Dataset Information

A SCN10A SNP biases human pain sensitivity.

ABSTRACT: Nav1.8 sodium channels, encoded by SCN10A, are preferentially expressed in nociceptive neurons and play an important role in human pain. Although rare gain-of-function variants in SCN10A have been identified in individuals with painful peripheral neuropathies, whether more common variants in SCN10A can have an effect at the channel level and at the dorsal root ganglion, neuronal level leading to a pain disorder or an altered normal pain threshold has not been determined.Candidate single nucleotide polymorphism association approach together with experimental pain testing in human subjects was used to explore possible common SCN10A missense variants that might affect human pain sensitivity. We demonstrated an association between rs6795970 (G?>?A; p.Ala1073Val) and higher thresholds for mechanical pain in a discovery cohort (496 subjects) and confirmed it in a larger replication cohort (1005 female subjects). Functional assessments showed that although the minor allele shifts channel activation by -4.3?mV, a proexcitatory attribute, it accelerates inactivation, an antiexcitatory attribute, with the net effect being reduced repetitive firing of dorsal root ganglion neurons, consistent with lower mechanical pain sensitivity.At the association and mechanistic levels, the SCN10A single nucleotide polymorphism rs6795970 biases human pain sensitivity.

SUBMITTER: Duan G

PROVIDER: S-EPMC5011395 | biostudies-literature | 2016 Jan-Dec

REPOSITORIES: biostudies-literature

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A SCN10A SNP biases human pain sensitivity.

Duan Guangyou G Han Chongyang C Wang Qingli Q Guo Shanna S Zhang Yuhao Y Ying Ying Y Huang Penghao P Zhang Li L Macala Lawrence L Shah Palak P Zhang Mi M Li Ningbo N Dib-Hajj Sulayman D SD Waxman Stephen G SG Zhang Xianwei X

Molecular pain 20160101

<h4>Background</h4>Nav1.8 sodium channels, encoded by SCN10A, are preferentially expressed in nociceptive neurons and play an important role in human pain. Although rare gain-of-function variants in SCN10A have been identified in individuals with painful peripheral neuropathies, whether more common variants in SCN10A can have an effect at the channel level and at the dorsal root ganglion, neuronal level leading to a pain disorder or an altered normal pain threshold has not been determined.<h4>Re ...[more]

PMID: 27590072

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Project description:Patients with complex regional pain syndrome (CRPS) report cognitive difficulties, affecting the ability to represent, perceive and use their affected limb. Moseley, Gallace & Spence (2009) observed that CRPS patients tend to bias the perception of tactile stimulation away from the pathological limb. Interestingly, this bias was reversed when CRPS patients were asked to cross their arms, implying that this bias is embedded in a complex representation of the body that takes into account the position of body-parts. Other studies have failed to replicate this finding (Filbrich et al., 2017) or have even found a bias in the opposite direction (Sumitani et al., 2007). Moreover, perceptual biases in CRPS patients have not often been compared to these of other chronic pain patients. Chronic pain patients are often characterized by an excessive focus of attention for bodily sensations. We might therefore expect that non-CRPS pain patients would show a bias towards instead of away from their affected limb. The aim of this study was to replicate the study of Moseley, Gallace & Spence (2009) and to extend it by comparing perceptual biases in a CRPS group with two non-CRPS pain control groups (i.e., chronic unilateral wrist and shoulder pain patients). In a temporal order judgment (TOJ) task, participants reported which of two tactile stimuli, one applied to either hand at various intervals, was perceived as occurring first. TOJs were made, either with the arms in a normal (uncrossed) position, or with the arms crossed over the body midline. We found no consistent perceptual biases in either of the patient groups and in either of the conditions (crossed/uncrossed). Individual differences were large and might, at least partly, be explained by other variables, such as pain duration and temperature differences between the pathological and non-pathological hand. Additional studies need to take these variables into account by, for example, comparing biases in CRPS (and non-CRPS) patients in an acute versus a chronic pain state.

Project description:BackgroundLess than two percent of the human genome is protein coding, yet that small fraction harbours the majority of known disease causing mutations. Despite rapidly falling whole genome sequencing (WGS) costs, much research and increasingly the clinical use of sequence data is likely to remain focused on the protein coding exome. We set out to quantify and understand how WGS compares with the targeted capture and sequencing of the exome (exome-seq), for the specific purpose of identifying single nucleotide polymorphisms (SNPs) in exome targeted regions.ResultsWe have compared polymorphism detection sensitivity and systematic biases using a set of tissue samples that have been subject to both deep exome and whole genome sequencing. The scoring of detection sensitivity was based on sequence down sampling and reference to a set of gold-standard SNP calls for each sample. Despite evidence of incremental improvements in exome capture technology over time, whole genome sequencing has greater uniformity of sequence read coverage and reduced biases in the detection of non-reference alleles than exome-seq. Exome-seq achieves 95% SNP detection sensitivity at a mean on-target depth of 40 reads, whereas WGS only requires a mean of 14 reads. Known disease causing mutations are not biased towards easy or hard to sequence areas of the genome for either exome-seq or WGS.ConclusionsFrom an economic perspective, WGS is at parity with exome-seq for variant detection in the targeted coding regions. WGS offers benefits in uniformity of read coverage and more balanced allele ratio calls, both of which can in most cases be offset by deeper exome-seq, with the caveat that some exome-seq targets will never achieve sufficient mapped read depth for variant detection due to technical difficulties or probe failures. As WGS is intrinsically richer data that can provide insight into polymorphisms outside coding regions and reveal genomic rearrangements, it is likely to progressively replace exome-seq for many applications.

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A SCN10A SNP biases human pain sensitivity.

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A SCN10A SNP biases human pain sensitivity.

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