3' untranslated region variable number tandem repeat (VNTR) polymorphism. A higher frequency of 9-repeat allele in PTSD patients.

Transcription

1 Table S2. Genetic variants implicated in human pain conditions a Functional class Gene Protein name Condition Genetic Polymorphism Minor Allele Frequency Transporters Metabolic genes and transcription regulators SLC6A3, or DAT1 SLC6A4, or 5-HTT, or SERT ABCB1, or MDR1 COMT Solute carrier family 6 (neurotransmi tter transporter, dopamine), member 3 Solute carrier family 6 (neurotransmi tter transporter, serotonin), member 4, or 5- hydroxytrypta mine transporter ATP-binding cassette, subfamily B, member 1, or Multidrug resistance 1, or P- glycoprotein Catechol-Omethyltransfer ase PTSD 3' untranslated region variable number tandem repeat (VNTR) polymorphism. A higher frequency of 9-repeat allele in PTSD patients. FMS 5-HTT gene-linked polymorphic region (5-HTTLPR) variants. A higher frequency of the S/S (short alleles) genotype in FM patients. CFS A higher frequency of longer 5-HTTLPR allelic variants in CFS patients. Migraine Polymorphism of the two regions VNTR and 5- HTTLRP. Associations with different alleles of VNTR in intron 2 and a higher frequency of the short 5-HTTLPR allelic variants in migraine patients. TMJD Polymorphism in variable number of tandem repeats (VNTR) in intron 2. A higher frequency of STin 2.10 allele in TMJD patients. D-IBS 5-HTTLPR polymorphism influenced response to a 5- HT3 antagonist in patients with diarrhea-predominant IBS. TMJD Pain sensitivity C3435T silent polymorphism in exon 26 changes substrate specificity. Cancer pain patients with different genotypes needed different morphine dosage. 3 major haplotypes determine COMT activity that inversely correlates with pain sensitivity and risk of TMJD. Val158Met polymorphism. Individuals with Met/Met genotype had a lower tolerance to pain and a higher Reported by Segman et al 2002 [1] Offenbaecher et al 1999, Cohen et al 2002 Review Refs [1] 0.12 Narita et al 2003 [2] Ogilvie et al 1998, Yilmaz et al 2001, Juhasz et al 2003, Borroni et al 2005, Marziniak et al Herken et al 2000 [4] Camilleri et al 2002 [5] Hoffmeyer et al 2000, Baar et al 2005, Kimchi- Sarfaty et al , 0.365, Diatchenko et al Zubieta et al 2003 [6;7] [8] [9] Page 1 of 7

2 CYP2D6 Cytochrome P450 2D6 GSTM1 Glutathione S- transferase mu GCH1 GTP cyclohydrolas e 1 MTHFR 5',10'- methylenetetr ahydrofolate reductase ACE Angiotensin I - converting enzyme NOS3, or enos SPTLC1, or SPT1 Endothelial nitric oxide synthase Serine palmitoyltrans ferase, long chain base subunit 1 Migraine FMS opioid Recurrent dysmenorr hea Recurrent dysmenorr hea LBP CSA HSAN I (hereditary sensory radicular neuropathy ) regional density. Val158Met polymorphism. Cancer patients with M/M genotype needed lower doses of morphine to relieve pain Val158Met polymorphism. A higher frequency of Met/Met and Met/Val genotype in migraineurs. Val158Met polymorphism. A higher frequency of Met/Met and Met/Val genotype in FM patients Over 75 different alleles code for different metabolizer phenotypes, ranging from ultrarapid metabolizer (UM) with the highest amount of enzyme to poor metabolizer (PM) with no enzyme. UMs developed opioid intoxication to small doses of codeine. PMs had tendency do not respond to standard doses of tramadol. CYP2D6 Arg296Cys mutation was associated with increased risk of recurrent dysmenorrhea. GSTM1 deletion was associated with increased risk of recurrent dysmenorrhea. A haplotype of the GCH1 gene was associated with less pain following diskectomy for persistent radicular LBP. C677T polymorphism was associated with elevated serum level of an excitatory amino acid homocysteine. Individuals with T/T genotype had increased risk for. 287bp deletion in intron 16. Higher frequency of allele D (deletion) in patients. This allele was associated with increased ACE level in serum. Glu298Asp polymorphism. Asp298 allele was associated with CSA in patients with hypertrophic cardiomyopathy. Autosomal dominant mutations Cys133Tyr, Cys133Trp, Val144Asp and Gly387Ala resulted in reduced SPT activity and impaired sphingolipid synthesis Rakvag et al Erdal et al 2001 [10] [11] Gursoy et al 2003 [6] Johansson et al 1993, Sachse et al 1997, Dalen et al 1997, Gasche et al 2004, Ingelman- Sundberg et al 2001, Stamer et al 2003 [6] no data Wu et al 2000 [12] no data Wu et al 2000 [12] Tegeder et al Kowa et al 2000, Lea et al 2004, Scher et al Lea et al 2005, Kowa et al 2005 [13] Ogimoto et al 2005 [14] Bejaoui et al 2001 and 2002, Dawkins et al 2001, Nicholson 1996 and 2001, Verhoeven 2004 [15;16] Page 2 of 7

3 Receptors HSN2 IKBKAP, or IKAP NGFB NTRK1, or TRKA ADRA2A and ADRA2C Hereditary sensory neuropathy 2 protein Inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex associated protein Nerve growth factor, beta subunit Neurotrophic tyrosine kinase,, type 1 Alpha-2A and alpha-2cadrenergic s ADRB2 Beta 2 adrenergic DRD2 DRD4 Dopamine D2 Dopamine D4 HSAN II (Morvan's syndrome) HSAN III (familial dysautono mia, Riley- Day syndrome) HSAN V HSAN IV (congenital insensitivity to pain with anhidrosis) C-IBS Autosomal recessive mutations led to truncated forms of deduced HSN2 protein which function is at present unknown. Nothern blot analysis of adult human tissues failed to detect HSN2 transcript, suggesting that the gene may be expressed on very low level. Two autosomal recessive mutations reported. The major haplotype mutation was located in the donor splice site in intron 20 and produced truncated protein. The minor haplotype mutation Arg696Pro in exon 19 disrupted a potential phophorylation site. Autosomal recessive mutation Trp211Arg in a highly conserved region of NGF protein. 43 known autosomal recessive mutations in TrkA gene led to inability to transduce nerve growth factor (NGF) into growing neurons and to death of the neural crest derived neurons. Lafreniere et al 2004, Riviere et al 2004, Roddier et al 2005, Takagi et al 2006, Coen et al 2006, Cho et al 2006 Andeson et al 2001, Slaugenhaupt et al 2001 [17] [18] Einarsdottir, 2004 [19] Indo et al 1996, Mardy et al 1999, Miura et al 2000, Shatzky et al 2000, Indo et al 2001 α 2C Del and α 2A C-1291G polymorphisms were associated with constipation-predominant IBS. 0.08, 0.43 Kim et al 2004 [5] VA α 2C Del allele carrier state was a risk factor of Park et al 2006 [20] VA. TMJD 3 major haplotypes were identified. Subjects with 0.41, 0.36, 0.21 Diatchenko et al 2006 [21] either high or low ADRB2 activity were at risk of developing TMJD though different etiological pathways. VA Gln27Glu polymorphism. Gln/Gln genotype was a risk Park et al 2006 [20] factor of VA. His313His silent polymorphism. A higher frequency of 0.27 Peroutka et al 1997 and NcoI C allele in patients with PTSD 3'-UTR polymorphism. DRD2 A1 allele may be a useful 0.38 Lawford et al 2003 [1] marker to predict an improvement in social functioning with SSRI paroxetine treatment in PTSD patients. MO Exon III tandem repeat polymorphism. Shortest and 0.104, 0.5 Mochi et al 2003 [22] longest alleles were less frequent in MO patients. FMS Exon III tandem repeat polymorphism. A lower Buskila et al 2004 [1] Page 3 of 7

4 Cytokines MC1R OPRM1, or MOR kappaopioid Melanocortin- 1 Opioid, mu-1 5-HTR2A 5- hydroxitrypta mine 2A, or serotonin 2A IL1A, IL1B, and IL1RN Interleukins 1- alpha and beta, interleukin antagonist IL1RN Interleukin 1 antagonist IL1B Interleukin 1- beta VVS Pain sensitivity TMJD LBP VVS frequency of 7-repeat allele in FM patients. Arg151Cys, Arg160Tyr and Asp294Asn polymorphism. Red-headed women with two variant MC1R alleles displayed greater from pentazocine. Arg151Cys, Arg160Tyr and Asp294Asn polymorphism. Red-headed subjects with two variant MC1R alleles displayed reduced sensitivity to noxious stimuli and greater from M6G. VVS cases were more likely to carry at least 1 of 6 lossof- function polymorphisms. A118G (Asn40Asp) polymorphism. Healthy volunteers with A/A genotype had lower pressure pain thresholds. A118G (Asn40Asp) polymorphism. Cancer pain patients with G/G genotype needed more morphine to achieve pain control. A118G (Asn40Asp) polymorphism. G allele had a lower frequency in chronic pain patients and carriers of A/A genotype in the high quartile of opioid use needed more morphine. T102C polymorphism: a higher frequency of C/C genotype in TMJD patients. T102C polymorphism was not directly related to the increased risk of migraine, but C/C genotype was significantly more frequent in patients. IL-1α C889T, IL-1β C3954T, and IL-1RN G1812A polymorphisms were associated with pain rating and risk of low back pain development. 2nd intron VNTR polymorphism: a higher frequency of homozygous for allele 2 genotype in VVS patients Mogil et al 2003 [23] Mogil et al 2005 [24] Foster et al 2004 [25] Fillingim et al 2005 [24] Klepstad et al 2004 [6] Janicki et al 2006 [26] Mutlu et al 2004 [27] Erdal et al 2001 [11] 0.29, 0.21, 0.17 Solovieva et al 2004 [28] Jeremias et al 2000, Foster et al 2004 VVS C3954T polymorphism. A higher frequency of IL-1β high producer allele T in women with VVS Gerber et al 2003 [29] BMS C3954T polymorphism. A higher frequency of IL-1β Guimaraes et al 2006 [30] high producer genotype C/T in BMS patients. IL6, or Interleukin 6, JRA Promoter G-174C polymorphism. G/G genotype was 0.58 Oen et al 2005 [31] [25] Page 4 of 7

5 Ion channels IFNB2 or interferon positively correlated with pain in JRA patients. beta-2 LBP T15A (Asp162Glu) polymorphism in exon 5. A higher Nopenen-Hietala et al [32] frequency of allele A and A/A and A/T genotypes in LBP patients IL10 Interleukin 10 IBS Promoter polymorphism G-1082A: a lower frequency 0.48 Gonsalkorale et al 2003 [5] of G/G genotype (high IL-10 producer) in IBS patients. TNF, or TNFA Tumor necrosis factor alpha IBS RA Promoter polymorphism G-308A. More IBS patients were positive for the A allele (high TNFα producer). Promoter polymorphism G-308A. Australian and van der Veek et al 2005 Danis et al 1995, Cuenca [5] [33] Chilean studies reported an increase in the A allele in RA patients, while G allele was increased in studies from Taiwan and Sweden. et al 2003, Yen et al 2001, Cvetkovic et al 2002 LTA, or TNFB Lymphotoxin alpha, or tumor necrosis factor beta MO A higher frequency of TNFB*2 allele in MO patients Trabace et al 2002 [22] HLA Human histocompatib ility leukocyte antigens (HLA) ATP1A2 Na + /K + - ATPase, alpha 2 subunit CACNA1A SCN1A Calcium channel Ca V 2.1, alpha 1A subunit Voltage-gated sodium channel Na V 1.1, alpha 1 subunit PHN Human histocompatibility leukocyte antigens HLA- A*3303, -B*4403, and -DRB1*1302 alleles and haplotype including those alleles were significantly associated with PHN , 0.08, Sato et al 2002 [34] BM Arg548His mutation was found in BM family. Ambrosini et al 2005 FHM type 2 Missense mutations and deletions led to loss of De Fusco et al function or alteration of the kinetics of Na+/K+-ATPase 2003,Vanmolkot et al pump and 2006, Swoboda et al 2004, Riant et al 2005, Pierelli et al 2006, Significantly increased sharing of CACNA1A marker Terwindt et al 2001 alleles in siblings with. FHM type 1 FHM type 3 Missense mutations in conserved functional domains of pore-forming α1a subunit of neuronal Ca V 2.1 channels resulted in increase of Ca 2+ influx. Gln1489Leu mutation was found in 3 FHM families and led to a faster Na V 1.1 channel recovery from fast inactivation. Ophoff et al 1996, Kors et al 2003, Kors et al 2004 Dichgans et al 2005 SCN9A Voltage-gated PE Missense mutations enhanced activation of Na V 1.7 Yang et al 2004, Drenth [35] Page 5 of 7

6 sodium channel Na V 1.7, alpha subunit channels. PEPD Missense mutations impaired inactivation of Na V 1.7 channels. CAIP, or Homozygous nonsense mutations caused loss of CIDP function of Na V 1.7 channels. et al 2005, Dib Hajj et al 2005, Harty et al 2006 Fertleman et al 2006 [36] Cox et al 2006, Goldberg et al 2007 a Abbreviations: BM- basilar migraine, BMS - burning mouth syndrome, CAIP - channelopathy-associated insensitivity to pain, CIDP - congenital indifference to pain, CFS - chronic fatigue syndrome, CSA - coronary spastic angina, FHM - familial hemiplegic migraine, FMS - fibromyalgia syndrome, HSAN - hereditary sensory and autonomic neuropathy, IBS - irritable bowel syndrome, JRA - juvenile rheumatoid arthritis, LBP - low back pain, M6G - morphine-6-glucuronide, - migraine with aura, MO - migraine without aura, NGF nerve growth factor, OA osteoarthritis, PE - primary erythermalgia, PEPD - paroxysmal extreme pain disorder, PHN - posrherpetic neuralgia, PTSD - post traumatic stress disorder, TMJD - temporomandibular joint disorder, VA - vasospastic angina, VNTR - variable number tandem repeat, VVS - vulvar vestibulitis syndrome, 5-HTTLPR - 5-HTT gene-linked polymorphic region. References 1 Ablin, J.N. et al. (2006) Mechanisms of Disease: genetics of fibromyalgia. Nat. Clin. Pract. Rheumatol. 2, Narita, M. et al. (2003) Association between serotonin transporter gene polymorphism and chronic fatigue syndrome. Biochem. Biophys. Res. Commun. 311, De Vries, B. et al. (2006) Genetic biomarkers for migraine. Headache 46, Herken, H. et al. (2001) Possible association of temporomandibular joint pain and dysfunction with a polymorphism in the serotonin transporter gene. Am. J. Orthod. Dentofacial Orthop. 120, Park, M.I. and Camilleri, M. (2005) Genetics and genotypes in irritable bowel syndrome: implications for diagnosis and treatment. Gastroenterol. Clin. North Am. 34, Lotsch, J. and Geisslinger, G. (2006) Current evidence for a genetic modulation of the response to analgesics. Pain 121, Kimchi-Sarfaty, C. et al. (2006) A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity. Science 315, Diatchenko, L. et al. (2005) Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum. Mol. Genet. 14, Zubieta, J.K. et al. (2003) COMT val158met genotype affects neurotransmitter responses to a pain stressor. Science 299, Rakvag, T.T. et al. (2005) The Val158Met polymorphism of the human catechol-o-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain 116, Erdal, M.E. et al. (2001) Association of the T102C polymorphism of 5-HT2A gene with aura in migraine. J. Neurol. Sci. 188, Wu, D. et al. (2000) Metabolic gene polymorphisms and risk of dysmenorrhea. Epidemiology 11, Tegeder, I. et al. (2006) GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat. Med. 12, Ogimoto, A. et al. (2005) Endothelial nitric oxide synthase gene polymorphism (Glu298Asp) in patients with coexistent hypertrophic cardiomyopathy and coronary spastic angina. J. Mol. Med. 83, Nagasako, E.M. et al. (2003) Congenital insensitivity to pain: an update. Pain 101, Verhoeven, K. et al. (2004) SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I. Neurology 62, Cho, H.J. et al. (2006) Novel mutation in the HSN2 gene in a Korean patient with hereditary sensory and autonomic neuropathy type 2. J. Hum. Genet. 51, Slaugenhaupt, S.A. et al. (2001) Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am. J. Hum. Genet. 68, Einarsdottir, E. et al. (2004) A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum. Mol. Genet. 13, Park, J.S. et al. (2006) Common adrenergic polymorphisms as novel risk factors for vasospastic angina. Am. Heart J. 151, Diatchenko, L. et al. (2006) Three major haplotypes of the beta2 adrenergic define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 141, Estevez, M. and Gardner, K.L. (2004) Update on the genetics of migraine. Hum. Genet. 114, Mogil, J.S. et al. (2003) The melanocortin-1 gene mediates female-specific mechanisms of in mice and humans. Proc. Natl. Acad. Sci. U.S.A. 100, Mogil, J.S. et al. (2005) Melanocortin-1 gene variants affect pain and in mice and humans. J. Med. Genet. 42, Foster, D.C. et al. (2004) Impact of genetic variation in interleukin-1 antagonist and melanocortin-1 genes on vulvar vestibulitis syndrome. J. Reprod. Med. 49, Janicki, P.K. et al. (2006) A genetic association study of the functional A118G polymorphism of the human gene in patients with acute and chronic pain. Anesth. Analg. 103, [37] [38] Page 6 of 7

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