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J Headache Pain. Aug 2010; 11(4): 317–326.
Published online Jun 29, 2010. doi:  10.1007/s10194-010-0230-3
PMCID: PMC3026586
NIHMSID: NIHMS264349
STin2 VNTR polymorphism in the serotonin transporter gene and migraine: pooled and meta-analyses
Markus Schürks,corresponding author1,5 Pamela M. Rist,1,2 and Tobias Kurth1,2,3,4
1Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Avenue East, 3rd Floor, Boston, MA 02215-1204 USA
2Department of Epidemiology, Harvard School of Public Health, Boston, USA
3INSERM Unit 708-Neuroepidemiology, Paris, France
4Faculty of Medicine, Pierre et Marie Curie University, Paris, France
5Department of Neurology, University Hospital Essen, Essen, Germany
Markus Schürks, Phone: +1-617-7328794, Fax: +1-617-7313843, mschuerks/at/rics.bwh.harvard.edu.
corresponding authorCorresponding author.
Received April 22, 2010; Accepted May 28, 2010.
Abstract
Data on the association between the SLC6A4 STin2 VNTR polymorphism and migraine are conflicting. To perform pooled and meta-analyses, we searched for studies published until September 2009 using electronic databases (MEDLINE, EMBASE, Science Citation Index) and reference lists of studies. Assessment for eligibility and extraction of data was performed by two independent investigators. We extracted allele and genotype frequencies for each study. We then calculated study-specific and pooled odds ratios (OR) and 95% confidence intervals (CI) assuming allele and genotype models. We also calculated pooled ORs and 95% CIs based on study-specific effect estimates for the allele model. We included five studies investigating the association between the STin2 VNTR polymorphism and migraine. Results from the allele model suggested a protective effect against migraine for the STin2.9 and STin2.10 alleles compared to the STin2.12 allele among populations of European descent, which however was not significant. Results from the genotype model indicated a significant ~25% reduced risk for migraine among carriers of the 10/12 genotype compared with carriers of the 12/12 genotype among all study populations (OR = 0.76, 95% CI 0.60–0.97) for any migraine, which was more pronounced among populations of European descent (OR = 0.68, 95% CI 0.53–0.87). Results for migraine with and without aura were of similar magnitude, but were not statistically significant. Our results suggest a protective effect of non-STin2.12 alleles compared to STin2.12 alleles, respectively, 10/12 and 10/10 genotypes compared to the 12/12 genotype against migraine among populations of European descent. Associations in non-European populations may differ.
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Selected References
These references are in PubMed. This may not be the complete list of references from this article.
1. Haut SR, Bigal ME, Lipton RB. Chronic disorders with episodic manifestations: focus on epilepsy and migraine. Lancet Neurol. 2006;5:148–157. doi: 10.1016/S1474-4422(06)70348-9. [PMC free article] [PubMed] [Cross Ref]
2. Hamel E. Serotonin and migraine: biology and clinical implications. Cephalalgia. 2007;27:1293–1300. doi: 10.1111/j.1468-2982.2007.01476.x. [PubMed] [Cross Ref]
3. Rudnick G, Clark J. From synapse to vesicle: the reuptake and storage of biogenic amine neurotransmitters. Biochim Biophys Acta. 1993;1144:249–263. doi: 10.1016/0005-2728(93)90109-S. [PubMed] [Cross Ref]
4. Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V, Blakely RD. Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci USA. 1993;90:2542–2546. doi: 10.1073/pnas.90.6.2542. [PubMed] [Cross Ref]
5. Hornung JP. The human raphe nuclei and the serotonergic system. J Chem Neuroanat. 2003;26:331–343. doi: 10.1016/j.jchemneu.2003.10.002. [PubMed] [Cross Ref]
6. Lesch KP, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL, Riederer P. Organization of the human serotonin transporter gene. J Neural Transm Gen Sect. 1994;95:157–162. doi: 10.1007/BF01276434. [PubMed] [Cross Ref]
7. Kaiser R, Tremblay PB, Schmider J, Henneken M, Dettling M, Muller-Oerlinghausen B, Uebelhack R, Roots I, Brockmoller J. Serotonin transporter polymorphisms: no association with response to antipsychotic treatment, but associations with the schizoparanoid and residual subtypes of schizophrenia. Mol Psychiatry. 2001;6:179–185. doi: 10.1038/sj.mp.4000821. [PubMed] [Cross Ref]
8. MacKenzie A, Quinn J. A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proc Natl Acad Sci USA. 1999;96:15251–15255. doi: 10.1073/pnas.96.26.15251. [PubMed] [Cross Ref]
9. Yilmaz M, Erdal ME, Herken H, Cataloluk O, Barlas O, Bayazit YA. Significance of serotonin transporter gene polymorphism in migraine. J Neurol Sci. 2001;186:27–30. doi: 10.1016/S0022-510X(01)00491-9. [PubMed] [Cross Ref]
10. Ogilvie AD, Russell MB, Dhall P, Battersby S, Ulrich V, Smith CA, Goodwin GM, Harmar AJ, Olesen J. Altered allelic distributions of the serotonin transporter gene in migraine without aura and migraine with aura. Cephalalgia. 1998;18:23–26. doi: 10.1046/j.1468-2982.1998.1801023.x. [PubMed] [Cross Ref]
11. Racchi M, Leone M, Porrello E, Rigamonti A, Govoni S, Sironi M, Montomoli C, Bussone G. Familial migraine with aura: association study with 5-HT1B/1D, 5-HT2C, and hSERT polymorphisms. Headache. 2004;44:311–317. doi: 10.1111/j.1526-4610.2004.04072.x. [PubMed] [Cross Ref]
12. Szilagyi A, Boor K, Orosz I, Szantai E, Szekely A, Kalasz H, Sasvari-Szekely M, Farkas V. Contribution of serotonin transporter gene polymorphisms to pediatric migraine. Headache. 2006;46:478–485. doi: 10.1111/j.1526-4610.2006.00379.x. [PubMed] [Cross Ref]
13. Lea RA, Dohy A, Jordan K, Quinlan S, Brimage PJ, Griffiths LR. Evidence for allelic association of the dopamine beta-hydroxylase gene (DBH) with susceptibility to typical migraine. Neurogenetics. 2000;3:35–40. [PubMed]
14. Sagoo GS, Little J, Higgins JP. Systematic reviews of genetic association studies. PLoS Med. 2009;6:e28. doi: 10.1371/journal.pmed.1000028. [PMC free article] [PubMed] [Cross Ref]
15. (2004) The international classification of headache disorders, 2nd edn. Cephalalgia 24(Suppl 1):9–160.
16. Headache Committee of the International Headache Society Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia. 1988;8(Suppl 7):1–96.
17. Fan JB, Sklar P. Meta-analysis reveals association between serotonin transporter gene STin2 VNTR polymorphism and schizophrenia. Mol Psychiatry. 2005;10:928–938. doi: 10.1038/sj.mp.4001690. [PubMed] [Cross Ref]
18. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. doi: 10.1136/bmj.327.7414.557. [PMC free article] [PubMed] [Cross Ref]
19. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–1101. doi: 10.2307/2533446. [PubMed] [Cross Ref]
20. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–634. [PMC free article] [PubMed]
21. Borroni B, Brambilla C, Liberini P, Rao R, Archetti S, Gipponi S, Volta GD, Padovani A. Functional serotonin 5-HTTLPR polymorphism is a risk factor for migraine with aura. J Headache Pain. 2005;6:182–184. doi: 10.1007/s10194-005-0179-9. [PMC free article] [PubMed] [Cross Ref]
22. Corominas R, Sobrido MJ, Ribasés M, Cuenca-León E, Blanco-Arias P, Narberhaus B, Roig M, Leira R, López-González J, Macaya A, Cormand B (2009) Association study of the serotoninergic system in migraine in the spanish population. Am J Med Genet B Neuropsychiatr Genet. doi:10.1002/ajmg.b.30972.
23. Gonda X, Rihmer Z, Juhasz G, Zsombok T, Bagdy G. High anxiety and migraine are associated with the s allele of the 5HTTLPR gene polymorphism. Psychiatry Res. 2007;149:261–266. doi: 10.1016/j.psychres.2006.05.014. [PubMed] [Cross Ref]
24. Juhasz G, Zsombok T, Laszik A, Gonda X, Sotonyi P, Faludi G, Bagdy G. Association analysis of 5-HTTLPR variants, 5-HT2a receptor gene 102T/C polymorphism and migraine. J Neurogenet. 2003;17:231–240. [PubMed]
25. Juhasz G, Zsombok T, Laszik A, Jakus R, Faludi G, Sotonyi P, Bagdy G. Despite the general correlation of the serotonin transporter gene regulatory region polymorphism (5-HTTLPR) and platelet serotonin concentration, lower platelet serotonin concentration in migraine patients is independent of the 5-HTTLPR variants. Neurosci Lett. 2003;350:56–60. doi: 10.1016/S0304-3940(03)00834-6. [PubMed] [Cross Ref]
26. Karwautz AF, Campos de Sousa S, Wober C, Wagner G, Li T, Konrad A, Zesch HE, Zormann A, Berger G, Wanner C, Wober-Bingol C, Collier DA. Family-based analysis of serotonin transporter gene polymorphisms in migraine with and without aura. Cephalalgia. 2007;27:773–780. doi: 10.1111/j.1468-2982.2007.01344.x. [PubMed] [Cross Ref]
27. Kim WK, Kim HS, Kim WJ, Lee KY, Park H, Kim CH, Kim SJ, Choi YC. Serotonin transporter gene polymorphism and migraine in the Korean population. Headache. 2005;45:1056–1060. doi: 10.1111/j.1526-4610.2005.05187.x. [PubMed] [Cross Ref]
28. Kotani K, Shimomura T, Shimomura F, Ikawa S, Nanba E. A polymorphism in the serotonin transporter gene regulatory region and frequency of migraine attacks. Headache. 2002;42:893–895. doi: 10.1046/j.1526-4610.2002.02209.x. [PubMed] [Cross Ref]
29. Marziniak M, Mossner R, Schmitt A, Lesch KP, Sommer C. A functional serotonin transporter gene polymorphism is associated with migraine with aura. Neurology. 2005;64:157–159. [PubMed]
30. Monari L, Mochi M, Valentino ML, Arnaldi C, Cortelli P, Monte A, Pierangeli G, Prologo G, Scapoli C, Soriani S, Montagna P. Searching for migraine genes: exclusion of 290 cM out of the whole human genome. Ital J Neurol Sci. 1997;18:277–282. doi: 10.1007/BF02083304. [PubMed] [Cross Ref]
31. Park JW, Han SR, Yang DW, Kim YI, Lee KS. Serotonin transporter protein polymorphism and harm avoidance personality in migraine without aura. Headache. 2006;46:991–996. doi: 10.1111/j.1526-4610.2006.00439.x. [PubMed] [Cross Ref]
32. Todt U, Freudenberg J, Goebel I, Heinze A, Heinze-Kuhn K, Rietschel M, Gobel H, Kubisch C. Variation of the serotonin transporter gene SLC6A4 in the susceptibility to migraine with aura. Neurology. 2006;67:1707–1709. doi: 10.1212/01.wnl.0000242883.96822.93. [PubMed] [Cross Ref]
33. Wieser T, Dresler K, Evers S, Gaul C, König D, Hölzl D, Berger K, Nyholt D, Deufel T (2009) No influence of 5-HTTLPR gene polymorphism on migraine symptomatology, comorbid depression, and chronification. Headache. doi:10.1111/j.1526-4610.2009.01428.x.
34. Kors EE, Vanmolkot KR, Haan J, Frants RR, Maagdenberg AM, Ferrari MD. Recent findings in headache genetics. Curr Opin Neurol. 2004;17:283–288. doi: 10.1097/00019052-200406000-00008. [PubMed] [Cross Ref]
35. Wessman M, Terwindt GM, Kaunisto MA, Palotie A, Ophoff RA. Migraine: a complex genetic disorder. Lancet Neurol. 2007;6:521–532. doi: 10.1016/S1474-4422(07)70126-6. [PubMed] [Cross Ref]
36. Coppola G, Pierelli F, Schoenen J. Is the cerebral cortex hyperexcitable or hyperresponsive in migraine? Cephalalgia. 2007;27:1427–1439. doi: 10.1111/j.1468-2982.2007.01500.x. [PubMed] [Cross Ref]
37. Humphrey PP. The discovery of a new drug class for the acute treatment of migraine. Headache. 2007;47(Suppl 1):S10–S19. doi: 10.1111/j.1526-4610.2007.00672.x. [PubMed] [Cross Ref]
38. Schürks M, Rist PM, Kurth T (2010) 5-HTTLPR polymorphism in the serotonin transporter gene and migraine: a systematic review and meta-analysis. Cephalalgia. doi:10.1177/0333102410362929. [PMC free article]
39. Schürks M, Kurth T, Stude P, Rimmbach C, Jesus J, Jonjic M, Diener HC, Rosskopf D. G protein beta3 polymorphism and triptan response in cluster headache. Clin Pharmacol Ther. 2007;82:396–401. doi: 10.1038/sj.clpt.6100159. [PubMed] [Cross Ref]
40. Kaiser R, Muller-Oerlinghausen B, Filler D, Tremblay PB, Berghofer A, Roots I, Brockmoller J. Correlation between serotonin uptake in human blood platelets with the 44-bp polymorphism and the 17-bp variable number of tandem repeat of the serotonin transporter. Am J Med Genet. 2002;114:323–328. doi: 10.1002/ajmg.10119. [PubMed] [Cross Ref]
43. Bayerer B, Engelbergs J, Savidou I, Boes T, Kuper M, Schorn CF, Wissmann A, Knop D, Diener HC, Limmroth V (2009) Single nucleotide polymorphisms of the serotonin transporter gene in migraine—an association study. Headache. doi:10.1111/j.1526-4610.2009.01553.x.
44. Goadsby PJ, Charbit AR, Andreou AP, Akerman S, Holland PR. Neurobiology of migraine. Neuroscience. 2009;161:327–341. doi: 10.1016/j.neuroscience.2009.03.019. [PubMed] [Cross Ref]
45. Lipton RB, Bigal ME. The epidemiology of migraine. Am J Med. 2005;118(Suppl 1):3S–10S. [PubMed]
46. Gelernter J, Cubells JF, Kidd JR, Pakstis AJ, Kidd KK. Population studies of polymorphisms of the serotonin transporter protein gene. Am J Med Genet. 1999;88:61–66. doi: 10.1002/(SICI)1096-8628(19990205)88:1<61::AID-AJMG11>3.0.CO;2-K. [PubMed] [Cross Ref]
47. Kunugi H, Hattori M, Kato T, Tatsumi M, Sakai T, Sasaki T, Hirose T, Nanko S. Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Mol Psychiatry. 1997;2:457–462. doi: 10.1038/sj.mp.4000334. [PubMed] [Cross Ref]
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