| Autor: |
Recla JM; The Jackson Laboratory, Bar Harbor, ME, United States.; IGERT Program in Functional Genomics, Graduate School of Biomedical Sciences and Engineering, The University of Maine, Orono, ME, United States., Bubier JA; The Jackson Laboratory, Bar Harbor, ME, United States., Gatti DM; The Jackson Laboratory, Bar Harbor, ME, United States., Ryan JL; The Jackson Laboratory, Bar Harbor, ME, United States., Long KH; The Jackson Laboratory, Bar Harbor, ME, United States., Robledo RF; The Jackson Laboratory, Bar Harbor, ME, United States., Glidden NC; Department of Genetics and Genome Sciences, UCONN Health, Farmington, CT, United States., Hou G; The Jackson Laboratory, Bar Harbor, ME, United States., Churchill GA; The Jackson Laboratory, Bar Harbor, ME, United States., Maser RS; The Jackson Laboratory, Bar Harbor, ME, United States., Zhang ZW; The Jackson Laboratory, Bar Harbor, ME, United States., Young EE; Department of Genetics and Genome Sciences, UCONN Health, Farmington, CT, United States.; School of Nursing, University of Connecticut, CT, United States.; Institute for Systems Genomics, University of Connecticut, Storrs, CT, United States., Chesler EJ; The Jackson Laboratory, Bar Harbor, ME, United States., Bult CJ; The Jackson Laboratory, Bar Harbor, ME, United States. |
| Abstrakt: |
Identification of genetic variants that influence susceptibility to pain is key to identifying molecular mechanisms and targets for effective and safe therapeutic alternatives to opioids. To identify genes and variants associated with persistent pain, we measured late-phase response to formalin injection in 275 male and female Diversity Outbred mice genotyped for over 70,000 single nucleotide polymorphisms. One quantitative trait locus reached genome-wide significance on chromosome 1 with a support interval of 3.1 Mb. This locus, Nociq4 (nociceptive sensitivity quantitative trait locus 4; MGI: 5661503), harbors the well-known pain gene Trpa1 (transient receptor potential cation channel, subfamily A, member 1). Trpa1 is a cation channel known to play an important role in acute and chronic pain in both humans and mice. Analysis of Diversity Outbred founder strain allele effects revealed a significant effect of the CAST/EiJ allele at Trpa1, with CAST/EiJ carrier mice showing an early, but not late, response to formalin relative to carriers of the 7 other inbred founder alleles (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, PWK/PhJ, and WSB/EiJ). We characterized possible functional consequences of sequence variants in Trpa1 by assessing channel conductance, TRPA1-TRPV1 interactions, and isoform expression. The phenotypic differences observed in CAST/EiJ relative to C57BL/6J carriers were best explained by Trpa1 isoform expression differences, implicating a splice junction variant as the causal functional variant. This study demonstrates the utility of advanced, high-precision genetic mapping populations in resolving specific molecular mechanisms of variation in pain sensitivity. |
