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

Abstract

BackgroundLymphedema (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.ResultsGenetic 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.ConclusionThe SNP associations found in the MMP-2, CEACAM-1, and VEGFR-3 genes indicate that angiogenic/lymphangiogenic pathways are important in LE clinical development.Electronic supplementary materialThe online version of this article (10.1186/s40246-017-0121-7) contains supplementary material, which is available to authorized users.

Morbidity management and surveillance of lymphatic filariasis disease and acute dermatolymphangioadenitis attacks using a mobile phone-based tool by community health volunteers in Ghana

“…In this study lymphedema cases recorded were significantly higher in females than in males, which is consistent with many reported cases in literature [ 27 – 30 ]. However, the cases identified among the various age groups as well as the districts were not different.…”

Transcriptome-wide analysis of filarial extract-primed human monocytes reveal changes in LPS-induced PTX3 expression levels

“…demonstrated that in W. bancrofti infected individuals with filaria-induced pathology, MMPs and their counterparts, the tissue inhibitor of metalloproteinases (TIMPs), are elevated 76 . Previous studies from our institute demonstrated that single nucleotide polymorphisms (SNPs) in MMP2 are a risk factor to develop lymph edema 77 , suggesting that MMP9 could also be involved in the development of filarial pathology. Similarly, SNPs of the pattern recognition receptors TLR4, NOD1 and NOD2 were shown to be associated with patent lymphatic filariasis 78 .…”

Lymphatic Vessel Network Structure and Physiology

“…To date, gene variants of FOXC2 and FLT4 (encodes VEGFR3) have been identified in lymphatic filariasis, the most common form of secondary lymphedema worldwide, and caused by infection with filarial worms, primarily Wuchereria bancrofti (56, 974). In addition, SNPs in the genes that encode VEGFR3, MMP-2, and carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1), all of which have roles in lymphangiogenesis, have also been identified to have significance in lymphatic filariasis (254). It is plausible that these gene variants may have a moderate impact lymphatic wall integrity or lymphatic valve maintenance, lowering the “margin of safety” against edema with high fluid loads, while not impairing lymph flow under normal fluid loads.…”