Identifying Common Genetic Risk Factors of Diabetic Neuropathies

Abstract

Type 2 diabetes mellitus (T2DM) is a global public health problem of epidemic proportions, with 60-70% of affected individuals suffering from associated neurovascular complications that act on multiple organ systems. The most common and clinically significant neuropathies of T2DM include uremic neuropathy, peripheral neuropathy, and cardiac autonomic neuropathy. These conditions seriously impact an individual's quality of life and significantly increase the risk of morbidity and mortality. Although advances in gene sequencing technologies have identified several genetic variants that may regulate the development and progression of T2DM, little is known about whether or not the variants are involved in disease progression and how these genetic variants are associated with diabetic neuropathy specifically. Significant missing heritability data and complex disease etiologies remain to be explained. This article is the first to provide a review of the genetic risk variants implicated in the diabetic neuropathies and to highlight potential commonalities. We thereby aim to contribute to the creation of a genetic-metabolic model that will help to elucidate the cause of diabetic neuropathies, evaluate a patient's risk profile, and ultimately facilitate preventative and targeted treatment for the individual.

Keywords: cardiac autonomic neuropathy; diabetic complications; diabetic neuropathy; diabetic peripheral neuropathy; genetic factors; type 2 diabetes mellitus; uremic neuropathy.

Figure 1

The multifactorial etiology of the diabetic neuropathies.

Figure 2

The effects of common genetic variants implicated in the diabetic neuropathies. The gene products of ACE, AKR1B1, APOE, MTHFR, NOS3, and VEGF are all involved in important molecular pathways that have been associated with type 2 diabetes (T2DM) and diabetic neuropathies. Certain genetic variants of these genes have been identified as risk factors for diabetic nephropathy (DN) and diabetic peripheral neuropathy (DPN) in particular. DN causes renal damage and a build-up of uremic toxins, which is thought to lead to uremic neuropathy (UN), suggesting that these genetic risk factors also affect the onset and progression of UN. The same genetic variants have also been implied in diabetic autonomic neuropathy and cardiac complications, suggesting their involvement in CAN, but their direct association with CAN in T2DM patients remains to be proven. Solid black arrows indicate that a statistically significant association has been published; dashed gray arrows indicate a suspected association.