Single nucleotide polymorphisms in the angiogenic and lymphangiogenic pathways are associated with lymphedema caused by Wuchereria bancrofti

• Main Authors: Linda Batsa Debrah, Anna Albers, Alexander Yaw Debrah, Felix F. Brockschmidt, Tim Becker, Christine Herold, Andrea Hofmann, Jubin Osei-Mensah, Yusif Mubarik, Holger Fröhlich, Achim Hoerauf, Kenneth Pfarr
• Format: Article
• Language: English
• Published: BMC 2017-11-01
• Series: Human Genomics
• Subjects: Lymphatic filariasis; Angiogenesis; Lymphangiogenesis; Single nucleotide polymorphisms; Genotypes
• Online Access: http://link.springer.com/article/10.1186/s40246-017-0121-7

Abstract Background Lymphedema (LE) is a chronic clinical manifestation of filarial nematode infections characterized by lymphatic dysfunction and subsequent accumulation of protein-rich fluid in the interstitial space—lymphatic filariasis. A number of studies have identified single nucleotide polymorphisms (SNPs) associated with primary and secondary LE. To assess SNPs associated with LE caused by lymphatic filariasis, a cross-sectional study of unrelated Ghanaian volunteers was designed to genotype SNPs in 285 LE patients as cases and 682 infected patients without pathology as controls. One hundred thirty-one SNPs in 64 genes were genotyped. The genes were selected based on their roles in inflammatory processes, angiogenesis/lymphangiogenesis, and cell differentiation during tumorigenesis. Results Genetic associations with nominal significance were identified for five SNPs in three genes: vascular endothelial growth factor receptor-3 (VEGFR-3) rs75614493, two SNPs in matrix metalloprotease-2 (MMP-2) rs1030868 and rs2241145, and two SNPs in carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1) rs8110904 and rs8111171. Pathway analysis revealed an interplay of genes in the angiogenic/lymphangiogenic pathways. Plasma levels of both MMP-2 and CEACAM-1 were significantly higher in LE cases compared to controls. Functional characterization of the associated SNPs identified genotype GG of CEACAM-1 as the variant influencing the expression of plasma concentration, a novel finding observed in this study. Conclusion The SNP associations found in the MMP-2, CEACAM-1, and VEGFR-3 genes indicate that angiogenic/lymphangiogenic pathways are important in LE clinical development.