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Association of the T102C polymorphism of 5-HT2A receptor gene with aura in migraine
Journal of the Neurological Sciences 188 Ž2001. 99–101 www.elsevier.comrlocaterjns
Short communication
Association of the T102C polymorphism of 5-HT2A receptor gene with aura in migraine M. Emin Erdal a , Hasan Herken b, Mustafa Yılmaz c , Yıldırım A. Bayazıt d,) a
Department of Medical Biology and Genetics, Faculty of Medicine, Mersin UniÕersity, Mersin, Turkey Department of Psychiatry, Faculty of Medicine, Gaziantep UniÕersity, Kolejtepe, Gaziantep, Turkey c Department of Neurology, Faculty of Medicine, Gaziantep UniÕersity, Kolejtepe, Gaziantep, Turkey Department of Otolaryngology, Faculty of Medicine, Gaziantep UniÕersity, Kolejtepe, Gaziantep, Turkey b
d
Received 14 March 2001; received in revised form 22 May 2001; accepted 4 June 2001
Abstract ObjectiÕe: To find out the significance of the 5-HT2A receptor gene polymorphism in migraine. Study design: A PCR study in which 61 migraineurs and 44 healthy controls were included. Methods: The T102C polymorphism of the 5-HT2A receptor gene was studied. The results of the migraineurs and controls were compared. The relationship between the gene polymorphism and aura was also assessed. Results: The representations of the 5-HT2A genotypes were similar in migraineurs and controls Ž p ) 0.05. as well as in the male and female migraineurs Ž p ) 0.05.. The family history of migraine did not associate with 5-HT2A receptor gene polymorphism Ž p ) 0.05.. There was a significant relationship between the presence of CrC genotype and migraine with aura Ž p s 0.02. while CrT and TrT genotypes were over represented in the patients with migraine without aura Ž p - 0.01.. Conclusion: The T102C polymorphism of the 5-HT2A receptor gene is not directly related to the increased risk of migraine. The associations between the genotypes of this gene and aura may suggest that 5-HT2A receptor gene polymorphism may be involved in determining the subtypes of or accompanying symptoms in the migraine disease. q 2001 Published by Elsevier Science B.V. Keywords: Migraine; 5-HT2A receptor; Serotonin; Polymorphism
1. Introduction Although it is believed that migraine has a strong genetic component, the type and number of genes involved in this disease has not been understood entirely. The serotonin Ž5-hydroxytryptamine; 5-HT. is a key neurotransmitter in the central nervous system, and dysregulation of serotonergic pathways has been implicated in the pathogenesis of many complex neuropsychiatric diseases. It was suggested that the 5-HT related genes may be involved in the pathogenesis of migraine w1,2x. The 5-HT is a neurotransmitter that occupies a uniquely important place in neurobiology because of its role in many physiologic processes such as sleep, appetite, thermoregulation, pain perception, hormone secretion, and sexual behavior. Abnormality of the serotonergic system has been implicated in a number of human diseases such as ) Corresponding author. Tel.: q90-342-336-5400; fax: q90-342-3365505. E-mail address: [email protected] ŽY.A. Bayazıt..
mental depression, migraine, epilepsy, obsessive-compulsive behavior, and affective disorder. Like other neurotransmitters, 5-HT is released into the synaptic junction and exerts its effect on specific receptors on the postsynaptic membranes. There are a number of 5-HT receptors identified, and each group is not only operationally but also structurally distinct, with each receptor group having its own distinct transducing system w3,4x. The activity of serotonergic system is under the control of the genes like 5HT1D Ž1p36.3–34.3., 5HT1B Ž6q13., 5HT2A Ž13q14–21., 5HT transporter Ž17q11.2–12., and CACNLB1 Ž17q11.2–22. Ž19p13. w5x. One of the 5-HT related genes, the 5-HT2A receptor gene, is mapped to chromosome 13q14–21 w6,7x. Recently, a silent polymorphism in the 5-HT2A receptor gene was identified which is defined by a T to C transition at position 102. This mutation does not alter the amino acid composition, and therefore has no influence on receptor protein w8x. It is unclear whether T102C polymorphism of the 5HT2A receptor gene is associated with migraine. In this
0022-510Xr01r$ - see front matter q 2001 Published by Elsevier Science B.V. PII: S 0 0 2 2 - 5 1 0 X Ž 0 1 . 0 0 5 5 6 - 1
M.E. Erdal et al.r Journal of the Neurological Sciences 188 (2001) 99–101
100
study, the purpose was to find out the significance of the 5-HT2A receptor gene polymorphism in migraine.
Table 2 The T102C polymorphism of the 5-HT2A receptor gene in the migraine subgroups Genotype
2. Materials and methods Sixty-one migraineurs and 44 healthy volunteers were included in the study. There were 9 Ž14.8%. male and 52 Ž85.2%. female migraineurs with the ages ranging from 21 to 49 Žmean, 33. years. There were 6 Ž13.6%. male and 38 Ž86.4%. female healthy controls with ages ranging from 19 to 53 Žmean, 35. years. The migraineurs and healthy controls were age and sex matched Ž p - 0.05.. The diagnosis of migraine was made on the basis of the criteria of the International Headache Society, 1988 w9x. Thirty-seven Ž60.7%. patients had migraine with aura ŽMA., and 24 Ž39.3%. had migraine without aura ŽMOA.. Seventeen migraineurs also had a family history of migraine. An informed consent was obtained from the subjects who participated in the study. The migraineurs and healthy controls were from the same geographic region and of the same ethnic origin. The migraineurs and controls were not relatives. There was only one migraineur from each family. Those who had mental retardation, drug dependence, and metabolic or psychiatric or neurological illness were excluded. Those whose first-degree relatives had endogenous psychoses or alcoholism were also excluded. The controls who had migraine history in the first-degree relatives were excluded. Physical and psychiatric examinations were carried out by the psychiatrist and neurologist following an interview. A cranial computed tomography or magnetic resonance imaging was obtained as indicated. The blood samples were taken for complete blood count and blood chemistry Želectrolytes, glucose, renal and liver function tests, and thyroid hormone level. as well as for the molecular analysis of 5-HT2A receptor polymorphism. 2.1. Molecular analysis A 5-ml blood sample was obtained and the DNA was extracted from the leukocytes using the QIAamp Blood Isolation kit ŽQIAGEN.. Primers flanking the 5-HT2A polymorphic site at position 102 Ž5-HT2A-F 5X-CTGTCT GCT ACA AGT TCT GGC TTT-3X ; 5-HT2A-R 5X-CTG
Migraine with aura Ž ns 37. Migraine without aura Ž ns 24.
TrT n Ž%.
TrC n Ž%.
CrC n Ž%.
7 Ž18.9.
15 Ž40.5.
15 Ž40.5.
6 Ž25.
16 Ž66.7.
2 Ž8.3.
CAG CTT TTT CTC TAG GG-3X . were used to generate a 342-bp fragment. PCR was performed in a final volume of 25 ml consisting of 50 ng DNA, 0.6 mmolrl of each primer, 200 mmolrl dNTPs, 10 mmolrl Tris–HCL ŽpH 8.3., 50 mmolrl KCL, 1.5 mmolrl MgCl 2 , and 1.25 U AmpliTag Gold ŽPerkin Elmer.. Annealing was carried out at 60 8C for 30 s, extension at 72 8C for 30 s, and denaturation at 95 8C for 30 s for 35 cycles. PCR products were digested with 10 U MspI ŽRoche Molecular Biochemicals. for 14 h and separated on a 2% agarose gel ŽFMC NuSieve 3:1, from Biozym.. Allele 1 ŽT102C allele. was represented by the uncut 342-bp PCR product and allele 2 ŽC102 allele. consisted of two fragments at 215 and 126 bp. 2.2. Statistics SPSS 8.0 for windows was used for the statistical analyses of the data, and chi-square test was used.
3. Results The representations of the 5-HT2A genotypes were similar in the migraineurs and controls Ž x 2 s 10.16, p s 0.62. as well as in the male and female migraineurs Ž x 2 s 0.004, p s 0.950. ŽTable 1.. The family history of migraine did not associate with 5-HT2A receptor gene polymorphism Ž x 2 s 1.035, p s 0.595.. There was a significant relationship between the presence of CrC genotype and MA Ž x 2 s 7.62, p s 0.02. while CrT and TrT genotypes were overrepresented in the patients with MOA Ž x 2 s 7.51, p - 0.006. ŽTable 2..
4. Discussion Table 1 The genotypic distribution of T102C polymorphism of the 5-HT2A receptor gene Genotype
Migraine Ž ns61. Control Ž ns 44.
CrC n Ž%.
CrT n Ž%.
TrT n Ž%.
17 Ž27.9. 12 Ž27.3.
31 Ž50.8. 19 Ž43.2.
13 Ž21.3. 13 Ž29.5.
Influence of the molecular mechanisms or variations should not be overlooked in diseases like the migraine. One of the most critical molecular systems involved in the migraine disease is the serotonergic system. This recent identification of the polymorphism of 5-HT transporter gene appears to be promising to better understand the serotonergic system as well as molecular changes in migraine disease.
M.E. Erdal et al.r Journal of the Neurological Sciences 188 (2001) 99–101
The 5-HT is a neurotransmitter that mediates a wide range of central nervous functions by activating multiple 5-HT receptor subtypes. A possible irregularity of serotonergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. w10x. The 5-HT which predominantly serves as an inhibitory neurotransmitter in the brain has long been implicated in migraine pathophysiology as well. It is now widely accepted that many disorders have a familial or genetic component. In this study, the family history of migraine did not associate with 5-HT2A receptor gene polymorphism. Thus, the polymorphism of this gene does not take part in the genetic transmission of migraine. It was also suggested that the MspI polymorphism in 5HT2A receptor gene is not associated with migraine occurrence, and excluded for involvement with migraine w11x. The T102C polymorphism of the 5-HT2A receptor gene is a recent discovery, the influence of which is unclear in migraine. According to our results, this polymorphism is not associated with the occurrence of migraine disease owing to similar representation of the genotypic variants CrC, CrT and TrC in the migraineurs and controls. Therefore, the polymorphism is not related to the occurrence of headache symptom in the patients. On the other hand, the polymorphism of this gene may be important in the subtypes of migraine because there was a significant relationship between the presence of CrC genotype and MA, while CrT and TrT genotypes were overrepresented in the patients with MOA. The cause of aura is not known properly although a variety of mechanisms is likely to be involved in the occurrence of aura. Susceptibility to MA and MOA has a genetic component, that is, these disorders are distinct w12,13x. It was proposed that this genetic susceptibility may, in some cases, be associated with a locus at or near the 5-HT transporter gene w13x. Although functional significance of the variants of T102C polymorphism of the 5-HT receptor gene is unclear, the association of its variants with aura may suggest that the functional status of the 5-HT receptor changes depending upon the genotypic variability which, in turn, modifies the 5-HT activity at the receptor level. Furthermore, these results also indicate that the genetic susceptibility to aura is partially under the control of 5-HT receptor gene. Some associations were found between the presence of the T102C allele and the presence of both visual and auditory hallucinations w14,15x. This finding enhances our contention that aura susceptibility is genetically controlled in which T102C polymorphism also plays a role. In conclusion, the polymorphism in the 5-HT2A receptor gene is not directly related to the increased risk of
101
migraine. The associations between the genotypes of this gene and aura may suggest that 5-HT2A receptor gene polymorphism may be involved in determining the subtypes of or accompanying symptoms in the migraine disease.
References w1x Lea RA, Dohy A, Jordan K, Quinlan S, Brimage PJ, Griffiths LR. Evidence for allelic association of the dopamine beta-hydroxylase gene ŽDBH. with susceptibility to typical migraine. Neurogenetics 2000;3:35–40. w2x MaassenVanDenBrink A, Vergouwe MN, Ophoff RA, Saxena PR, Ferrari MD, Frants RR. 5-HT1B receptor polymorphism and clinical response to sumatriptan. Headache 1998;38:288–91. w3x Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, et al. International union of pharmacology classification of receptors for 5-hydroxytryptamine Žserotonin.. Pharmacol Rev 1994; 46:157–203. w4x Hartig PR, Hoyer D, Humphrey PP, Martin GR. Alignment of receptor nomenclature with the human genome: classification of 5-HT1B and 5-HT1D receptor subtypes. Trends Pharmacol Sci 1996;17:103–5. w5x Monari L, Mochi M, Valentino ML, Arnaldi C, Cortelli P, De Monte A, et al. Searching for migraine genes: exclusion of 290 cM out of the whole human genome. Ital J Neurol Sci 1997;18:277–82. w6x Blairy S, Massat I, Staner L, Le Bon O, Van Gestel S, VanBroeckhoven C, et al. 5-HT2a receptor polymorphism gene in bipolar disorder and harm avoidance personality trait. Am J Med Genet 2000;96:360–4. w7x Sparkes RS, Lan N, Klisak I, Mohandas T, Diep A, Kojis T, et al. Assignment of a serotonin 5HT-2 receptor gene ŽHTR2. to human chromosome 13q14–q21 and mouse chromosome 14. Genomics 1991;9:461–5. w8x Bondy B, Spaeth M, Offenbaecher M, Glatzeder K, Stratz T, Schwartz M, et al. The T102C polymorphism of the 5-HT2A receptor gene in fibromyalgia. Neurobiol Dis 1999;6:433–9. w9x Headache Classification Committee of the International Headache Society, Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8:1–96. ŽSuppl.. w10x Vogt IR, Shimron-Abarbanell D, Neidt H, Erdmann J, Cichon S, Schulze TG, et al. Investigation of the human serotonin 6 Ž5-HT6. receptor gene in bipolar affective disorder and schizophrenia. Am J Med Genet 2000;96:217–21. w11x Nyholt DR, Curtain RP, Gaffney PT, Brimage P, Goadsby PJ, Griffiths LR. Migraine association and linkage analyses of the human 5-hydroxytryptamine Ž5HT2A. receptor gene. Cephalalgia 1996;16:463–7. w12x Russell MB, Olesen J. Increased familial risk and evidence of genetic factor in migraine. BMJ Br Med J 1995;311:541–4. w13x Ferrari MD. Migraine. Lancet 1998;351:1043–51. w14x EMASS Collaborative Group, Williams J, McGuffin P, Nothen M, Owen MJ. Meta-analysis of association between the 5-HT Ž2A. receptor T102C polymorphism and schizophrenia. Lancet 1997; 349:1221. ŽLetter.. w15x Holmes C, Arranz MJ, Powell JF, Collier DA, Lovestone S. 5-HT-2A and 5-HT-2C receptor polymorphisms and psychopathology in late onset Alzheimer’s disease. Hum Mol Genet 1998;7:1507–9.
Short communication
Association of the T102C polymorphism of 5-HT2A receptor gene with aura in migraine M. Emin Erdal a , Hasan Herken b, Mustafa Yılmaz c , Yıldırım A. Bayazıt d,) a
Department of Medical Biology and Genetics, Faculty of Medicine, Mersin UniÕersity, Mersin, Turkey Department of Psychiatry, Faculty of Medicine, Gaziantep UniÕersity, Kolejtepe, Gaziantep, Turkey c Department of Neurology, Faculty of Medicine, Gaziantep UniÕersity, Kolejtepe, Gaziantep, Turkey Department of Otolaryngology, Faculty of Medicine, Gaziantep UniÕersity, Kolejtepe, Gaziantep, Turkey b
d
Received 14 March 2001; received in revised form 22 May 2001; accepted 4 June 2001
Abstract ObjectiÕe: To find out the significance of the 5-HT2A receptor gene polymorphism in migraine. Study design: A PCR study in which 61 migraineurs and 44 healthy controls were included. Methods: The T102C polymorphism of the 5-HT2A receptor gene was studied. The results of the migraineurs and controls were compared. The relationship between the gene polymorphism and aura was also assessed. Results: The representations of the 5-HT2A genotypes were similar in migraineurs and controls Ž p ) 0.05. as well as in the male and female migraineurs Ž p ) 0.05.. The family history of migraine did not associate with 5-HT2A receptor gene polymorphism Ž p ) 0.05.. There was a significant relationship between the presence of CrC genotype and migraine with aura Ž p s 0.02. while CrT and TrT genotypes were over represented in the patients with migraine without aura Ž p - 0.01.. Conclusion: The T102C polymorphism of the 5-HT2A receptor gene is not directly related to the increased risk of migraine. The associations between the genotypes of this gene and aura may suggest that 5-HT2A receptor gene polymorphism may be involved in determining the subtypes of or accompanying symptoms in the migraine disease. q 2001 Published by Elsevier Science B.V. Keywords: Migraine; 5-HT2A receptor; Serotonin; Polymorphism
1. Introduction Although it is believed that migraine has a strong genetic component, the type and number of genes involved in this disease has not been understood entirely. The serotonin Ž5-hydroxytryptamine; 5-HT. is a key neurotransmitter in the central nervous system, and dysregulation of serotonergic pathways has been implicated in the pathogenesis of many complex neuropsychiatric diseases. It was suggested that the 5-HT related genes may be involved in the pathogenesis of migraine w1,2x. The 5-HT is a neurotransmitter that occupies a uniquely important place in neurobiology because of its role in many physiologic processes such as sleep, appetite, thermoregulation, pain perception, hormone secretion, and sexual behavior. Abnormality of the serotonergic system has been implicated in a number of human diseases such as ) Corresponding author. Tel.: q90-342-336-5400; fax: q90-342-3365505. E-mail address: [email protected] ŽY.A. Bayazıt..
mental depression, migraine, epilepsy, obsessive-compulsive behavior, and affective disorder. Like other neurotransmitters, 5-HT is released into the synaptic junction and exerts its effect on specific receptors on the postsynaptic membranes. There are a number of 5-HT receptors identified, and each group is not only operationally but also structurally distinct, with each receptor group having its own distinct transducing system w3,4x. The activity of serotonergic system is under the control of the genes like 5HT1D Ž1p36.3–34.3., 5HT1B Ž6q13., 5HT2A Ž13q14–21., 5HT transporter Ž17q11.2–12., and CACNLB1 Ž17q11.2–22. Ž19p13. w5x. One of the 5-HT related genes, the 5-HT2A receptor gene, is mapped to chromosome 13q14–21 w6,7x. Recently, a silent polymorphism in the 5-HT2A receptor gene was identified which is defined by a T to C transition at position 102. This mutation does not alter the amino acid composition, and therefore has no influence on receptor protein w8x. It is unclear whether T102C polymorphism of the 5HT2A receptor gene is associated with migraine. In this
0022-510Xr01r$ - see front matter q 2001 Published by Elsevier Science B.V. PII: S 0 0 2 2 - 5 1 0 X Ž 0 1 . 0 0 5 5 6 - 1
M.E. Erdal et al.r Journal of the Neurological Sciences 188 (2001) 99–101
100
study, the purpose was to find out the significance of the 5-HT2A receptor gene polymorphism in migraine.
Table 2 The T102C polymorphism of the 5-HT2A receptor gene in the migraine subgroups Genotype
2. Materials and methods Sixty-one migraineurs and 44 healthy volunteers were included in the study. There were 9 Ž14.8%. male and 52 Ž85.2%. female migraineurs with the ages ranging from 21 to 49 Žmean, 33. years. There were 6 Ž13.6%. male and 38 Ž86.4%. female healthy controls with ages ranging from 19 to 53 Žmean, 35. years. The migraineurs and healthy controls were age and sex matched Ž p - 0.05.. The diagnosis of migraine was made on the basis of the criteria of the International Headache Society, 1988 w9x. Thirty-seven Ž60.7%. patients had migraine with aura ŽMA., and 24 Ž39.3%. had migraine without aura ŽMOA.. Seventeen migraineurs also had a family history of migraine. An informed consent was obtained from the subjects who participated in the study. The migraineurs and healthy controls were from the same geographic region and of the same ethnic origin. The migraineurs and controls were not relatives. There was only one migraineur from each family. Those who had mental retardation, drug dependence, and metabolic or psychiatric or neurological illness were excluded. Those whose first-degree relatives had endogenous psychoses or alcoholism were also excluded. The controls who had migraine history in the first-degree relatives were excluded. Physical and psychiatric examinations were carried out by the psychiatrist and neurologist following an interview. A cranial computed tomography or magnetic resonance imaging was obtained as indicated. The blood samples were taken for complete blood count and blood chemistry Želectrolytes, glucose, renal and liver function tests, and thyroid hormone level. as well as for the molecular analysis of 5-HT2A receptor polymorphism. 2.1. Molecular analysis A 5-ml blood sample was obtained and the DNA was extracted from the leukocytes using the QIAamp Blood Isolation kit ŽQIAGEN.. Primers flanking the 5-HT2A polymorphic site at position 102 Ž5-HT2A-F 5X-CTGTCT GCT ACA AGT TCT GGC TTT-3X ; 5-HT2A-R 5X-CTG
Migraine with aura Ž ns 37. Migraine without aura Ž ns 24.
TrT n Ž%.
TrC n Ž%.
CrC n Ž%.
7 Ž18.9.
15 Ž40.5.
15 Ž40.5.
6 Ž25.
16 Ž66.7.
2 Ž8.3.
CAG CTT TTT CTC TAG GG-3X . were used to generate a 342-bp fragment. PCR was performed in a final volume of 25 ml consisting of 50 ng DNA, 0.6 mmolrl of each primer, 200 mmolrl dNTPs, 10 mmolrl Tris–HCL ŽpH 8.3., 50 mmolrl KCL, 1.5 mmolrl MgCl 2 , and 1.25 U AmpliTag Gold ŽPerkin Elmer.. Annealing was carried out at 60 8C for 30 s, extension at 72 8C for 30 s, and denaturation at 95 8C for 30 s for 35 cycles. PCR products were digested with 10 U MspI ŽRoche Molecular Biochemicals. for 14 h and separated on a 2% agarose gel ŽFMC NuSieve 3:1, from Biozym.. Allele 1 ŽT102C allele. was represented by the uncut 342-bp PCR product and allele 2 ŽC102 allele. consisted of two fragments at 215 and 126 bp. 2.2. Statistics SPSS 8.0 for windows was used for the statistical analyses of the data, and chi-square test was used.
3. Results The representations of the 5-HT2A genotypes were similar in the migraineurs and controls Ž x 2 s 10.16, p s 0.62. as well as in the male and female migraineurs Ž x 2 s 0.004, p s 0.950. ŽTable 1.. The family history of migraine did not associate with 5-HT2A receptor gene polymorphism Ž x 2 s 1.035, p s 0.595.. There was a significant relationship between the presence of CrC genotype and MA Ž x 2 s 7.62, p s 0.02. while CrT and TrT genotypes were overrepresented in the patients with MOA Ž x 2 s 7.51, p - 0.006. ŽTable 2..
4. Discussion Table 1 The genotypic distribution of T102C polymorphism of the 5-HT2A receptor gene Genotype
Migraine Ž ns61. Control Ž ns 44.
CrC n Ž%.
CrT n Ž%.
TrT n Ž%.
17 Ž27.9. 12 Ž27.3.
31 Ž50.8. 19 Ž43.2.
13 Ž21.3. 13 Ž29.5.
Influence of the molecular mechanisms or variations should not be overlooked in diseases like the migraine. One of the most critical molecular systems involved in the migraine disease is the serotonergic system. This recent identification of the polymorphism of 5-HT transporter gene appears to be promising to better understand the serotonergic system as well as molecular changes in migraine disease.
M.E. Erdal et al.r Journal of the Neurological Sciences 188 (2001) 99–101
The 5-HT is a neurotransmitter that mediates a wide range of central nervous functions by activating multiple 5-HT receptor subtypes. A possible irregularity of serotonergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. w10x. The 5-HT which predominantly serves as an inhibitory neurotransmitter in the brain has long been implicated in migraine pathophysiology as well. It is now widely accepted that many disorders have a familial or genetic component. In this study, the family history of migraine did not associate with 5-HT2A receptor gene polymorphism. Thus, the polymorphism of this gene does not take part in the genetic transmission of migraine. It was also suggested that the MspI polymorphism in 5HT2A receptor gene is not associated with migraine occurrence, and excluded for involvement with migraine w11x. The T102C polymorphism of the 5-HT2A receptor gene is a recent discovery, the influence of which is unclear in migraine. According to our results, this polymorphism is not associated with the occurrence of migraine disease owing to similar representation of the genotypic variants CrC, CrT and TrC in the migraineurs and controls. Therefore, the polymorphism is not related to the occurrence of headache symptom in the patients. On the other hand, the polymorphism of this gene may be important in the subtypes of migraine because there was a significant relationship between the presence of CrC genotype and MA, while CrT and TrT genotypes were overrepresented in the patients with MOA. The cause of aura is not known properly although a variety of mechanisms is likely to be involved in the occurrence of aura. Susceptibility to MA and MOA has a genetic component, that is, these disorders are distinct w12,13x. It was proposed that this genetic susceptibility may, in some cases, be associated with a locus at or near the 5-HT transporter gene w13x. Although functional significance of the variants of T102C polymorphism of the 5-HT receptor gene is unclear, the association of its variants with aura may suggest that the functional status of the 5-HT receptor changes depending upon the genotypic variability which, in turn, modifies the 5-HT activity at the receptor level. Furthermore, these results also indicate that the genetic susceptibility to aura is partially under the control of 5-HT receptor gene. Some associations were found between the presence of the T102C allele and the presence of both visual and auditory hallucinations w14,15x. This finding enhances our contention that aura susceptibility is genetically controlled in which T102C polymorphism also plays a role. In conclusion, the polymorphism in the 5-HT2A receptor gene is not directly related to the increased risk of
101
migraine. The associations between the genotypes of this gene and aura may suggest that 5-HT2A receptor gene polymorphism may be involved in determining the subtypes of or accompanying symptoms in the migraine disease.
References w1x Lea RA, Dohy A, Jordan K, Quinlan S, Brimage PJ, Griffiths LR. Evidence for allelic association of the dopamine beta-hydroxylase gene ŽDBH. with susceptibility to typical migraine. Neurogenetics 2000;3:35–40. w2x MaassenVanDenBrink A, Vergouwe MN, Ophoff RA, Saxena PR, Ferrari MD, Frants RR. 5-HT1B receptor polymorphism and clinical response to sumatriptan. Headache 1998;38:288–91. w3x Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, et al. International union of pharmacology classification of receptors for 5-hydroxytryptamine Žserotonin.. Pharmacol Rev 1994; 46:157–203. w4x Hartig PR, Hoyer D, Humphrey PP, Martin GR. Alignment of receptor nomenclature with the human genome: classification of 5-HT1B and 5-HT1D receptor subtypes. Trends Pharmacol Sci 1996;17:103–5. w5x Monari L, Mochi M, Valentino ML, Arnaldi C, Cortelli P, De Monte A, et al. Searching for migraine genes: exclusion of 290 cM out of the whole human genome. Ital J Neurol Sci 1997;18:277–82. w6x Blairy S, Massat I, Staner L, Le Bon O, Van Gestel S, VanBroeckhoven C, et al. 5-HT2a receptor polymorphism gene in bipolar disorder and harm avoidance personality trait. Am J Med Genet 2000;96:360–4. w7x Sparkes RS, Lan N, Klisak I, Mohandas T, Diep A, Kojis T, et al. Assignment of a serotonin 5HT-2 receptor gene ŽHTR2. to human chromosome 13q14–q21 and mouse chromosome 14. Genomics 1991;9:461–5. w8x Bondy B, Spaeth M, Offenbaecher M, Glatzeder K, Stratz T, Schwartz M, et al. The T102C polymorphism of the 5-HT2A receptor gene in fibromyalgia. Neurobiol Dis 1999;6:433–9. w9x Headache Classification Committee of the International Headache Society, Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8:1–96. ŽSuppl.. w10x Vogt IR, Shimron-Abarbanell D, Neidt H, Erdmann J, Cichon S, Schulze TG, et al. Investigation of the human serotonin 6 Ž5-HT6. receptor gene in bipolar affective disorder and schizophrenia. Am J Med Genet 2000;96:217–21. w11x Nyholt DR, Curtain RP, Gaffney PT, Brimage P, Goadsby PJ, Griffiths LR. Migraine association and linkage analyses of the human 5-hydroxytryptamine Ž5HT2A. receptor gene. Cephalalgia 1996;16:463–7. w12x Russell MB, Olesen J. Increased familial risk and evidence of genetic factor in migraine. BMJ Br Med J 1995;311:541–4. w13x Ferrari MD. Migraine. Lancet 1998;351:1043–51. w14x EMASS Collaborative Group, Williams J, McGuffin P, Nothen M, Owen MJ. Meta-analysis of association between the 5-HT Ž2A. receptor T102C polymorphism and schizophrenia. Lancet 1997; 349:1221. ŽLetter.. w15x Holmes C, Arranz MJ, Powell JF, Collier DA, Lovestone S. 5-HT-2A and 5-HT-2C receptor polymorphisms and psychopathology in late onset Alzheimer’s disease. Hum Mol Genet 1998;7:1507–9.