Study of a supplement and a genetic test for lymphedema management

Study of a supplement and a genetic test for lymphedema management

Authors

  • Sandro Michelini Department of Vascular Rehabilitation, San Giovanni Battista Hospital, Rome, Italy
  • Marina Cestari Study Centre Pianeta Linfedema, Terni, Italy; Lymphology Sector of the Rehabilitation Service, USLUmbria2, Terni, Italy
  • Serena Michelini Unit of Physical Medicine and Rehabilitation, Sant‘Andrea Hospital, “Sapienza” University of Rome, Rome, Italy
  • Giorgio Camilleri EBTNA-LAB, Rovereto (TN), Italy
  • Luca De Antoni MAGI EUREGIO, Bolzano, Italy
  • Willy Nelson Sonna MAGI EUREGIO, Bolzano, Italy
  • Matteo Bertelli EBTNA-LAB, Rovereto (TN), Italy; MAGI EUREGIO, Bolzano, Italy; MAGI’S LAB, Rovereto (TN), Italy

Keywords:

lymphedema, hydroxytyrosol, leukotriene B4, food supplement

Abstract

Malformations in the lymphatic vasculature, injury, surgery, trauma or toxic damage may lead to swelling of the limbs caused by inefficient lymphatic uptake and flow (lymphedema). Lymphedema can be congenital or acquired. Primary lymphedema is rare and caused by mutations in single genes, secondary lymphedema is more common and caused by a trauma in association with a genetic predisposition. We decided to develop a genetic test that would determine the genetic predisposition to the onset of lymphedema and to predict the course of the disease by analyzing polymorphisms involved in leukotriene B4 (LTB4) synthetic pathway, and variants involved in the onset of secondary lymphedema. There are not many compounds available for the treatment of the negative effects of lymph accumulation, we therefore designed a food supplement based on the hydroxytyrosol, that has anti-oxidant, anti-bacterial and anti-inflammatory activities.

References

Brouillard P, Boon L, Vikkula M. Genetics of lymphatic anomalies. J Clin Invest 2014; 124: 898–904

Lee BB, Villavicencio JL. Primary lymphoedema and lymphatic malformation: are they the two sides of the same coin? Eur J Vasc Endovasc Surg 2010; 39: 646–653

Grada AA, Phillips TJ. Lymphedema: Pathophysiology and clinical manifestations. J Am Acad Dermatol 2017; 77: 1009-1020

Tian W, Rockson SG, Jiang X, et al. Leukotriene B4 antagonism ameliorates experimental lymphedema. Sci Transl Med 2017; 9: eaal3920

Bertelli M, Kiani AK, Paolacci S, et al. Molecular pathways involved in lymphedema: Hydroxytyrosol as a candidate natural compound for treating the effects of lymph accumulation. J Biotechnol 2020; 308: 82-6.

Jang J, Wei J, Kim M, et al. Leukotriene B4 receptor 2 gene polymorphism (rs1950504, Asp196Gly) leads to enhanced cell motility under low-dose ligand stimulation. Exp Mol Med 2017; 49: e402.

Nejatian N, Häfner AK, Shoghi F, Badenhoop K, Penna-Martinez M. 5-Lipoxygenase (ALOX5): Genetic susceptibility to type 2 diabetes and vitamin D effects on monocytes. J Steroid Biochem Mol Biol 2019; 187: 52-7.

Mougey E, Lang JE, Allayee H, et al. ALOX5 polymorphism associates with increased leukotriene production and reduced lung function and asthma control in children with poorly controlled asthma. Clin Exp Allergy 2013; 43: 512-20.

Šerý O, Hlinecká L, Povová J, et al. Arachidonate 5-lipoxygenase (ALOX5) gene polymorphism is associated with Alzheimer's disease and body mass index. J Neurol Sci 2016; 362: 27-32.

Nair J, Shanker J, Jambunathan S, Arvind P, Kakkar VV. Expression analysis of leukotriene-inflammatory gene interaction network in patients with coronary artery disease. J Atheroscler Thromb 2014; 21: 329-45.

Debrah LB, Albers A, Debrah AY, et al. Single nucleotide polymorphisms in the angiogenic and lymphangiogenic pathways are associated with lymphedema caused by Wuchereria bancrofti. Hum Genomics 2017; 11: 26.

Sheik Y, Qureshi SF, Mohhammed B, Nallari P. FOXC2 and FLT4 gene variants in lymphatic filariasis. Lymphat Res Biol 2015; 13: 112-119.

Wang E, Nie Y, Fan X, et al. Minor alleles of genetic variants in second heart field increase the risk of hypoplastic right heart syndrome. J Genet 2019; 98: 45.

Olszewski WL, Zagozda M, Zaleska MT, Durlik M. Predilection to dermato-lymphangio-adenitis in obstructive lymphedema of lower limbs depending on genetic polymorphisms at TNFα-308G>A, CCR2-190G>A, CD14-159C>T, TLR2 2029C>T, TLR4 1063A>G, TLR4 1363C>T, TGFβ 74G>C, and TGFβ 29T>C. Lymphat Res Biol 2018; 16: 109-16.

Pander J, Gelderblom H, Guchelaar HJ. Pharmacogenetics of EGFR and VEGF inhibition. Drug Discov Today 2007; 12: 1054-60.

Chen HY, Chen YM, Wu J, et al. Effects of HGF gene polymorphisms and protein expression on transhepatic arterial chemotherapeutic embolism efficacy and prognosis in patients with primary liver cancer. Onco Targets Ther 2017; 10: 803-10.

Krivospitskaya O, Elmabsout AA, Sundman E, et al. A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis. Mol Med 2012; 18: 712-8.

Kretowski A, Adamska E, Maliszewska K, et al. The rs340874 PROX1 type 2 diabetes mellitus risk variant is associated with visceral fat accumulation and alterations in postprandial glucose and lipid metabolism. Genes Nutr 2015; 10: 4.

Newman B, Lose F, Kedda MA, et al. Possible genetic predisposition to lymphedema after breast cancer. Lymphat Res Biol 2012; 10: 2-13.

Miaskowski C, Dodd M, Paul SM, et al. Lymphatic and angiogenic candidate genes predict the development of secondary lymphedema following breast cancer surgery. PLoS One 2013; 8: e60164.

Wang D, Pan G. Association of rs2910164 polymorphism in miRNA-146 and rs3746444 polymorphism in miRNA-499 with inflammatory arthritis: A meta-analysis. Biomed Res Int 2019; 2019: 7305750.

Castellanos-Rubio A, Ghosh S. Disease-associated SNPs in inflammation-related lncRNAs. Front Immunol 2019; 10: 420.

https://www.ebi.ac.uk/gwas/genes/CALCRL

https://www.ebi.ac.uk/gwas/variants/rs2333496

https://www.ebi.ac.uk/gwas/genes/EPHB4

https://www.ebi.ac.uk/gwas/genes/PLA2G4A

Leung G, Baggott C, West C, et al. Cytokine candidate genes predict the development of secondary lymphedema following breast cancer surgery. Lymphat Res Biol 2014; 12: 10-22.

Farinola N, Piller NB. CYP2A6 polymorphisms: is there a role for pharmacogenomics in preventing coumarin-induced hepatotoxicity in lymphedema patients? Pharmacogenomics 2007; 8: 151-8. doi:10.2217/14622416.8.2.151

Ly CL, Kataru RP, Mehrara BJ. Inflammatory manifestations of lymphedema. Int J Mol Sci 2017; 18: 171.

Angeli V, Randolph GJ. Inflammation, lymphatic function, and dendritic cell migration. Lymphat Res Biol 2006; 4: 217–28.

Rutkowski JM, Moya M, Johannes J, Goldman J, Swartz MA. Secondary lymphedema in the mouse tail: Lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9. Microvasc Res 2006; 72: 161–71.

Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 2008; 214: 199–210.

Murphy RC, Gijón MA. Biosynthesis and metabolism of leukotrienes. Biochem J 2007; 405: 379-95.

Ciana P, Fumagalli M, Trincavelli ML, et al. The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO J 2006; 25: 4615–27.

Henderson WR Jr. The role of leukotrienes in inflammation. Ann Int Med 1994; 121: 684-97.7

Crooks SW, Stockley RA. Leukotriene B4. Int J Biochem Cell Biol 1998; 30: 173-8.

De la Puerta R, Ruiz Gutierrez V, Hoult JR. Inhibition of leukocyte 5-lipoxygenase by phenolics from virgin olive oil. Biochem Pharmacol 1999; 57: 445-9.

Laughton MJ, Evans PJ, Moroney MA, Hoult JR, Halliwell B. Inhibition of mammalian 5-lipoxygenase and cyclo-oxygenase by flavonoids and phenolic dietary additives. Relationship to antioxidant activity and to iron ion-reducing ability. Biochem Pharmacol 1991; 42: 1673-81.

Downloads

Published

09-11-2020

How to Cite

1.
Michelini S, Cestari M, Michelini S, et al. Study of a supplement and a genetic test for lymphedema management. Acta Biomed. 2020;91(13-S):e2020013. doi:10.23750/abm.v91i13-S.10658