First-Stage Genome Wide Association Study (GWAS) of Lymphatic Filariasis Pathology

• Applicant: Kenneth Pfarr, Ph.D.
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Human Genetics
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 271596474

Filarial nematodes infect approximately 120 million people in developing countries and cause lymphatic filariasis, a neglected disease. The majority of infected individuals have no or just mild, transient clinical symptoms (e.g., recurrent debilitating fever), while others suffer severe clinical disease including lymphedema (LE, estimated worldwide prevalence of 7% in infected men and women) or hydrocele (estimated prevalence of 30-50% of infected men). Pathology and parasite load are inversely correlated, suggesting that containment of parasites by the immune system leads to inflammation-related disease. Studies have consistently shown that susceptibility to infection, parasite load and lymphatic pathology cluster in families independent of household and environment pointing to genetic factors involved in disease pathology. In line with these findings, we have recently discovered a significant association between the Leu10Pro variant of Transforming Growth Factor-beta1 with presence of nematode larvae in the blood. We have also found a significant association of Vascular Endothelial Growth Factor-A (VEGF-A) promoter Single Nucleotide Polymorphisms (SNPs) with hydrocele. Thus, understanding the genetics of lymphatic filariasis provides deep insights into disease symptoms which will be of future importance for the development of new prevention and treatment strategies. To identify the genetic basis of lymphatic filariasis, we propose a stage-1 Genome Wide Association Study (GWAS) in a Ghanaian cohort. We have biobanked DNA from 1,600 unrelated volunteers with clinical disease or infection only. These were collected and used in earlier case-control studies of 130 SNPs. For the stage-1 GWAS, we will recruit an additional 1,200 unrelated volunteers with lymphatic filariasis and 1,200 infected persons with no clinical disease. This will increase our collective to 2,000 cases with lymphedema or hydrocele that will be compared to 2,000 controls (infected without clinical lymphatic disease). In parallel, we will build a biobank of peripheral blood mononuclear cells (PBMCs) for future characterization of genes found to be associated with lymphatic filariasis. This proposal will strengthen the collaboration between the groups in Bonn and Kumasi, train new Ghanaian and German scientists in infectiology, molecular genetics, and immunology and further sustain a new generation of primary investigators. Our collaboration is designed for long term, continued research. Thus, we will recruit Ghanaian patients with lymphatic filariasis continuously for multistage GWAS, which finally will help to elucidate the disease etiology.

• DFG Programme: Research Grants
• International Connection: Ghana
• Co-Investigators: Professor Dr. Achim Hoerauf; Professor Dr. Johannes Schumacher
• International Co-Applicant: Professor Alex Yaw Debrah, Ph.D.