The Genomics of Diabetic Neuropathy

For the vast majority of human diseases individual susceptibility is to some degree influenced by genetic variation. Understanding the genetics of common disorders such as diabetes mellitus, heart disease and auto-immune disorders has provided novel insights into disease pathogenesis, identified new drug targets and, through combining multiple genetic risk variants into polygenic risk scores, enabling risk stratification [1]. In this chapter we will discuss how genomics is informing our knowledge of diabetic neuropathy and also key consequences of diabetic neuropathy such as neuropathic pain. Compared to our understanding of the genomics of diabetes per se this field (and indeed the genomics of other diabetes complications such as retinopathy and nephropathy) is still very much in its infancy [2]. The most important reason for this is the fact that large cohorts with detailed harmonised phenotyping of neuropathy and neuropathic pain have not yet been fully developed. As will be apparent from other chapters in this book, the phenotype of neuropathy is ideally captured by a combination of relevant patient reported outcomes, examination findings and investigations such as nerve conduction studies with harmonised definitions. Given the subjective nature of pain, neuropathic pain is arguably an even harder phenotype to capture, and important information such as the duration, quality and localisation of pain and whether this is likely attributable to diabetic neuropathy (e.g., bilateral pain in the feet) is required [3, 4]. These issues are now beginning to be appreciated in large population cohorts such as UK-Biobank, and such cohorts, allied to advances in sequencing technology/analytics and the development of human cellular models, should significantly advance our understanding of the genomics of diabetic neuropathy over the next decade. We will briefly highlight the broad approaches used in human genomics and how they have been applied to diabetes before focusing on the current state of knowledge in diabetic neuropathy.