Candidate gene polymorphisms/abnormalities and their proposed evidence-based associations in chronic venous disease
| Reference . | Study details . | Gene . | Proposed function . | Polymorphisms/abnormality . | Results . | Strength of association . |
|---|---|---|---|---|---|---|
| VV | ||||||
| 20 | Basic science | VEGF-A/VEGF-R2 | Vessel wall integrity, angiogenesis | Increased mRNA/protein expression | Increased VEGF-A and VEGF-R2 content in VV vs normal wall tissue | P < .001 |
| VEGF-A: 41.76 vs 25.79 ng/g | ||||||
| VEGF-R2: 57.47 vs 28.92 ng/g | ||||||
| 6 | Basic science/genetic microarrays | HSP-90 | Protein degradation | Upregulated | 32/74 genes upregulated in VV compared with control | VV:CV (control veins) ≥2-fold increase in intensity |
| ILK | Cell signaling, apoptosis | |||||
| TGF-β1 | Cell proliferation and apoptosis | |||||
| 24 | Basic science/twin linkage analysis using marker gene D16S520 | FOXC2 | Lymphatic and vascular/venous development | Functional variants | Concordance rates significantly higher for monozygotic vs dizygotic (VV: 67% vs 45%) | P = 2.2E-6 |
| 26 | Basic science | FOXC2 mutations (varied) | Great saphenous vein reflux in 18/18 with various FOXC2 mutations (deep vein reflux: 14/18) vs 1/12 in referents | P < .0001 | ||
| 25 | Basic science/genomic analysis and sequencing | 1. −91C → G | SNPs in proximal upstream region of FOXC2 in VV/hemorrhoid patients (not in controls) | NA | ||
| 2. −41G → A | –SNP 1: 5/24 (20.8%) | |||||
| 3. −41G → T | –SNP 2: 2/24 (8%) | |||||
| –SNP 3: 1/24 (4.2%) | ||||||
| 19 | Basic science/vein immunostaining | Type I/III collagen | ECM integrity | Type III collagen deposition decreased | Type III collagen dpm/106: ∼290 vs ∼40 (control vs varicose vein smooth muscle cells, n = 8); no difference in type I collagen and mRNA expression | P < .005 |
| 8 | Basic science/gene expression | Overexpression | Relative mRNA expression in varicose vs nonvaricose vein tissue: type I collagen 2.33, type III collagen 1.70 | Type I: P < .001 | ||
| Type III: P < .01 | ||||||
| MGP | Vein wall remodelling | Overexpression | Higher relative MGP expression in varicose vs nonvaricose vein tissue (1.74 vs 1.1) | P < .0001 | ||
| 27 | Basic science/gene expression | Oct-1 | Cellular response to stress/regulation of gene expression | Upregulation | Significantly higher mRNA levels and protein expression of Oct-1 in varicose veins vs normal vein tissue | P < .001 |
| Venous ulcers/wound healing | ||||||
| 28 | Basic science case-control study | TNF-α | Inflammation | −308G → A | Presence of allele: 43.1% in ulcer patients vs 22.6% in controls | OR: 2.48 |
| P = .000155 | ||||||
| BAT1 | Apoptosis; linkage with TNFα | Intron 10 [–/C] | Presence of allele: 28.8% in ulcer patients vs 16.3% in controls | OR: 2.00 | ||
| P = .012 | ||||||
| 9 | Basic science/gene expression | a-FGF/FGF-R2 | Connective tissue regeneration, wound healing, ECM metabolism | Overexpression of aFGF and increased aFGF mRNA | Vein wall aFGF content: 32.21 pg/g of protein in VV vs 24.68 pg/g in normal veins | P < .001 |
| No significant difference in FGF-R expression | ||||||
| 29 | Basic science/genetic analysis | FGF-R2: 2451A → G (Grzela et al) (rs7895676) (rs2981578) | Heterozygotes: 53.66% in leg ulcer patients vs 45.12% in controls | P = .0103 | ||
| Homozygotes: 23.17% vs 13.42% | ||||||
| 30 | Basic science case control study | ERβ | Estrogen receptor; inflammatory and repair processes | Upstream regulatory regions, including 0N exon and promoter | Cases vs controls | 1. P = .025 |
| 1. −16849C → T | 1. 58% vs 49% | 2. P = .010 | ||||
| 2. −13850T → C | 2. 34% vs 25% | 3. P = .002 | ||||
| 3. −10808G → T | 3. 13% vs 7% | 4. P = .013 | ||||
| 4. −1569C → A | 4. 47% vs 38% | T-T-T-A haplotype OR: 2.9 | ||||
| T-T-T-A haplotype significantly associated with venous ulceration | ||||||
| 31 | Basic science/DNA array study | HFE | Regulation of iron absorption | 282G → A | Heterozygotes: 9.9% in ulcer patients vs 1.8% in controls | OR: 4.5 |
| Homozygotes: 0.6% vs 0% | P = .001 | |||||
| FPN1 | Iron export | −8C → G | Heterozygotes: 34% in ulcer patients vs 30.8% in controls | OR: 5.2 | ||
| Homozygotes: 8.6% vs 2.3% | P = .005 | |||||
| CVI | ||||||
| 32 | Basic science/genetics | MTHFR | Homocysteine metabolism | 677C → T | Based on CEAP classification: | P < .001 |
| C2-3: 10% homozygous for C677T | ||||||
| C4-6: 20% | ||||||
| Overall, 15% homozygous for C677T vs 5% in healthy population | ||||||
| 4 | Basic science/DNA extraction and genotyping | α-2 Type I collagen (COL1A2) | ECM integrity | rs3917 (7-base pair indel polymorphism in 3′UTR) | Indel polymorphism present in 12.2% of CVI cases vs 8% controls | OR: 1.60 P = .008 |
| LDS | ||||||
| 33 | Basic science/pathology + gene expression | Procollagen (COL1A1) | ECM integrity | Overexpression | Increased procollagen type I mRNA (COL1A1) in LDS vs other patient groups from increased mesenchymal cells/fibroblasts (LDS vs control: 180 vs 97 per 50 000 μm2) | P < .001 |
| MMPs: VV, CVI, venous ulcers | ||||||
| 31 | Basic science/DNA array study | MMPs | ECM degradation | MMP-12: −82A → G | Smaller ulcer size in patients with −82GG genotype | P = .001 |
| −82GG: 5.4 ± 2 cm2 | ||||||
| −82AA + AG: 11.1 ± 17.1 cm2 | ||||||
| 40 | Basic science/genotyping | MMP-9: −1562C/C | −1562C allele frequency: 81.7% in VV group vs 48.3% in controls | P = .000 | ||
| OR: 6.102 | ||||||
| 38 | Basic science (mice) | MMP-9−/− | Vein walls of MMP9−/− mice had 45% less collagen content/fibrosis vs controls at 8 and 21 d after stasis thrombosis injury | P < .01 | ||
| 23 | Basic science/gene expression | Overexpression of MMP-1 mRNA and MMP-2 protein | CVI patients, class 1-6 | MMP-1 mRNA: P < .01 | ||
| MMP-1 mRNA: 0.002 (control) vs 4.15 (class 4) vs 31.2 (class 6) | TIMP-1: P < .05 | |||||
| TIMP-1: 2.56 (control) vs 23.45 (class 6) | ||||||
| Active component of MMP-2 increased in class 4-5 patients relative to MMP-1 and TIMP-1 | ||||||
| 41 | Basic science/gene expression | Overexpression of MMP-1,2,13 | Increased expression of MMP-1, -2, and -13 mRNA in lesional skin (stasis dermatitis) vs controls | P < .05 | ||
| 42 | Basic science/gene expression | Overexpression of MMP-1,2,3,8,9,12,13 | MMP-1, -2, -3, -8, -9, -12, and -13 protein levels elevated in ulcer tissue vs controls; MMP-1, -9, -8, and -13 had at least an 80-fold increase | P < .005 (majority) | ||
| 36 | Basic science/gene expression (mice) | Overexpression of MMP-2 and MMP-14 (MT1-MMP) | During resolution of DVT: 71% increase in MMP-2 activity in ligated cavae (DVT generated) vs controls; MMP-14 mRNA upregulated 2.5-fold compared with controls | P < .05 | ||
| 8 | Basic science/gene expression | TIMPs | Inhibitors of MMP | Overexpression of TIMP-1 | Higher relative TIMP-1 mRNA expression in varicose vs nonvaricose veins (2.06 ± 0.26) | P < .01 |
| 40 | Basic science/genotyping | TIMP-2: −418G -→ C | Allele frequency: 23.3% in VV group vs 14.2% in controls | P = .038 | ||
| OR: 2.213 | ||||||
| Unclear significance | ||||||
| 34 | Basic science/gene expression | Diminished TIMP-1,2 | Low gene expression and immunoreactivity of TIMP-1,2 in stasis dermatitis vs controls | NS | ||
| PTS | ||||||
| 37 | Basic science (mice) | IL-6 | Inflammation | IL-6 as therapeutic target | Mice with IVC thrombus treated with anti-IL-6 had decreased vein wall fibrosis (intimal thickness reduced by 44%) vs those treated with control rat IgG | P < .05 |
| Reference . | Study details . | Gene . | Proposed function . | Polymorphisms/abnormality . | Results . | Strength of association . |
|---|---|---|---|---|---|---|
| VV | ||||||
| 20 | Basic science | VEGF-A/VEGF-R2 | Vessel wall integrity, angiogenesis | Increased mRNA/protein expression | Increased VEGF-A and VEGF-R2 content in VV vs normal wall tissue | P < .001 |
| VEGF-A: 41.76 vs 25.79 ng/g | ||||||
| VEGF-R2: 57.47 vs 28.92 ng/g | ||||||
| 6 | Basic science/genetic microarrays | HSP-90 | Protein degradation | Upregulated | 32/74 genes upregulated in VV compared with control | VV:CV (control veins) ≥2-fold increase in intensity |
| ILK | Cell signaling, apoptosis | |||||
| TGF-β1 | Cell proliferation and apoptosis | |||||
| 24 | Basic science/twin linkage analysis using marker gene D16S520 | FOXC2 | Lymphatic and vascular/venous development | Functional variants | Concordance rates significantly higher for monozygotic vs dizygotic (VV: 67% vs 45%) | P = 2.2E-6 |
| 26 | Basic science | FOXC2 mutations (varied) | Great saphenous vein reflux in 18/18 with various FOXC2 mutations (deep vein reflux: 14/18) vs 1/12 in referents | P < .0001 | ||
| 25 | Basic science/genomic analysis and sequencing | 1. −91C → G | SNPs in proximal upstream region of FOXC2 in VV/hemorrhoid patients (not in controls) | NA | ||
| 2. −41G → A | –SNP 1: 5/24 (20.8%) | |||||
| 3. −41G → T | –SNP 2: 2/24 (8%) | |||||
| –SNP 3: 1/24 (4.2%) | ||||||
| 19 | Basic science/vein immunostaining | Type I/III collagen | ECM integrity | Type III collagen deposition decreased | Type III collagen dpm/106: ∼290 vs ∼40 (control vs varicose vein smooth muscle cells, n = 8); no difference in type I collagen and mRNA expression | P < .005 |
| 8 | Basic science/gene expression | Overexpression | Relative mRNA expression in varicose vs nonvaricose vein tissue: type I collagen 2.33, type III collagen 1.70 | Type I: P < .001 | ||
| Type III: P < .01 | ||||||
| MGP | Vein wall remodelling | Overexpression | Higher relative MGP expression in varicose vs nonvaricose vein tissue (1.74 vs 1.1) | P < .0001 | ||
| 27 | Basic science/gene expression | Oct-1 | Cellular response to stress/regulation of gene expression | Upregulation | Significantly higher mRNA levels and protein expression of Oct-1 in varicose veins vs normal vein tissue | P < .001 |
| Venous ulcers/wound healing | ||||||
| 28 | Basic science case-control study | TNF-α | Inflammation | −308G → A | Presence of allele: 43.1% in ulcer patients vs 22.6% in controls | OR: 2.48 |
| P = .000155 | ||||||
| BAT1 | Apoptosis; linkage with TNFα | Intron 10 [–/C] | Presence of allele: 28.8% in ulcer patients vs 16.3% in controls | OR: 2.00 | ||
| P = .012 | ||||||
| 9 | Basic science/gene expression | a-FGF/FGF-R2 | Connective tissue regeneration, wound healing, ECM metabolism | Overexpression of aFGF and increased aFGF mRNA | Vein wall aFGF content: 32.21 pg/g of protein in VV vs 24.68 pg/g in normal veins | P < .001 |
| No significant difference in FGF-R expression | ||||||
| 29 | Basic science/genetic analysis | FGF-R2: 2451A → G (Grzela et al) (rs7895676) (rs2981578) | Heterozygotes: 53.66% in leg ulcer patients vs 45.12% in controls | P = .0103 | ||
| Homozygotes: 23.17% vs 13.42% | ||||||
| 30 | Basic science case control study | ERβ | Estrogen receptor; inflammatory and repair processes | Upstream regulatory regions, including 0N exon and promoter | Cases vs controls | 1. P = .025 |
| 1. −16849C → T | 1. 58% vs 49% | 2. P = .010 | ||||
| 2. −13850T → C | 2. 34% vs 25% | 3. P = .002 | ||||
| 3. −10808G → T | 3. 13% vs 7% | 4. P = .013 | ||||
| 4. −1569C → A | 4. 47% vs 38% | T-T-T-A haplotype OR: 2.9 | ||||
| T-T-T-A haplotype significantly associated with venous ulceration | ||||||
| 31 | Basic science/DNA array study | HFE | Regulation of iron absorption | 282G → A | Heterozygotes: 9.9% in ulcer patients vs 1.8% in controls | OR: 4.5 |
| Homozygotes: 0.6% vs 0% | P = .001 | |||||
| FPN1 | Iron export | −8C → G | Heterozygotes: 34% in ulcer patients vs 30.8% in controls | OR: 5.2 | ||
| Homozygotes: 8.6% vs 2.3% | P = .005 | |||||
| CVI | ||||||
| 32 | Basic science/genetics | MTHFR | Homocysteine metabolism | 677C → T | Based on CEAP classification: | P < .001 |
| C2-3: 10% homozygous for C677T | ||||||
| C4-6: 20% | ||||||
| Overall, 15% homozygous for C677T vs 5% in healthy population | ||||||
| 4 | Basic science/DNA extraction and genotyping | α-2 Type I collagen (COL1A2) | ECM integrity | rs3917 (7-base pair indel polymorphism in 3′UTR) | Indel polymorphism present in 12.2% of CVI cases vs 8% controls | OR: 1.60 P = .008 |
| LDS | ||||||
| 33 | Basic science/pathology + gene expression | Procollagen (COL1A1) | ECM integrity | Overexpression | Increased procollagen type I mRNA (COL1A1) in LDS vs other patient groups from increased mesenchymal cells/fibroblasts (LDS vs control: 180 vs 97 per 50 000 μm2) | P < .001 |
| MMPs: VV, CVI, venous ulcers | ||||||
| 31 | Basic science/DNA array study | MMPs | ECM degradation | MMP-12: −82A → G | Smaller ulcer size in patients with −82GG genotype | P = .001 |
| −82GG: 5.4 ± 2 cm2 | ||||||
| −82AA + AG: 11.1 ± 17.1 cm2 | ||||||
| 40 | Basic science/genotyping | MMP-9: −1562C/C | −1562C allele frequency: 81.7% in VV group vs 48.3% in controls | P = .000 | ||
| OR: 6.102 | ||||||
| 38 | Basic science (mice) | MMP-9−/− | Vein walls of MMP9−/− mice had 45% less collagen content/fibrosis vs controls at 8 and 21 d after stasis thrombosis injury | P < .01 | ||
| 23 | Basic science/gene expression | Overexpression of MMP-1 mRNA and MMP-2 protein | CVI patients, class 1-6 | MMP-1 mRNA: P < .01 | ||
| MMP-1 mRNA: 0.002 (control) vs 4.15 (class 4) vs 31.2 (class 6) | TIMP-1: P < .05 | |||||
| TIMP-1: 2.56 (control) vs 23.45 (class 6) | ||||||
| Active component of MMP-2 increased in class 4-5 patients relative to MMP-1 and TIMP-1 | ||||||
| 41 | Basic science/gene expression | Overexpression of MMP-1,2,13 | Increased expression of MMP-1, -2, and -13 mRNA in lesional skin (stasis dermatitis) vs controls | P < .05 | ||
| 42 | Basic science/gene expression | Overexpression of MMP-1,2,3,8,9,12,13 | MMP-1, -2, -3, -8, -9, -12, and -13 protein levels elevated in ulcer tissue vs controls; MMP-1, -9, -8, and -13 had at least an 80-fold increase | P < .005 (majority) | ||
| 36 | Basic science/gene expression (mice) | Overexpression of MMP-2 and MMP-14 (MT1-MMP) | During resolution of DVT: 71% increase in MMP-2 activity in ligated cavae (DVT generated) vs controls; MMP-14 mRNA upregulated 2.5-fold compared with controls | P < .05 | ||
| 8 | Basic science/gene expression | TIMPs | Inhibitors of MMP | Overexpression of TIMP-1 | Higher relative TIMP-1 mRNA expression in varicose vs nonvaricose veins (2.06 ± 0.26) | P < .01 |
| 40 | Basic science/genotyping | TIMP-2: −418G -→ C | Allele frequency: 23.3% in VV group vs 14.2% in controls | P = .038 | ||
| OR: 2.213 | ||||||
| Unclear significance | ||||||
| 34 | Basic science/gene expression | Diminished TIMP-1,2 | Low gene expression and immunoreactivity of TIMP-1,2 in stasis dermatitis vs controls | NS | ||
| PTS | ||||||
| 37 | Basic science (mice) | IL-6 | Inflammation | IL-6 as therapeutic target | Mice with IVC thrombus treated with anti-IL-6 had decreased vein wall fibrosis (intimal thickness reduced by 44%) vs those treated with control rat IgG | P < .05 |
ER, estrogen receptor; HFE, hemochromatosis; NA, not available; NS, not significant; VV, varicose veins.