Table 1.
Polymorphisms that can predispose to secondary lymphedema and/or modulated the clinical course of lymphedema
| Gene | Gene function (GeneCards) | rs ID, alleles | Association | Ref. |
| LTB4R2 | Chemotaxis mediation of granulocytes and macrophages | rs1950504, A/G | Enhanced ROS generation/AKT phosphorylation under LTB4 low-dose conditions. Enhanced cell motility under low-dose ligand stimulation | 6 |
| ALOX5 | Catalyzes the first step in leukotriene biosynthesis and has a role in inflammatory processes | rs4987105, C/T | Lower 25(OH)D3 and 1,25(OH)2D3, and higher C-reactive protein levels in homozygote CC carriers. This may indicate a chronic inflammatory profile. It modulates the response to the leukotriene antagonist montelukast | 7 |
| rs59439148, del(GGGGGC)4/3/2/del(G)5C/dup(G)5C/dup(GGGGGC)2/3 | Determination of the expression levels of ALOX5. Two copies of a minor variant of the ALOX5 promoter SP1 tandem repeat polymorphism is associated with increased cysteinyl leukotriene production | 8 | ||
| rs4769874, G/A | GG genotype is associated with modest increase in body mass index. The A-allele potentiates the expression of ALOX5 and/or the function of FLAP | 9 | ||
| LTA4H | Epoxide hydrolase that catalyzes the final step in the biosynthesis of leukotriene B4 | rs17525495, C/T | T allele associated with lower levels of LTA4H. The presence of the T allele significantly increased the proportion of Crohn’s patients requiring glucocorticoids | 10 |
| rs1978331, C/T | ||||
| MMP2 | Metalloproteinase involved in remodeling of the vasculature, angiogenesis, tissue repair, inflammation | rs1030868, G/A | A allele, higher risk of secondary lymphedema | 11 |
| rs2241145, G/C | C, higher risk of secondary lymphedema | 11 | ||
| CEACAM1 | Cell-cell adhesion molecule with roles in angiogenesis, modulation of immune response. Inflammasome activity reduction. Blood vessel remodeling through endothelial cell differentiation and migration. Vascular permeability regulation | rs8110904, G/A | A, higher risk of secondary lymphedema | 11 |
| rs8111171, G/T | T, higher risk of secondary lymphedema | 11 | ||
| FOXC2 | Transcriptional activator. Involved in the mesenchymal tissue formation | rs199772307, G/A | AA genotype more frequent in lymphatic filariasis patients, influence on the severity of lymphedema | 12 |
| rs34221221, A/G | G allele, increased expression | 13 | ||
| TNF | Cellular responses to cytokines and stress. It regulates the immunological response to infections | rs1800629, G/A | High percentage of TNFa homozygotes GG in patients with dermato-lymphangio-adenitis in obstructive lymphedema of lower limbs | 14 |
| TLR2 | Key role in the innate immune system. It is expressed in macrophages, B lymphocytes, mast cells | rs121917864, C/T | Low percentage of CT heterozygotes and TT homozygotes in patients with dermato-lymphangio-adenitis in obstructive lymphedema of lower limbs | |
| TLR4 | Key role in the innate immune system. It is expressed in macrophages, B lymphocytes, mast cells | rs4986791, C/T | High percentage of CT heterozygotes and TT homozygotes in patients with dermato-lymphangio-adenitis in obstructive lymphedema of lower limbs | |
| VEGFA | Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels | rs699947, C/A | -2578C>A Lower or higher expression | 15 |
| -1154G>A | A allele, lower expression | 15 | ||
| -460C>T | T allele, increased promoter activity | 15 | ||
| +405G>C | C allele, lower or higher expression | 15 | ||
| +936C>T | T allele, lower expression | 15 | ||
| HGF | Role in angiogenesis, tumorigenesis, tissue regeneration | rs5745652, C/T | CC genotype is associated with lower serum HGF levels | 16 |
| rs2074725, C/A | CA and AA genotypes are associated with lower serum HGF levels | 16 | ||
| CYP26B1 | Involved in the metabolism of retinoic acid | rs2241057, A/G | G allele associated with higher levels of retinoic acid catabolism and reduced retinoid availability | 17 |
| PROX1 | Critical role in neurogenesis, development of the heart, eye lens, liver, pancreas and lymphatic system | rs340874, T/C | CC genotype is associated with higher nonesterified fatty acids levels, lower glucose oxidation, higher accumulation of visceral fat | 18 |
| RORC | Essential for lymphoid organogenesis | rs11801866, A/T | T allele, higher risk of secondary lymphedema, might affect transcription factor binding sites | 19 |
| rs12128071, G/A | It might affect transcription factor binding sites | 19 | ||
| rs12045886, A/G | G allele, secondary lymphedema predisposition after breast cancer surgery | 19 | ||
| LCP2 | T-cell antigen receptor mediated signaling | rs572192, C/T | T allele, secondary lymphedema predisposition after breast cancer surgery | 20 |
| rs6866733, C/G,T | T allele, secondary lymphedema predisposition after breast cancer surgery | 20 | ||
| rs315721, A/G | AG and GG genotype are associated with a 50% decrease in the odds of developing secondary lymphedema | 20 | ||
| NRP2 | It binds interacts with vascular endothelial growth factor (VEGF) | rs849530, G/T | TT and TG genotype are associated with 62% decrease in the odds of developing secondary lymphedema | 20 |
| rs849563, T/A,G | G allele, secondary lymphedema predisposition after breast cancer surgery | 20 | ||
| rs16837641, G/A,C,T | A allele, secondary lymphedema predisposition after breast cancer surgery | 20 | ||
| SYK | Regulation of innate and adaptive immunity, vascular development. Plays a crucial role in the innate immune response to fungal, bacterial and viral pathogens. Activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. It is involved in vascular development where it may regulate blood and lymphatic vascular separation | rs158689, T/A | AA and AT genotypes are associated with 3.43-fold increase in the odds of developing secondary lymphedema | 20 |
| VCAM1 | Pathophysiologic role in immune responses and leukocyte emigration to sites of inflammation | rs3176861, C/T | CT and TT genotypes are associated with a 45.0% decrease in the odds of developing secondary lymphedema | 20 |
| miR499 | miR-499 gene targets are involved in remodeling and inflammation-related signaling pathways; including fibrogenic and immune-modulator pathways | rs3746444, A/C,G | Associated with inflammatory arthritis susceptibility. The A allele creates an altered target gene set. Disruption of 667 genes of the miR-499a targets and creation of new 763 genes | 21 |
| CDKN2B-AS1 | Interacts with polycomb repressive complex-1 and -2, leading to epigenetic silencing | rs1333048, A/C,G | AA genotype is associated with elevated C-reactive protein plasma levels | 22 |
| CALCRL | Receptor for calcitonin-gene-related peptide together with RAMP1 and receptor for adrenomedullin together with RAMP3 and RAMP2 | rs185008808, C/T | Common colds susceptibility | 23 |
| rs61739909, A/G | Waist-hip ratio | 23 | ||
| rs10177093, G/C,T | Waist-hip ratio | 23 | ||
| VEGFC | Growth factor active in angiogenesis of veins and lymphatics, endothelial cell growth, stimulating their proliferation, migration, permeability of blood vessels | rs2333496, C/T | T allele, waist-hip ratio increase | 24 |
| rs7664413, C/T | T allele, secondary lymphedema predisposition after breast cancer surgery | 20 | ||
| EPHB4 | Regulation of cell adhesion and migration, angiogenesis, blood vessel remodeling, permeability | rs314313, T/A,C,G | G allele, Crohn’s disease/ulcerative colitis/inflammatory bowel disease susceptibility | 25 |
| rs314311, T/G | T allele, low density lipoprotein cholesterol levels decrease | |||
| PLA2G4A | Hydrolyzes arachidonyl phospholipids for releasing arachidonic acid. Implicated in the initiation of the inflammatory response. | rs10798069, G/T | G allele, Crohn’s disease/Inflammatory bowel disease | 26 |
| IL1R1 | Mediator involved in cytokine-induced immune and inflammatory responses. | rs949963, C/T | A allele, secondary lymphedema predisposition after breast cancer surgery | 27 |
| IL4 | B-cell activation, DNA synthesis stimulation, expression induction of MHC-II on resting B-cells, secretion enhancement and cell surface expression of IgE, IgG, expression regulation CD23 IgE receptor on lymphocytes and monocytes, expression induction of IL31RA in macrophages, autophagy stimulation in dendritic cells | rs2227284, T/C,G | A allele, secondary lymphedema predisposition after breast cancer surgery | 27 |
| IL6 | Inducer of the acute phase response, final differentiation of B cells into Ig-secreting cells, lymphocyte and monocyte differentiation, generation of Th17 cells, myokine, increase the breakdown of fats, improve insulin resistance | rs2066992, G/A,C,T | T allele, secondary lymphedema predisposition after breast cancer surgery | 27 |
| IL10 | Cytokine produced by monocytes, lymphocytes, pleiotropic effects in immunoregulation, inflammation, down-regulation of Th1 cytokines expression, MHC-II, stimulator of macrophages, B cell survival enhancement, proliferation, antibody production | rs1518111, T/C | T allele, secondary lymphedema predisposition after breast cancer surgery | 27 |
| rs1518110, A/C,G,T | A allele, secondary lymphedema predisposition after breast cancer surgery | |||
| NFKB2 | Pleiotropic transcription factor ubiquitously expressed involved in inflammation, immunity, differentiation, cell growth, tumorigenesis, apoptosis | rs1056890, G/A,C | A allele, secondary lymphedema predisposition after breast cancer surgery | 27 |
| ANGPT2 | Endothelial cell migration and proliferation | rs6990020, C/A,T | C allele, secondary lymphedema predisposition after breast cancer surgery | 20 |
| SOX17 | Embryonic vascular development, postnatal angiogenesis | rs12541742, C/G,T | T allele, secondary lymphedema predisposition after breast cancer surgery | 20 |
| FLT4 | Lymphangiogenesis and maintenance of the lymphatic endothelium | rs75614493, C/T | C, higher risk of secondary lymphedema | 11 |
| rs10464063, A/G | G allele, secondary lymphedema predisposition after breast cancer surgery | 19 | ||
| rs307814, G/A | A allele, secondary lymphedema predisposition after breast cancer surgery | |||
| rs307811, C/T | T allele, secondary lymphedema predisposition after breast cancer surgery | |||
| rs11960332, C/T | T allele, secondary lymphedema predisposition after breast cancer surgery | |||
| rs11739214, G/C | C allele, secondary lymphedema predisposition after breast cancer surgery | |||
| KDR | Endothelial proliferation, survival, migration, tubular morphogenesis, sprouting. | rs2239702, G/A | A allele, secondary lymphedema predisposition after breast cancer surgery | 19 |
| rs4576072, A/G | G allele, secondary lymphedema predisposition after breast cancer surgery | |||
| rs10020464, C/A,T | T allele, secondary lymphedema predisposition after breast cancer surgery | 20 | ||
| rs11133360, C/T | C allele, secondary lymphedema predisposition after breast cancer surgery | |||
| CYP2A6 | High coumarin 7-hydroxylase activity | rs1801272, T/A | A allele, significant reduction of coumarin metabolism | 28 |