A Genome-wide Association Study Provides Evidence of Sex-specific Involvement of Chr1p35.1 (ZSCAN20-TLR12P) and Chr8p23.1 (HMGB1P46) With Diabetic Neuropathic Pain

• The case definition of diabetic neuropathic pain in this study is matched with those used in epidemiological studies.
• We confirmed that diabetic neuropathic pain is a heritable trait.
• We provided new genetic evidence of sex-specific involvement of two chromosome loci with diabetic neuropathic pain.Using a pragmatic case definition, we identified two new genetic areas that may be involved in diabetic neuropathic pain, a common and debilitating complication of diabetes. One of these is more significant in males, the other in females. Furthermore, we calculated that the contribution of genes to developing neuropathic pain in diabetic men is about twice that in diabetic women. These findings help to explain why some people are more vulnerable to this complication, and help to elucidate the biological mechanisms of neuropathic pain. They will inform personalised (gender-specific) approaches to treatment, and the development of new drugs.

Neuropathic pain is defined as pain arising as a direct consequence of a lesion or a disease affecting the somatosensory system and it affects around 1 in 4 diabetic patients in the UK. The purpose of this genome-wide association study (GWAS) was to identify genetic contributors to this disorder. Cases of neuropathic pain were defined as diabetic patients with a multiple prescription history of at least one of five drugs specifically indicated for the treatment of neuropathic pain. Controls were diabetic individuals who were not prescribed any of these drugs, nor amitriptyline, carbamazepine, or nortriptyline. Overall, 961 diabetic neuropathic pain cases and 3260 diabetic controls in the Genetics of Diabetes Audit and Research Tayside (GoDARTS) cohort were identified. We found a cluster in the Chr1p35.1 (ZSCAN20-TLR12P) with a lowest P value of 2.74 × 10− 7 at rs71647933 in females and a cluster in the Chr8p23.1, next to HMGB1P46 with a lowest P value of 8.02 × 10− 7 at rs6986153 in males. Sex-specific narrow sense heritability was higher in males (30.0%) than in females (14.7%). This GWAS on diabetic neuropathic pain provides evidence for the sex-specific involvement of Chr1p35.1 (ZSCAN20-TLR12P) and Chr8p23.1 (HMGB1P46) with the disorder, indicating the need for further research.