This is the first of a four-part report on selected talks from the 10th IASP Research Symposium, The Genetics of Pain: Science, Medicine and Drug Development. See also Part 2, Part 3, and Part 4, or download a PDF of the entire report.
Pain researchers convened on 7-9 February 2012 for a first-of-its-kind symposium dedicated to the genetics of pain. The meeting, sponsored by the International Association for the Study of Pain (IASP) and organized by the Genetics and Pain Special Interest Group, drew 120 registrants and 20 faculty to Miami Beach, Florida, US, for talks that ran the gamut from gene discovery in fruit flies to clinical development of ion channel blockers.
The meeting signaled a coming of age for the field of pain genetics. In his talk,Clifford Woolf, Children's Hospital Boston, US, said that he is not a geneticist, but he joined the pain genetics train looking for research tools. "And it has been a wonderful ride—sometimes on a ghost train, sometimes stalled in a siding, and sometimes running out of control and almost derailed." The meeting, he said, showed that the study of the genetics of pain "has become mainstream in neurobiology, and that's exciting."
Of mice (and rats) and men (and women)
The opening session, on preclinical studies of pain genetics, highlighted the central place of rodents in the discovery of pain genes, and in understanding the interplay of genes and environment. The talks showed the power of a translational approach that moves from animals to humans and back again to uncover candidate pain genes, elucidate mechanisms, and validate targets.
Organizers of the 10th IASP Research Symposium, The Genetics of Pain: Science, Medicine and Drug Development (front, from left) Inna Belfer, Roy Levitt, Luda Diatchenko, (rear) William Lariviere, Michael Costigan.
The first speaker of the conference,Marshall Devor, Hebrew University, Jerusalem, Israel, laid the groundwork for talks to come. Discovering genes that influence individual variation in pain sensitivity or risk for chronic pain serves two purposes, he said. First, it opens doors to understanding individual patients: making a diagnosis, illuminating a prognosis, predicting drug responses, or even comforting patients by telling them, "It's not your fault." Second, gene discovery and, in particular, unbiased genomewide methods will benefit many patients by uncovering novel pain mechanisms and potential new treatment targets. The real power, as Devor sees it, is the "promise for finding pathways in the physiology of pain that we never dreamed of before."
The study of monogenetic pain diseases—rare occurrences like familial migraine, congenital insensitivity to pain, or congenital pain syndromes—has illuminated important players in pain pathways. But to identify genes that contribute to more common pain conditions, other approaches are needed. Linkage analysis is used when researchers have access to family members with and without pain. When it is impossible to do family studies (in post-operative pain, e.g., where every family member would have to have had the same operation), the alternative is association studies. Here, groups of unrelated people are compared on a case-control basis to identify genetic variants that are distributed unevenly in those with pain and those without. Association studies test either a limited number of pre-selected genes (a candidate gene approach) or all variants in an unbiased screen (a genomewide approach).
Devor said he believes genomewide association studies (GWAS) in humans are "the path to real discovery," but such investigations are expensive, and so far very few have been funded for pain. He made the case that doing genomewide scans in animals is a way to "jumpstart" human studies, enabling the ultimate identification of human genes at a much lower cost. Identifying mouse strains that vary in the phenotype of choice (or making such lines by selective breeding) allows for the mapping of a phenotype to one or more quantitative trait loci (QTL). This can lead to the identification of the responsible pain gene or genes, which can then be confirmed in humans.
An example of this is the discovery that a variant of the CACNG2 gene is a risk factor for chronic pain after breast surgery (Nissenbaum et al., 2010). More than a decade ago, Devor collaborated with Jeffrey Mogil, McGill University, Montreal, Canada, and others to phenotype a panel of 12 common mouse strains in multiple pain tests, including autotomy after nerve injury, a model of neuropathic pain (Mogil et al., 1999). Further breeding and linkage analysis, and the use of inbred recombinant strains, led to the identification of a locus on chromosome 15 (Seltzer et al., 2001;Devor et al., 2005), which was ultimately narrowed to 155 candidate genes. Using expression data, functional annotation, and single nucleotide polymorphism (SNP) association, Devor and colleagues zeroed in on a single candidate, CACNG2. As the group reported in 2010, when they then looked at variants in the corresponding human gene, they found a haplotype of three SNPs that was associated with an increased risk of pain after mastectomy in a sample of 549 Israeli women, some of whom had pain and some of whom did not.
Marshall Devor. Image credit: William Lariviere.
"If this can be replicated, it's useful," Devor said. Possibly, if a woman is genetically more likely to develop pain, that information may be part of a decision on what type of surgery to have, for example.
CACNG2 encodes the voltage-dependent calcium channel gamma subunit 2 (also known as stargazin), a protein which both regulates the trafficking of AMPA-type glutamate receptors and controls the excitability of neurons. The gene has been implicated in epilepsy, indicating a "deep connection between epilepsy and neuropathic pain having to do with excitability of neural networks," Devor said.
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