Alpha-defensin haplotypes and IgA nephropathy risk

The human alpha-defensin genes DEFA1 and DEFA3 encode short antimicrobial peptides that are important components of the innate immune system, and are subject to copy number variation (CNV) with individuals having between 3 and 18 copies. Association studies have demonstrated that genetic variants near to DEFA1 and DEFA3 are associated with the serious kidney disease IgA nephropathy. In collaboration with groups in Guangzhou and Singapore, Prof Armour’s group have shown that the association signal can be attributed to the CNV region, with two specific variants implicated: one variant provides protection against IgA nephropathy and is specific to Asian populations; the second variant predisposes to IgA nephropathy in both Europeans and Asians. The structures of the variants implicated in IgA nephropathy, and the features leading to the associations with disease, are currently unknown. This project will combine detailed analysis of publicly available sequence data (from the 1000 Genomes Project), novel approaches to long-read sequencing (using Nanopore devices) and examination of datasets from affected individuals to understand how alpha-defensin variants predispose to IgA nephropathy. This project would give the student experience in the analysis of genetic variation relevant to disease, high-resolution characterisation of copy number variation, and manipulation of large datasets.

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