Table 1.
Lymphatic and angiogenic genes and single nucleotide polymorphisms analyzed for lymphedema versus no lymphedema.
Table 2.
Differences in demographic and clinical characteristics between patients with (n = 155) and without (n = 387) lymphedema.
Table 3.
Multiple logistic regression analyses for phenotypic predictors of the development of lymphedema.
Table 4.
Multiple logistic regression analyses for FOXC2. LCP2, NRP2, SYK, VCAM1, and VEGF-C genotypes and halotypes to predict the development of lymphedema.
Figure 1.
FOXC2 Gene Structure and Linkage Disequilibrium.
An ideogram of forkhead box C2 (FOXC2) is presented above the white bar that represents the physical distance along human chromosome 16 (chr16: 85,158,358–85,160,040; genome assembly 36.3, NM_005251.2). Exons are represented as thick bars. Reference sequence identifiers (rsID) for each single nucleotide polymorphism (SNP) are plotted both in terms of their physical distance (i.e., the white bar at the top of the figure) and equidistantly to render the pairwise linkage disequilibrium (LD) estimates that were calculated and visualized with Haploview 4.2. The gene structure for FOXC2 was rendered with FancyGene 1.4. The correlation statistic (r2 and D') is provided in the heatmap. LD-based haplotype block definition was based on the D' confidence interval method. The haploblock is indicated in a bolded triangle and its component SNPs are rendered in bold font. Pairwise D' value (range: 0–1, inclusive) was rendered in color, with darker red diamond representing D' value approaching 1.0. When the r2 value (range of 0–100, inclusive) is not equal to 0 or 100, it is provided in a given diamond. The 2-SNP haplotype associated with LE is composed of one rare and one common allele of two SNPs located in the immediate early promoter (rs34221221; rare “C” allele) and immediately downstream of the FOXC2 coding region (rs1035550; common “C” allele).
Figure 2.
Differences between the lymphedema and no lymphedema groups.
A – Differences between the lymphedema and no lymphedema groups in the percentages of patients who were homozygous for the common allele (AA) or heterozygous or homozygous for the rare allele (AG+GG) for rs315721 in lymphocyte cytosolic protein 2 (LCP2). B – Differences between the lymphedema and no lymphedema groups in the percentages of patients who were homozygous or heterozygous for the common allele (TT+TG) or homozygous for the rare allele (GG) for rs849530 in neuropilin-2 (NRP2). C – Differences between the lymphedema and no lymphedema groups in the percentages of patients who were homozygous or heterozygous for the common allele (AA+AT) or homozygous for the rare allele (TT) for rs158689 in protein tyrosine kinase (SYK). D – Differences between the lymphedema and no lymphedema groups in the percentages of patients who were homozygous for the common allele (CC) or heterozygous or homozygous for the rare allele (CT+TT) for rs3176861 in vascular cell adhesion molecule 1 (VCAM1).
Figure 3.
NRP2 Gene Structure and Linkage Disequilibrium.
An ideogram of neuropilin 2 (NRP2) is presented above the white bar that represents the physical distance along human chromosome 2 (chr2: 206,255,469–206,371,102; genome assembly 36.3, NM_201266.1). Exons are represented as thick bars. Gray lines connecting the exons represent introns. Reference sequence identifiers (rsID) for each single nucleotide polymorphism (SNP) are plotted both in terms of their physical distance (i.e., the white bar at the top of the figure) and equidistantly to render the pairwise linkage disequilibrium (LD) estimates that were calculated and visualized with Haploview 4.2. The gene structure for NRP2 was rendered with FancyGene 1.4. The correlation statistics (r2 and D') are provided in the heatmap. LD-based haplotype block definition was based on the D' confidence interval method. The haploblock is indicated in a bolded triangle and its component SNPs are rendered in bold font. Pairwise D' values (range: 0–1, inclusive) were rendered in color, with darker red diamonds representing D' values approaching 1.0. When the r2 values (range of 0–100, inclusive) are not equal to 0 or 100, they are provided in a given diamond. The 3-SNP haplotype associated with LE consists of one rare and two common alleles of three SNPs (rs849530 “G” rare allele, rs950219 “G” common allele, rs3771052 “G” common allele) located in intron 1 of the gene.
Figure 4.
VEGFC Gene Structure and Linkage Disequilibrium.
An ideogram of vascular endothelial growth factor C (VEGFC) is presented above the white bar that represents the physical distance along human chromosome 4 (chr4: 177,841,685–177,950,889; genome assembly 36.3, NM_005429.2). Exons are represented as thick bars. Gray lines connecting the exons represent introns. Reference sequence identifiers (rsID) for each single nucleotide polymorphism (SNP) are plotted both in terms of their physical distance (i.e., the white bar at the top of the figure) and equidistantly to render the pairwise linkage disequilibrium (LD) estimates that were calculated and visualized with Haploview 4.2. The gene structure for VEGFC was rendered with FancyGene 1.4. The correlation statistics (r2 and D') are provided in the heatmap. LD-based haplotype block definition was based on the D' confidence interval method. The haploblock is indicated in a bolded triangle and its component SNPs are rendered in bold font. Pairwise D' values (range: 0–1, inclusive) were rendered in color, with darker red diamonds representing D' values approaching 1.0. When the r2 values (range of 0–100, inclusive) are not equal to 0 or 100, they are provided in a given diamond. The 2-SNP haplotype associated with LE consists of one rare and one common allele of two SNPs (rs3775202 “G” rare allele, rs3775195 “C” common allele) located in intron 4 of the gene. Of note, the strong linkage disequilibrium estimates observed in public databases (i.e., HapMap) resulted in the selection of 8 SNPs that tagged the entire coding region of the VEGFC gene.