First-Stage Genome Wide Association Study (GWAS) of Lymphatic Filariasis Pathology
Human Genetics
Final Report Abstract
Human genetic factors that confer susceptibility and/or resistance to infectious diseases remain unclear. One of such infectious disease is lymphatic filariasis (LF). LF, a major cause of secondary nonhereditary lymphedema results from infection with any of the three filarial species Wuchereria bancrofti, Brugia malayi and B. timori. About 40 million people infected with the filarial parasites present with the symptomatic LF manifestations of lymphedema (LE) and hydrocele. These symptoms develop in only a subgroup of exposed people, and hosts’ genetics have been shown to account for the disease heterogeneity. This study presents the first genome-wide association study (GWAS) to identify genetic markers involved in LF disease. A total of 4427 participants comprising 1933 cases, patients with positive LF antigen test and/or LE or hydrocele, and 2471 controls, patients without any overt filarial disease, were enrolled for the study. Unrelated participants were genotyped with the Illumina® Infinium global screening array (GSA) with multi-disease drop in (MD) [GSA 2.0MD]. Genotyping identified eight (8) novel single nucleotide polymorphisms (SNPs) and three (3) HLA haplotypes (HLA-DRB1*03:02, -DQB1*04:02 and -C*17:01) associated with LF. Three SNPs were of genome-wide significance (rs2245413, rs2245710 and rs7742085). Rs2245413 and rs2245710 SNPs on Chr10 were associated with renal abnormalities and hydrocele respectively, while rs7742085 on Chr6 was associated with LE. Predicted functions of the identified SNPs were mainly neutral or resulted in changes in gene expression levels. The HLA-A allele was predicted to cause a change in protein structure. Post-GWAS analysis found one lead risk SNP rs346535 in the genomic loci 19:4277100- 44617384 to be associated with filarial hydrocele. The candidate genes identified in this risk region included PLAUR, KCNN4, PHLDB3, CADM4, MEGF8, ZNF428, ETHE1, CIC, XRCC1, TMEM145, CXCL17, SRRM5 and PRR19. Additional studies are needed to functionally determine causality of the identified SNPs in LF disease etiology and/or the genes for which they are a proxy marker. Further research of the HLA alleles associated with susceptibility or resistance to LE, as well as amino acid sequence analyses of the epitope binding region, are needed to elucidate the role of HLA in the pathogenesis of LE. SNPs with suggestive thresholds should be replicated in a stage 2 GWAS to identify the true SNPs/genetic variations and loci. It is especially important that capacity building in human genetic analysis is being achieved, as there is a need for more studies that include African populations as the focus. African populations differ significantly from Americans of African descent, which are usually analyzed as an example of a “black/non-white” population. The project also aided another German African Cooperation Projects in Infectiology.
Publications
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Single nucleotide polymorphisms in angiogenic and inflammation pathway genes are associated with patent lymphatic filariasis. Am J Trop Med Hyg 93, 523
Osei-Mensah, J., Batsa-Debrah, L., Albers, A., Lust, L., Brockschmidt, F.F., Herold, C., Mubarik, Y., Becker, T., Fröhlich, H., Pfarr, K., Hoerauf, A. & Debrah, A.
