Publication Alert: HLA Class II Locus and Susceptibility to Podoconiosis

Published in the New England Journal of Medicine, CRGGH postdoctoral fellow, Fasil Tekola Ayele, Ph.D., along with CRGGH Deputy Director and Director, shed light on the genetic basis of endemic nonfilarial elephantiasis, otherwise known as podoconiosis or "mossy foot". This international collaborative research project is the first study of a non-communicable disease using genome-wide association for any African population.

This study personifies much of the CRGGH mission given the gene-environment interaction and the clear cultural and social impact of this debilitating disease. It also highlights the importance of training international researchers that work to contribute to their native country.

Excerpted from the NHGRI press release:

The researchers generated a dataset from study-participant DNA, screening more than 550,000 single-nucleotide polymorphisms (SNPs), which are sites in an individual's DNA that contain a different chemical base when compared to a standard reference human genome sequence. They found significant podoconiosis association for eight SNPs within or nearby a stretch of DNA on chromosome 6, called the HLA class II locus.

The researchers performed a second validation step, called a family-based association study, using DNA samples from 202 sets of child-parent trios from affected families. The researchers detected six SNPs that showed significant association¿those that mapped to HLA class II region genes and most strongly associated with podoconiosis in the GWAS, validating the GWAS results.

Further analysis of direct HLA tests of 94 affected persons and 94 controls confirmed that podoconiosis susceptibility is increased by inheriting altered DNA in the HLA class II locus from one or both parents. The researchers estimated that the SNPs found through the GWAS¿which alone comprise a portion of the genetic factors in podoconiosis¿explained about 16 percent of the variance in the disease occurrence. They also found that individuals with those gene variants were 2 to 3 times as likely to become affected if exposed to the volcanic rock soil.

The HLA class II locus is also particularly associated with T cell-mediated immunity, according to co-author Adebowale Adeyemo, M.D., NHGRI staff scientist and CRGGH deputy director. The research findings point to the fact that podoconiosis is likely to be a T cell-mediated inflammatory disease. Mineral particles are absorbed through the skin of the foot and build up in the lymphatic system, causing inflammation and scarring that can obstruct blood vessels in an affected individual's feet.

In addition to the NIH researchers who conducted the GWAS, the study team included members from the Brighton and Sussex Medical School and the Clinical Transplantation Laboratory in the United Kingdom and the Armauer Hansen Research Institute in Addis Ababa, Ethiopia. Part of the team led by senior authors Gail Davey, M.D., and Melanie Newport, M.D, Ph.D., of the Brighton and Sussex Medical School, conducted preliminary epidemiology work in the Ethiopian highlands and also had developed a clinical staging system for people with the condition¿from early to late stages.

**UPDATED 3/29**: See also the NEJM Perspective piece by Dr. Molyneux