Download Pain genetics: past, present and future

Review
Pain genetics: past, present and future
Jeffrey S. Mogil1,2
1
2
Department of Psychology, McGill University, Montreal, QC, H3A 1B1, Canada
Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A 1B1, Canada
Chronic pain is a classic example of gene environment
interaction: inflammatory and/or nerve injuries are
known or suspected to be the etiology of most chronic
pain syndromes, but only a small minority of those subjected to such injuries actually develop chronic pain. Once
chronic pain has developed, pain severity and analgesic
response are also highly variable among individuals. Although animal genetics studies have been ongoing for
over two decades, only recently have comprehensive
human twin studies and large-scale association studies
been performed. Here, I review recent and accelerating
progress in, and continuing challenges to, the identification of genes contributing to such variability. Success in
this endeavor will hopefully lead to both better management of pain using currently available therapies and the
development and/or prioritizing of new ones.
Individual differences in pain and analgesia
Chronic pain is probably the most prevalent human health
problem, contributing to individual morbidity and mortality
and imposing high societal costs [1]. Current management of
chronic, non-cancer pain is far from optimal, with existing
analgesics characterized by limited efficacy and a high
adverse-effect burden. Decades of robust government and
industry investment have yielded few basic research-toclinical translational successes, and many have looked to
the molecular genetics revolution as a new way forward [2].
In fact, genetic approaches in pain research, as elsewhere,
are now fully integrated into the research enterprise. For
example, according to the PainGenes Database (http://
paingeneticslab.ca/4105/06_02_pain_genetics_database.
asp) [3], at least 358 genes are thought to be relevant to pain
or analgesia based on the phenotype of null mutant
mice, and many hundreds of pain-regulated genes have
been identified by gene expression profiling (microarray)
studies [4].
In this review, I focus solely on mendelian genetics, as
one of the greatest challenges to both pain treatment and
analgesic development is robust interindividual variability. Individual differences are evinced on at least three
different levels. First, there is great variability in the
development of chronic pain syndromes per se, currently
conceptualized by many as a transition from acute to
chronic pain. Many chronic pain states are known or
presumed to be secondary to traumatic or infectious injury
to soft tissues and especially to nerves (i.e. neuropathic
pain), but most individuals experiencing these insults do
not develop chronic pain (e.g. [5]). In this sense, chronic
pain is the prototypical example of a gene environment
Corresponding author: Mogil, J.S. ([email protected])
258
interaction: the insult is required, but so too are susceptibility factors that might be inherited. Second, assuming a
chronic pain state exists, the intensity of the pain (and of
other symptoms, signs and sequelae) is highly variable and
often not at all predictable from the severity of the presumed injury or disease (e.g. radiographically determined
joint degeneration in osteoarthritis [6]). Such variability
can also be demonstrated quite easily for acute pain in the
laboratory, with standardized noxious heat stimuli eliciting pain ratings near zero in some individuals and near
maximal (‘worst pain imaginable’) in others (e.g. [7]). Variable pain ratings are associated with similar variability in
pain-evoked cortical activations [8], suggestive of true
differences in subjective perception of the stimulus. Finally, great variability exists in patients’ analgesic responses
to both opioids (e.g. [9]) and non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. [10]); however, analgesia genetics will not be considered in detail here.
Of course, individual differences could be explained by
environmental (including stochastic) as well as inherited
factors. Familial aggregation and twin studies of chronic
pain syndromes have recently been performed to disentangle these possibilities [11–17]. Heritability estimates range
widely, but most studies demonstrated at least moderate
heritability. Most existing twin studies have measured the
concordance of the painful disease itself among twin pairs,
but not the twin–twin correlation of pain ratings. This fact
is relevant because genes underlying pain could be involved in either the predisposition to develop chronic pain
syndromes or determining actual pain levels within those
syndromes, or both; it is still unclear what the overlap
between these categories is. Better estimates of the heritability of pain itself would come from acute pain tests
under controlled laboratory conditions, and two recent
studies have established the heritabilities of many such
assays in the h2 = 22–60% range [18,19]. There is currently
no extant twin study of analgesic heritability, although one
is in progress [20].
Lessons from animal pain genetics
Heritability of preclinical assays of pain is moderate-tohigh (0.30<h2<0.76; median: h2 = 0.46) [21], in excellent
agreement with human twin studies using analogous stimuli [18,19]. In addition to quantitative variation in pain
and analgesic sensitivity, strain differences in pain-related
anatomy, electrophysiology and neurochemistry have been
observed [22–24]. Genetic correlation studies using artificially selected (selectively bred) lines and inbred strain
panels have revealed: (i) unique inheritance of different
pain symptoms (e.g. thermal, mechanical, chemical)
0168-9525/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tig.2012.02.004 Trends in Genetics, June 2012, Vol. 28, No. 6
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Trends in Genetics June 2012, Vol. 28, No. 6
regardless of etiology; (ii) common inheritance of analgesic efficacy against the same pain symptom, regardless of
the drug used; and (iii) an inverse relationship between
pain sensitivity and analgesic response [22,23]. Recent
studies have evaluated these claims in humans. Contradictory data have been gathered regarding the existence
of genetic factors common to multiple pain states (i.e.
pain ‘stoicism’ genes) [25,26] versus genetic dissociation
of different pain modalities (i.e. thermal, mechanical or
ischemic) [18,27–29]. This debate is far from academic,
as it is common practice in human genetic association
studies to pool across modality to preserve statistical
power. Several groups [30–32] have observed that, as
in mice, basal heat pain thresholds can predict response
to clinical opioid analgesia in humans. It has been suggested that high basal pain sensitivity indicates reduced
pain-inhibitory capacity, and that the latter may represent a risk factor for chronic pain development [33].
A test of this intriguing hypothesis awaits large prospective studies.
Other major findings from animal pain genetics studies
include the surprisingly common and robust observance of
sex–strain interactions (see [34]), and the interaction of
genotype differences in pain sensitivity with environmental factors, such as diet [35], conspecific aggression [36],
social housing [37], experimenter (and other laboratory
effects) [38] and circadian rhythmicity [39].
A growing number of quantitative trait loci (QTLs) associated with variable pain sensitivity among inbred strains
have been discovered in mice and, in a handful of cases, the
probable gene underlying the QTL has been identified
(Table 1). It is notable that several of these QTLs have
sex-specific effects [40–46]. Association studies have subsequently confirmed the relevance of some of the human
analogs of these genes in clinical and/or human experimental pain states.
Little attention has been paid to comparative genetics
among animal species, but a few findings are noteworthy.
First, the insensitivity to capsaicin pain and thermal
hyperalgesia (i.e. increased sensitivity to noxious thermal
stimuli after injury) of birds [47] and naked mole-rats [48]
have been elucidated at the genetic level, identifying amino
acid substitutions in the Trpv1 capsaicin receptor gene in
the former [47] and a promoter deletion in the tachykinin,
precursor 1 (Tac1; substance P) gene in the latter [49].
Naked mole-rats are also insensitive to acid, recently found
to be the result of a variant Nav1.7 sodium channel gene
[50], also known to play an important role in some human
monogenic pain disorders (see below). Robust species specificity of the genetic mediation of pain is also suggested by a
recent meta-analysis of microarray (gene expression profiling) studies of chronic pain, in which almost no genes in
the dorsal root ganglia that were consistently up- or downregulated by nerve or inflammatory injury in the rat could
be confirmed as similarly regulated by those injuries in the
mouse [4]. This is a disturbing finding, because extrapolation of genetic findings from one rodent species to humans
is undermined by the inability to extrapolate from one
rodent to another.
Single-gene disorders of pain
The ‘low-hanging fruit’ of human genetics are inherited
mendelian disorders in which a single, mutated gene
produces with high penetrance an obvious disease state.
The mutations underlying such diseases can be elucidated
via genetic linkage mapping. A handful of rare, monogenic
disorders of pain are known, including the hereditary
sensory and autonomic neuropathies (HSANs), in which
Table 1. Pain-relevant QTLs in mice in which the gene affected by the underlying variant has been proposed
Phenotype
Heat pain f
Inflammatory pain g
Chronic pain h
Location a
4:71 cM
4:80 Mb
7:33 cM
7:50 cM
9:60 cM
10:70 cM
12:110 cM
14:34 Mb
5:123 Mb
8:28 Mb
Gene b
Oprd1
Tyrp1
Trpv1
Calca
Atp1b3
Avpr1a
Yy1
Mapk8
P2rx7
Chrna6
Sex c
< only
Both
Both
<>,
Both
< only
Both
Both
<>,
<>,
Evidence d
Ph., Pos.
cSNP, MUT
Pos.
Expr., KD, Mut., Ph.
KD, Ph.
Expr., Mut., Ph.
Expr., Mut.
Expr., Ph.
cSNP, Ph.
Expr., Mut.
15:80 Mb
Cacng2
Both
Expr., Mut.
Refs
[46,106]
[4]
[106]
[32]
[84]
[45]
[108]
[107]
[108]
Wieskopf, J. et al.,
unpublished
[109]
Human? e
Yes
No
No
No
No
Yes
No
No
Yes
Yes
Yes
Refs
[7]
[45]
[108]
Wieskopf, J. et al.,
unpublished
[109]
a
Mouse chromosome, followed by peak of linkage in either centiMorgans (cM) or Mb from the proximal end of the chromosome.
b
Genes encode the following proteins: Atp1b3, sodium-potassium ATPase, b3 subunit; Avpr1a, arginine vasopressin receptor 1A; Calca, calcitonin gene-related
polypeptide; Chnra6, nicotinic cholinergic receptor, a6 subunit; Cacng2, voltage-dependent calcium channel, g2 subunit (stargazer); Mapk8, mitogen-activated protein
kinase 8; Oprd1, delta-opioid receptor; P2rx7, P2X7 purinoceptor; Trpv1, transient receptor potential cation channel, V1; Tyrp1, tyrosinase-related protein 1; Yy1, yin-yang 1
transcription factor.
c
<: male; ,: female; both: linkage equally strong in male and female subjects; < only: linkage only observed in male subjects; <>,: linkage observed significantly more
strongly in male versus female subjects.
d
cSNP: coding region SNP with functional consequences in some strains; Expr.: strain-dependent expression levels; KD: knockdown (via antisense or siRNA); Mut.:
differential phenotype in mutant (transgenic knockout, transgenic knockin, congenic or spontaneous mutant) mouse; Ph.: effect on phenotype of protein-relevant
pharmacological ligand; Pos.: inferred by correspondence of gene location with peak of linkage.
e
Yes: positive genetic association of a variant within the analogous human gene and a similar trait in humans subjects; No: no relevant human association study yet
performed, or negative data obtained.
f
Assays include hot-plate test, hot water tail-withdrawal test and radiant heat paw-withdrawal (Hargreaves’) test.
g
Assay used was 5% formalin test.
h
Assays used were mechanical allodynia following spared nerve injury and autotomy following sciatic and/or saphenous nerve transection.
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Table 2. Single-gene pain disorders in which the responsible gene(s) have been identified
Disorder a
OMIM number
Syndromes featuring absence of pain
243 000
CAIP
162 400
HSAN-1
613 640
613 708
614 116
201 300
HSAN-II
613 115
614 213
223 900
HSAN-III
HSAN-IV (CIPA)
HSAN-V
Syndromes featuring pain
Familial periodic fever
FHM-I
FHM-II
FHM-III
FMF
Hereditary pancreatitis
HNA
PEPD
Primary erythermalgia
Gene
Protein
Refs b
SCN9A
SPTLC1
SPTLC2
ATL1
DNMT1
HSN2
FAM134B
KIF1A
IKBKAP
[110]
[111]
[112]
[113]
[114]
[115]
[116]
256 800
608 654
NTRK1
NGFB
Voltage-gated sodium channel, IXa (Nav1.7)
Serine palmitoyltransferase, long-chain 1
Serine palmitoyltransferase, long-chain 2
Atlastin GTPase 1
DNA methyltransferase 1
Splice variant of WNK1 gene c
Family with sequence similarity 134, B
Kinesin family member 1A
Inhibitor of k light polypeptide gene
enhancer in B cells, kinase complex-associated protein
Neurotrophic tyrosine kinase receptor 1
Nerve growth factor, b subunit
142 680
141 500
602 481
609 634
134 610/249 100
167 800
167 800
162 100
167 400
133 020
TNFRSF1A
CACNA1A
ATP1A2
SCN1A
MEFV
PRSS1
SPINK1
SEPT9
SCN9A
SCN9A
Tumor necrosis factor receptor superfamily, 1A
Voltage-gated calcium channel, P/Q type, a1A
Sodium-potassium ATPase, a2 subunit
Voltage-gated sodium channel, Ia (Nav1.1)
Familial Mediterranean fever gene (pyrin)
Trypsin-1
Serine protease inhibitor, Kazal-type 1
Septin 9
Voltage-gated sodium channel, IXa (Nav1.7)
Voltage-gated sodium channel, IXa (Nav1.7)
[117,118]
[119]
[120,121]
[122]
[123]
[124]
[125]
[126]
[127]
[128]
[129]
[130]
a
Based on a search of the Online Mendelian Inheritance in Man (OMIM) database (http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim) using the keyword ‘pain’.
Syndromes are included if pain is reported as a defining symptom of the disorder in the ‘Description’ subsection. Excludes inherited dysplasias, myotonias, and
Charcot–Marie–Tooth disease, all of which can be painful. Abbreviations: CAIP, channelopathy-associated indifference to pain; CIPA, congenital insensitivity to pain with
anhidrosis; FHM, familial hemiplegic migraine; FMF, familial Mediterranean fever; HNA, hereditary neuralgic amyotrophy; HSAN, hereditary sensory and autonomic
neuropathy; PEPD, paroxysmal extreme pain (familial rectal pain) disorder.
b
The reference provided is the first to identify unambiguously a causal gene variant. In many cases, prior linkage mapping studies existed in which the gene was
hypothesized to be responsible.
might even explain variability in more common pain
states, the more direct approach to uncovering common
disease-related gene variants is the genetic association
study. This technique has now been adopted earnestly
by clinical pain researchers, leading to an acceleration
in published findings (Figure 1), and progress has been
reviewed in depth elsewhere (e.g. [23,58,59]). A wide variety of genes has now been tentatively associated with both
experimental and clinical pain states (Figure 2 and the
80
No. of findings
pain sensibility is markedly absent (also known as congenital insensitivity to pain; [51,52]), the familial hemiplegic
migraine (FHM) disorders [53], and neurological channelopathies presenting as paroxysmal pain disorders (primary erythromelalgia, paroxysmal extreme pain disorder and
familial episodic pain syndrome) [54]. Genes and mutations responsible for many known disorders of this type
have now been found (Table 2). These genes encode proteins of different functional classes (e.g. ion channels,
enzymes, transcription factors and trophic factors), and
perhaps the only common thread is the involvement in
several disorders of the SCN9A gene encoding the Nav1.7
sodium channel, leading to its current status as a highpriority drug development target. Evidence that SCN9A
might play a role in more common pain states was provided
by the observation that there is significant association of
the R1150W variant (rs6746030) with osteoarthritis, sciatica and post-amputation pain (but not post-discectomy
pain or chronic pancreatitis pain) [55]. A recent study
failed to replicate the osteoarthritis association in two
separate cohorts, but found an association between the
R1150W variant and multiple regional pain [56]. In the
migraine genetics field, association studies have been
largely unable to demonstrate the involvement of FHM
genes in common migraines (e.g. [57]).
60
40
20
0
1975 1980 1985 1990 1995 2000 2005 2010 2015
Year of publication
TRENDS in Genetics
Candidate gene association studies of pain
Although genes responsible for rare inherited disorders
may provide excellent targets for drug development and
260
Figure 1. Number of pain-relevant candidate gene association study findings in
humans by year of publication. See online supplementary material for details of
each finding.
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Trends in Genetics June 2012, Vol. 28, No. 6
(a)
(f)
Acute pain
ADRB2
COMT
HTR2A
IL1RN
KCNJ6
MAOA
MAOB
OPRM1
Inflammatory pain
CFTR
HLA (all)
IL1
IL6
MEFV
SPINK1
0
0
5
10
15
5
20
No. of findings
(b)
(g)
Back pain
CACN2D3
CASP9
CILP
COL1A1
COL9A2
COL9A3
GCH1
IL1A
IL1B
IL1RN
IL6
KCNS1
SCN9A
0
5
10
15
20
No. of findings
(c)
10
15
20
15
20
No. of findings
Musculoskeletal pain
ACAN
ANP32A
ASPN
COL6A4P1
COMT
DIO2
EDG2
ESR1
GDF5
HFE
IL1RN
P2RX7
PCSK6
SCN9A
SMAD3
TRPV1
0
Cancer pain
5
10
No. of findings
ARRB2
COMT
GCH1
IL6
IL8
NFKBIA
OPRM1
PTGS2
STAT6
TNF
(h)
Neuropathic pain
ADRA1A
CACNG2
HLA (all)
0
5
10
15
20
KCNS1
P2RX7
SCN9A
No. of findings
TRPA1
TRPV1
(d)
Experimental pain
0
5
10
15
20
No. of findings
ADRA2C
AVPR1A
COMT
DRD3
DRD4
FAAH
GCH1
KCNS1
MAOA
MC1R
OPRD1
OPRM1
SLC6A3
SLC6A4
TRPA1
TRPV1
(i)
Visceral pain
CYP2D6
ESR1
GC
GNB3
GSTM1
IL16
0
5
10
15
20
No. of findings
(e)
MIF
PGR
PTGS1
SERPINE1
TACR1
TPRV1
Idiopathic (functional) pain
5
0
10
15
20
No. of findings
ADRA1D
ADRA2A
ADRB2
CNR1
COMT
GSTM1
HTR2A
HTR3E
IL1
IL10
IL1RN
MBL2
MC1R
MTHFD1
MTRR
SHMT1
SLC6A4
SOD2
TNF
(j)
Widespread pain
ADRB2
APOE
CHRBP
COMT
DRD4
HTR2A
MC2R
POMC
SCN9A
SERPINA6
SLC6A4
0
5
10
15
20
No. of findings
0
5
10
15
20
No. of findings
TRENDS in Genetics
Figure 2. Number of pain-relevant candidate gene association study findings in humans by phenotype (see online supplementary material for details). Genes with at least
one positive association are shown in green; negative associations are shown in red.
supplementary material online, a searchable and sortable
compendium of individual association findings, positive
and negative, from 1976 to 2011), as well as pain endophenotypes, such as cortical activation in the so-called
‘pain matrix’, wind-up (i.e. increased pain owing to temporal summation), and conditioned pain modulation (i.e.
counter-irritation). In most cases, genes were chosen for
study based on their known or presumed role in pain
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physiology, and/or because of their well-studied and highfrequency variants. In other cases, the genes were originally identified in animals (mice, rats or Drosophila) using
whole-genome QTL, mutant screening or microarray profiling; these have been especially heuristic. Nonetheless,
pain genetics has so far been dominated by investigations
of an exceedingly restricted number of genes, with 10 genes
(or gene complexes) accounting for over half of the extant
findings (Figure 3). As in other fields, replication of these
associations has been inconsistent at best, with follow-up
studies finding no association, association in the opposite
direction phenotypically, association in some but not other
cohorts, or associations but with different single nucleotide
polymorphisms (SNPs) or haplotypes from those originally
reported; potential reasons for this have been the subject of
considerable debate [60–62]. Only one true meta-analysis
has been performed so far, on the N40D (A118G) polymorphism of the OPRM1 gene encoding the m-opioid receptor.
Although the preclinical data are solid, no overall statistical relationship was found between OPRM1 genotype and
opioid requirements or pain levels in patients [63].
In addition to the general problems of sample size,
design, subject ascertainment, selective publication bias
(‘winner’s curse’), population substructure confound, and
so on, the pain field struggles with the ‘lumping/splitting’
problem hinted at previously. It is not at all clear whether
one should expect to find genes broadly affecting multiple
pain syndromes or symptoms, or whether completely different sets of genes ultimately underlie, say, back pain
versus post-herpetic neuralgia, or even thermal versus
mechanical hypersensitivity experienced by the same patient. A more subtle point is this: if one does find a gene
variant with broad effects on chronic pain, is it more likely
that the gene participates in pain physiology per se, or in
the physiology of psychological modulators of pain (e.g.
Key:
COMT
OPRM1
GCH1
HLA (all)
SLC6A4
HTR2A
IL1A,B
IL1RN
TRPV1
TNF
All others
TRENDS in Genetics
Figure 3. Popular candidate genes in pain genetic research. Studies of variants
within these 10 genes outnumber studies of all other genes combined.
Abbreviations: COMT, catechol-O-methyltransferase; GCH1, GTP cyclohydrolase
1; HLA, human lymphocyte antigen (major histocompatibility complex); HTR2A,
serotonin receptor, 2A; IL1A,B, interleukin-1 receptor a or b; IL1RN, interleukin-1
receptor antagonist; OPRM1, m-opioid receptor; SLC6A4, solute carrier family 6,
member 4 (serotonin transporter); TRPV1, transient receptor potential cation
channel, V1; TNF, tumor necrosis factor.
262
anxiety, depression, anger or catastrophizing)? There is
some evidence to suggest the latter (e.g. [64–66]) and,
although this makes no difference whatsoever to the issue
of explaining variability, it might diminish interest in that
gene as a target for drug development.
Multi-gene association studies
Despite the current explosion of interest, human pain
genetics has lagged behind genetics efforts in other fields
of biomedicine, for reasons including its subjective quantification, relatively low funding levels, a dearth of familial
aggregation and twin studies (until recently), and the
relative lack of interested epidemiologists, geneticists
and biostatisticians [67]. Migraine genetics is the exception, with at least three genome-wide association studies
(GWAS) having been published so far [68–70], but migraine genetics has been reviewed extensively by others
and will not be considered here. GWAS of disorders with
pain as a major symptom, including endometriosis [71],
Crohn’s disease [72] and osteoarthritis [73,74], have been
published, but pain intensity in these studies was neither
measured nor analyzed. Only one GWAS has been published so far with pain itself as a dependent measure,
relating to pain levels after third molar extraction and
inhibition of that pain by the NSAID ketorolac [75]. Although a true GWAS, with all subjects genotyped using the
Affymetrix 500K SNP chip, the total sample size was only n
= 112, and the only association surviving correction for
multiple comparisons was with a SNP in an unannotated
gene (LOC400680) in linkage disequilibrium with the
ZNF429 gene encoding a zinc finger protein. A modified
GWAS (using DNA-pooled ‘good’ versus ‘poor’ responders)
of opioid (morphine, oxycodone and fentanyl) analgesia in
patients with cancer has recently been reported, with the
strongest association by far with rs12948783, upstream of
the rhomboid 5 homolog 2 (RHBDF2) gene of unknown
function [76]. No polymorphisms in any known opioid
receptor genes were found to be associated. Of interest
is the fact that the strongest effect by far in this study was
European country of origin (P<2.210–16), suggesting the
importance of ethnic differences.
Although not a GWAS, preliminary results of a particularly ambitious multi-center, multi-gene study of temporomandibular disorder (TMD; an orofacial chronic pain
disorder affecting 5–10% of the population [77,78]) have
just been published. Called OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment), it comprised a
case–control study and large prospective cohort study of
3200 initially TMD-free individuals recruited at four study
sites, of which 260 have already developed diagnosed TMD
during the initial 5-year study period. A panel of 3295 SNPs
representing 23 high-priority and 358 trait-relevant gene
targets (the ‘Pain Research Panel’) was genotyped in 166
chronic TMD cases and 1442 controls, supplemented by an
additional 182 cases and 170 controls from a non-OPPERA
cohort [79]. No associations achieved strict experiment-wide
significance, and only two existing associations [with catechol-O-methyltransferase (COMT) and 5-hydroxytryptamine (serotonin) receptor 2A (HTR2A)] were supported;
however, these two involved different SNPs than reported
previously. By contrast, several new suggestive associations
Review
were evinced, to genes known to play important roles in pain
physiology [e.g. calcium channel, voltage-dependent, alpha
2/delta subunit 1 (CACNA2D1), nerve growth factor (NGF)
and tachykinin, precursor 1 (TAC1)] and to genes with no
currently known function in pain [e.g. calcium/calmodulindependent protein kinase IV (CAMK4), cholinergic receptor,
muscarinic 2 (CHRM2), interferon-related developmental
regulator 1 (IFRD1), G protein-coupled receptor kinase 5
(GRK5) and nuclear receptor subfamily 3, group C, member
1 (glucocorticoid receptor; NR3C1)]. Attempts are ongoing to
increase the statistical power and confirm some of these
associations in independent TMD cohorts and cohorts of
other patients with chronic pain. Ongoing work investigating the murine analogs of some of these genes has found
strong evidence for their involvement in pain in the mouse
(L.M., A.K., S.B.S., R.E.S., J.-S.A., D.L., L.G., N.S., W.M.,
J.S.M., and L.D., unpublished). Although not part of
OPPERA, this same group has just published another large
multi-gene association study of fibromyalgia using the 350gene Pain Research Panel [80]. One gene, TAAR1 (encoding
the G-protein coupled trace amine-associated receptor 1),
showed evidence of association in both cohorts examined.
There was no overlap with OPPERA-associated genes.
OPPERA itself represents a perfect microcosm of current enthusiasms and frustrations with human genetic
association studies. Candidate gene guesses are overwhelmingly proven wrong [81], supporting the value of
blinded genome-wide approaches in both animals and
humans. Replication is difficult, and a disappointingly
small percentage of genetic and trait variance has so far
been explained. On a more positive note, truly heuristic
biological information has been gained in some cases, and
it is hard to envisage how this information would have been
obtained using any other approach.
How many pain genes are there?
As research into the genetics of pain and analgesia accelerates, a reasonable question to start asking is how many
pain genes are there to find? Part of the difficulty in answering is a matter of definition: are pain genes only those genes
contributing to pain variability? What about those contributing to susceptibility to painful diseases (e.g. arthritis), but
not pain within those diseases? What about genes involved
in, say, the development of nociceptors, their housekeeping
functions, or genes related to very common neurochemical
signaling systems (e.g. glutamate or GABA) with functions
well beyond pain? Defined via significant transgenic knockout mouse phenotypes [3] or significant regulation in chronic
pain states [4], many hundreds of pain genes in rodents have
already been tentatively discovered. Presumably many
more await discovery. Just how many genes will affect pain
variability enough to be easily identified as such depends on:
(i) their average effect size (which could be very weak indeed
[82]); (ii) the breadth versus specificity of their effects; (iii)
how applicable the common disease-common variant hypothesis is to pain [58]; and (iv) practical issues, such as the
number and size of phenotyped patient cohorts. Effect sizes
of pain genes are often not reported and are probably
systematically overestimated [83]. Some murine pain QTLs
appear to have exquisitely specific effects; for example,
the Nociq1 QTL that has been shown to be mediated by
Trends in Genetics June 2012, Vol. 28, No. 6
expression levels of Atp1b3 (encoding the b3 subunit of the
sodium-potassium pump) affects responses in the early (0–
10 min) phase of the formalin test, but not afterwards and in
no other preclinical assay [84]. It seems somewhat clear by
now that pain does not have its own APOE or BRCA1; there
is no genetic association in the field so far that has been
consistently replicated or explained a large proportion of
trait variance. Attention in the pain field, as elsewhere, is
starting to turn to more complex approaches.
Beyond genetics: epistasis, gene environment
interactions, small RNAs, epigenetics and other -omics
Both linkage and association study methodologies attempt
to isolate the additive effect of DNA variants. It is well
appreciated that trait variance is also impacted by gene gene interactions (epistasis), gene environment interactions and environmental factors per se, the effects of which
might be mediated by epigenetic regulation. The first few
examples of these phenomena in the pain field have recently been demonstrated.
Two studies [85,86] observed interactions between the
V158 M (G1947A) variant of COMT and the N40D (A118G)
variant of OPRM1 in the determination of pain-related
morphine consumption. In both cases, although the genotypic effect of the individual variants were non- or only
marginally significant, the joint genotype at both genes
considered simultaneously achieved significance. Although the results of the two studies are not directly
comparable and it remains unclear whether the gene
effects were truly interactive and not just additive, epistasis between pain genes is probably a common phenomenon.
Recent work has uncovered and elucidated a gene sex
environment interaction of relevance to pain. A promoter
SNP (rs10877969) upstream of the arginine vasopressin
receptor 1A (AVPR1A) gene significantly affects capsaicin
pain sensitivity, but only in men and, moreover, only when
those men report subjective stress at the time of capsaicin
testing [45]. This gene was identified via QTL mapping in
mice, and a reanalysis of the murine data sets uncovered
the fact that Avpr1a also had an analogous sex- and stressspecific effect on pain in this species. It is conceivable that
any number of failures to replicate genetic association
study findings may be ultimately explainable in terms of
interactions between gene variants and organismal factors
and environmental testing conditions.
One of the more intriguing recent developments in
cellular genomics is that naturally occurring noncoding
miRNAs can profoundly inhibit gene expression by degrading mRNAs and regulating epigenetic machinery [87]. A
handful of recent studies have documented changes in
miRNA levels in pain states [88]. Causational evidence
of miRNA involvement in pain comes from the demonstration that conditional deletion in nociceptors of the miRNAproducing enzyme, Dicer, blocks inflammatory pain hypersensitivity [89], and that small interfering-RNA-mediated
knockdown of one miRNA, miR-103, produces hypersensitivity to pain in naı̈ve rats [90].
There is currently great interest in the possibility
that the study of epigenetic mechanisms might provide
novel insight into pain chronicity. Indeed, the concept
that changes in chromatin structure might underlie
263
Review
acute-to-chronic pain transitioning, pain ‘priming’ effects
[91–93] and effects of neonatal pain experience on adult pain
sensitivity (e.g. [94,95]), is compelling. Although no one has
yet shown this to be true, the first evidence of epigenetic
regulation by chronic pain in rodents is appearing in the
literature (reviewed in [96]). Changes in the expression of
pain-related genes [e.g. glutamate decarboxylase 2 (Gad2),
potassium voltage-gated channel, Shal-related subfamily,
member 3 (Kcnd3), methyl CpG binding protein 2 (Mecp2),
Oprm1, Scn9a and secreted protein, acidic, cysteine-rich
(Sparc)] are correlated with histone modifications [97–101],
chronic pain states feature abnormal DNA methylation
and histone acetylation [98,100,101], and treatment with
histone deacetylase (HDAC) inhibitors is analgesic
[99,102,103]. The value of these initial demonstrations is
limited by their correlational nature and the non-specificity
of HDAC inhibitors, but studies of the epigenetics of pain are
likely to yield many surprises in the near future.
Although the focus so far has been on genomics and
transcriptomics, other ‘-omics’ techniques continue to develop, and have the theoretical advantage of being closer to
real biological actions than are DNA and mRNA. Two painrelevant papers have just published. In one, tissue metabolites were profiled by mass spectrometry (metabolomics),
identifying dysregulation in sphingomyelin–ceramide metabolism in neuropathic rats and suggesting inhibition of
N,N-dimethylsphingosine production as a novel analgesic
strategy [104]. In the other, cadaverous nerves from
patients with complex regional pain syndrome (type 2)
were subjected to proteomic analysis, identifying an absence of zinc-binding metallothioneins in these sufferers of
chronic pain [105].
Concluding remarks
Despite its delayed entry, pain genetics is now proceeding
at a particularly rapid pace. As is not unusual in science,
increasing knowledge has revealed the size of the problem
to be far larger than anticipated. At the present time, I am
not optimistic about pain geneticists explaining enough
trait variance in clinical pain states or analgesic response
to serve as a guide to individualized pain therapy any time
soon. However, heuristic advances by pain geneticists are
likely to accelerate and refine analgesic development
efforts, leading ironically perhaps to new pain treatments
for some rather than all.
Acknowledgments
The author is supported by the Canadian Institutes for Health Research,
Canada Research Chairs program, and the Louise and Alan Edwards
Foundation.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tig.2012.02.004.
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