age- and gender-matched controls from the pre-existing Biofortis database.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PXE cohort 2019-2020 | Other | PXE patient cohort monitored at referral centre from 2019 to 2020: fecal and blood samples |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fecal and blood samples | Diagnostic Test | Fecal samples for intestinal microbiota analysis; Blood and fecal samples for assessment of various forms of vitamin K |
|
| Measure | Description | Time Frame |
|---|---|---|
| Fecal samples for intestinal microbiota analysis | Gut microbiota composition and relative abundance of species (via metagenomic sequencing) | 15 min |
| Fecal samples for assessment of various forms of vitamin K | Fecal Vitamin K species | 15 min |
| Blood samples for assessment of various forms of vitamin K | Plasma Vitamin K species | 15 min |
| Blood samples for assessment of dp-ucMGP | Plasma dp-ucMGP | 15 min |
| Blood samples for assessment of PIVKA-II | Serum PIVKA-II | 15 min |
| Severity of ocular and cardiovascular PXE manifestations and extent of PXE skin changes | Modified Phenodex score:
|
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Ludovic MARTIN, MD, PhD | Contact | +332.41.35.55.76 | LuMartin@chu-angers.fr |
| Name | Affiliation | Role |
|---|---|---|
| Ludovic MARTIN, MD, PhD | Department of Dermatology, University Hospital of Angers | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Biofortis Mérieux NutriSciences | Active, not recruiting | Saint-Herblain | Pays de la Loire Region | 44800 | France | |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24969777 | Background | Jansen RS, Duijst S, Mahakena S, Sommer D, Szeri F, Varadi A, Plomp A, Bergen AA, Oude Elferink RP, Borst P, van de Wetering K. ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report. Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):1985-9. doi: 10.1161/ATVBAHA.114.304017. Epub 2014 Jun 26. | |
| 24277820 |
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| ID | Term |
|---|---|
| D011561 | Pseudoxanthoma Elasticum |
| D002114 | Calcinosis |
| ID | Term |
|---|---|
| D020141 | Hemostatic Disorders |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006474 | Hemorrhagic Disorders |
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| ID | Term |
|---|---|
| D003672 | Defecation |
| D001800 | Blood Specimen Collection |
| ID | Term |
|---|---|
| D004068 | Digestive System Physiological Phenomena |
| D055688 | Digestive System and Oral Physiological Phenomena |
| D013048 | Specimen Handling |
| D019411 | Clinical Laboratory Techniques |
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| 15 min |
| Department of Dermatology, University Hospital of Angers |
| Recruiting |
| Angers |
| Pays de Loire |
| 49933 |
| France |
|
| Department of Biochemistry, University Maastricht | Active, not recruiting | Maastricht | 6229 | Netherlands |
| Background |
| Jansen RS, Kucukosmanoglu A, de Haas M, Sapthu S, Otero JA, Hegman IE, Bergen AA, Gorgels TG, Borst P, van de Wetering K. ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20206-11. doi: 10.1073/pnas.1319582110. Epub 2013 Nov 25. |
| 28416300 | Background | Pomozi V, Brampton C, van de Wetering K, Zoll J, Calio B, Pham K, Owens JB, Marh J, Moisyadi S, Varadi A, Martin L, Bauer C, Erdmann J, Aherrahrou Z, Le Saux O. Pyrophosphate Supplementation Prevents Chronic and Acute Calcification in ABCC6-Deficient Mice. Am J Pathol. 2017 Jun;187(6):1258-1272. doi: 10.1016/j.ajpath.2017.02.009. Epub 2017 Apr 14. |
| 17724449 | Background | Gheduzzi D, Boraldi F, Annovi G, DeVincenzi CP, Schurgers LJ, Vermeer C, Quaglino D, Ronchetti IP. Matrix Gla protein is involved in elastic fiber calcification in the dermis of pseudoxanthoma elasticum patients. Lab Invest. 2007 Oct;87(10):998-1008. doi: 10.1038/labinvest.3700667. Epub 2007 Aug 27. |
| 18222176 | Background | Hendig D, Zarbock R, Szliska C, Kleesiek K, Gotting C. The local calcification inhibitor matrix Gla protein in pseudoxanthoma elasticum. Clin Biochem. 2008 Apr;41(6):407-12. doi: 10.1016/j.clinbiochem.2007.12.023. Epub 2008 Jan 11. |
| 17942075 | Background | Li Q, Jiang Q, Schurgers LJ, Uitto J. Pseudoxanthoma elasticum: reduced gamma-glutamyl carboxylation of matrix gla protein in a mouse model (Abcc6-/-). Biochem Biophys Res Commun. 2007 Dec 14;364(2):208-13. doi: 10.1016/j.bbrc.2007.09.122. Epub 2007 Oct 4. |
| 20368697 | Background | Vanakker OM, Martin L, Schurgers LJ, Quaglino D, Costrop L, Vermeer C, Pasquali-Ronchetti I, Coucke PJ, De Paepe A. Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX mutations in the PXE-like syndrome. Lab Invest. 2010 Jun;90(6):895-905. doi: 10.1038/labinvest.2010.68. Epub 2010 Apr 5. |
| 21725681 | Background | Gorgels TG, Waarsing JH, Herfs M, Versteeg D, Schoensiegel F, Sato T, Schlingemann RO, Ivandic B, Vermeer C, Schurgers LJ, Bergen AA. Vitamin K supplementation increases vitamin K tissue levels but fails to counteract ectopic calcification in a mouse model for pseudoxanthoma elasticum. J Mol Med (Berl). 2011 Nov;89(11):1125-35. doi: 10.1007/s00109-011-0782-y. Epub 2011 Jul 2. |
| 8642453 | Background | Shearer MJ, Bach A, Kohlmeier M. Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health. J Nutr. 1996 Apr;126(4 Suppl):1181S-6S. doi: 10.1093/jn/126.suppl_4.1181S. |
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| 7823718 | Background | Shearer MJ. Vitamin K. Lancet. 1995 Jan 28;345(8944):229-34. doi: 10.1016/s0140-6736(95)90227-9. No abstract available. |
| 23858094 | Background | Walther B, Karl JP, Booth SL, Boyaval P. Menaquinones, bacteria, and the food supply: the relevance of dairy and fermented food products to vitamin K requirements. Adv Nutr. 2013 Jul 1;4(4):463-73. doi: 10.3945/an.113.003855. |
| 6127606 | Background | Bentley R, Meganathan R. Biosynthesis of vitamin K (menaquinone) in bacteria. Microbiol Rev. 1982 Sep;46(3):241-80. doi: 10.1128/mr.46.3.241-280.1982. No abstract available. |
| 1492156 | Background | Conly JM, Stein K. The production of menaquinones (vitamin K2) by intestinal bacteria and their role in maintaining coagulation homeostasis. Prog Food Nutr Sci. 1992 Oct-Dec;16(4):307-43. |
| 23590754 | Background | Beulens JW, Booth SL, van den Heuvel EG, Stoecklin E, Baka A, Vermeer C. The role of menaquinones (vitamin K(2)) in human health. Br J Nutr. 2013 Oct;110(8):1357-68. doi: 10.1017/S0007114513001013. Epub 2013 Apr 16. |
| 1539565 | Background | Conly JM, Stein K. Quantitative and qualitative measurements of K vitamins in human intestinal contents. Am J Gastroenterol. 1992 Mar;87(3):311-6. |
| 17158229 | Background | Schurgers LJ, Teunissen KJ, Hamulyak K, Knapen MH, Vik H, Vermeer C. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood. 2007 Apr 15;109(8):3279-83. doi: 10.1182/blood-2006-08-040709. Epub 2006 Dec 7. |
| 8527227 | Background | Suttie JW. The importance of menaquinones in human nutrition. Annu Rev Nutr. 1995;15:399-417. doi: 10.1146/annurev.nu.15.070195.002151. |
| 2333843 | Background | Usui Y, Tanimura H, Nishimura N, Kobayashi N, Okanoue T, Ozawa K. Vitamin K concentrations in the plasma and liver of surgical patients. Am J Clin Nutr. 1990 May;51(5):846-52. doi: 10.1093/ajcn/51.5.846. |
| 15613016 | Background | Berkner KL, Runge KW. The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis. J Thromb Haemost. 2004 Dec;2(12):2118-32. doi: 10.1111/j.1538-7836.2004.00968.x. |
| 17598002 | Background | Cranenburg EC, Schurgers LJ, Vermeer C. Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost. 2007 Jul;98(1):120-5. |
| 19692494 | Background | McCann JC, Ames BN. Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am J Clin Nutr. 2009 Oct;90(4):889-907. doi: 10.3945/ajcn.2009.27930. Epub 2009 Aug 19. |
| 11085828 | Background | Shearer MJ. Role of vitamin K and Gla proteins in the pathophysiology of osteoporosis and vascular calcification. Curr Opin Clin Nutr Metab Care. 2000 Nov;3(6):433-8. doi: 10.1097/00075197-200011000-00004. |
| 9807700 | Background | Shanahan CM, Proudfoot D, Farzaneh-Far A, Weissberg PL. The role of Gla proteins in vascular calcification. Crit Rev Eukaryot Gene Expr. 1998;8(3-4):357-75. doi: 10.1615/critreveukargeneexpr.v8.i3-4.60. |
| 17138823 | Background | Schurgers LJ, Spronk HM, Soute BA, Schiffers PM, DeMey JG, Vermeer C. Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats. Blood. 2007 Apr 1;109(7):2823-31. doi: 10.1182/blood-2006-07-035345. |
| 23415960 | Background | Li Q, Guo H, Chou DW, Harrington DJ, Schurgers LJ, Terry SF, Uitto J. Warfarin accelerates ectopic mineralization in Abcc6(-/-) mice: clinical relevance to pseudoxanthoma elasticum. Am J Pathol. 2013 Apr;182(4):1139-50. doi: 10.1016/j.ajpath.2012.12.037. Epub 2013 Feb 15. |
| 9052783 | Background | Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997 Mar 6;386(6620):78-81. doi: 10.1038/386078a0. |
| 22516724 | Background | Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue calcification. Adv Nutr. 2012 Mar 1;3(2):166-73. doi: 10.3945/an.111.001628. |
| 19386744 | Background | Shea MK, O'Donnell CJ, Hoffmann U, Dallal GE, Dawson-Hughes B, Ordovas JM, Price PA, Williamson MK, Booth SL. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr. 2009 Jun;89(6):1799-807. doi: 10.3945/ajcn.2008.27338. Epub 2009 Apr 22. |
| 15309455 | Background | Vermeer C, Shearer MJ, Zittermann A, Bolton-Smith C, Szulc P, Hodges S, Walter P, Rambeck W, Stocklin E, Weber P. Beyond deficiency: potential benefits of increased intakes of vitamin K for bone and vascular health. Eur J Nutr. 2004 Dec;43(6):325-35. doi: 10.1007/s00394-004-0480-4. Epub 2004 Feb 5. |
| 15514282 | Background | Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, Hofman A, Witteman JC. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004 Nov;134(11):3100-5. doi: 10.1093/jn/134.11.3100. |
| 19179058 | Background | Gast GC, de Roos NM, Sluijs I, Bots ML, Beulens JW, Geleijnse JM, Witteman JC, Grobbee DE, Peeters PH, van der Schouw YT. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis. 2009 Sep;19(7):504-10. doi: 10.1016/j.numecd.2008.10.004. Epub 2009 Jan 28. |
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| D006402 |
| Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D012868 | Skin Abnormalities |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D012873 | Skin Diseases, Genetic |
| D030342 | Genetic Diseases, Inborn |
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D012871 | Skin Diseases |
| D002128 | Calcium Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D011677 | Punctures |
| D013514 | Surgical Procedures, Operative |
| D008919 | Investigative Techniques |