Background/Purpose: SCN9A gene encodes a tetrodotoxin sensitive Na_v1.7 Sodium channel expressed in dorsal root ganglia, peripheral nerves, olfactory nerves and inner ear. Rare Mutations in SCN9A are associated with a spectrum of pain disorders from erythromelalgia (gain of function) to congenital insensitivity to pain. We planned a case control study to explore the association of intronic SNPs rs6754031(T >G) and rs6746030 (G >A) of which rs6754031 minor allele (GG) was previously associated with Fibromyalgia.

Methods: Patients diagnosed as Fibromyalgia using ACR1990 and/or ACR2016 criteria and consenting to genetic study were included. Healthy controls with no widespread pain or connective tissue disease or medical comorbidity were included. Although a sample size of 250 each was targeted, study was terminated due to slow recruitment during covid pandemic. DNA was extracted by phenol-chloroform method. Genotyping was done by real time PCR. All continuous variables among baseline characteristics are expressed in mean (SD) and comparison by one way ANOVA while Fisher’s exact test was used for frequency tables. Odds Ratios and confidence intervals were estimated using Logistic Regression using a recessive minor allele (G) model using STATA14.

Results: A total of 118 FMS patients (88% female) of mean age of onset 35 (±9.6) years and 118 healthy controls (78% female) of age 34.7 (±10.9) years were included. Clinical features and comorbidities of patients are given in Table 1. SCN9A polymorphism rs6754031 was in Hardy Weinberg equilibrium among controls (P=0.83) while SNP rs6746030 was not (P=0.002). The two SNPs were independent of each other consistent with genomic distance and lack of linkage. Genotyping results are given in Table 2. Of the 118 patients, 74 were classified Fibromyalgia by both ACR2016 and ACR1990 criteria while 33 and 11 subjects were classified by ACR2016 and ACR1990 alone respectively. Minor allele of rs6754031 (GG versus TT/TG) was associated with Fibromyalgia OR=2.62 (1.15-6.00) and diagnosis of Fibromyalgia by ACR2016 OR=3.26 (1.42-7.46) but not with ACR1990 OR=1.21 (0.55-2.66) using a recessive model (Table 3). On multivariate analysis, association of rs6754031 GG with ACR2016 (OR 5.05 CI 1.90-13.45 P< 0.001) strengthened while ACR1990 (OR 0.47 CI 0.18-1.20 P=0.113) showed a negative trend. Among core Fibromyalgia features, rs6754031(GG) was associated with non-restorative sleep (waking unrefreshed) OR=1.61(1.00-2.57) P=0.048.

Conclusion: Our study supports previously reported association of rs6754031 GG with Fibromyalgia with a differential association between ACR2016 and ACR1990 underscoring the heterogeneity of Fibromyalgia.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tetrodotoxin-sensitive-nav1-7-sodium-channel-scn9a-gene-polymorphism-rs6754031t-g-is-associated-with-fibromyalgia/