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The sodium channel Nav1.7, which is encoded by the SCN9A gene, has previously been implicated in a wide range of painful conditions, however its role in diabetic peripheral neuropathy is unknown. Now, research suggests that several SCN9A gene variants play a role in the etiology of neuropathic pain in diabetic peripheral neuropathy.
Hao Wang, PhD, of the National Institute of Neurological Disorders and Stroke (NINDS) and previously Janssen Research and Development, and colleagues evaluated the relationship between common and rare genetic variants in SCN9A and chronic neuropathic pain in diabetic peripheral neuropathy in a cohort of 938 patients from 6 clinical studies and 2 control groups (POPRES, n=2624 and Coriell, n=1029).
The researchers conducted a 2-stage case-control study: In stage 1, exonic regions of SCN9A were sequenced in a subset of 244 patients with neuropathic pain, and variants were compared with POPRES controls; and in stage 2, the top associated variants were genotyped in the entire case collection and Coriell controls while restricting analysis to matching patients from the U.S. and Canada only.
CLINICAL CHART: Neuropathic Pain Treatments
A total of 170 gene variants were identified in the patient cohort in stage 1. Approximately 62 overlapped with POPRES variants, while approximately 107 variants were not detected in POPRES controls. Overall, 7 variants exhibited a P-value <0.00238 and were included in genotyping in stage 2.
After initial genotyping, 4 variants (Asp1908Gly, Val991Leu/Met932Leu, and an intronic variant rs74449889) remained significantly associated with neuropathic pain and were found to occur at a higher frequency in patients with neuropathic pain associated with diabetic peripheral neuropathy than in controls (odds ratios ~2.1 to 2.6, P=0.05 to 0.009). Val991Leu/Met932Leu was also found to be associated with pain severity as measured by the Numeric Rating Scale, and was shown to cause hyperexcitability in dorsal root ganglia neurons.
“Our findings … suggest an apparent differential distribution of rare variants between cases and controls in the sequencing cohort,” the authors wrote. “All 3 variant sets showed significant rare variant association, suggesting that the observed distribution of minor alleles in cases and controls has an ‘unusual distribution.’”
The results, with some limitations, indicate a possible role for variants of SCN9A in neuropathic pain, and suggest that evaluation of Nav1.7 channel blockers as a therapeutic target in a pain population is warranted.
