Ⅷ-1 AF

Ⅷ－1	片頭痛は遺伝するか，また片頭痛に関与している遺伝子にはどのようなものがあるか

1) Russell MB, Olesen J. Increased familial risk and evidence of genetic 　 factor in migraine. BMJ. 1995 Aug 26;311(7004):541-4.
論文抄録	OBJECTIVE--To investigate familial occurrence of migraine with and without aura. DESIGN--Familial occurrence of migraine with and without aura among first degree relatives and spouses of probands with migraine with or without aura and those who had never had migraine. All interviews of first degree relatives and spouses were done blindly by a neurological resident. The operational diagnostic criteria of the International Headache Society were used. SETTING--General population from Copenhagen County . SUBJECTS--The 378 probands had 1109 first degree relatives and 229 spouses. MAIN OUTCOME MEASURES--Patterns of familial aggregation of migraine with and without aura as assessed by calculation of the population relative risk. RESULTS--Compared with the general population the first degree relatives of probands with migraine without aura had 1.9 times the risk of migraine without aura and 1.4 times the risk of migraine with aura. The first degree relatives of probands with migraine with aura had nearly four times the risk of migraine with aura and no increased risk of migraine without aura. The first degree relatives of probands who had never had migraine had no increased risk of migraine either with or without aura. Spouses of probands with migraine without aura had 1.4 times the risk of migraine without aura whereas spouses of probands with migraine with aura had no increased risk of migraine with aura. CONCLUSION--The different familial patterns indicate that migraine without aura and migraine with aura have a different aetiology. Migraine without aura seems to be caused by a combination of genetic and environmental factors whereas migraine with aura is probably determined largely or exclusively by genetic factors.
文献 PubMed－ID	PMID: 7663209
エビデンスレベル	VI
文献タイトル (日本語)	片頭痛における高い家族性リスクと遺伝因子の証拠
目的	前兆のある，またはない片頭痛の家族内発症について検討する
研究デザイン	横断研究
研究施設	Department of Neurology, Glostrup Hospital , University of Copenhagen , Denmark .
対象患者	378名の発端者と1109名の第一度近親者，229名の配偶者
介入
主要評価項目とそれに用いた統計学的手法	Probability (relative is affected \| proband is affected)/ (Probability (random member of the population affected))の算出
結果	Compared with the general population the first degree relatives of probands with migraine without aura had 1.9 times the risk of migraine without aura and 1.4 times the risk of migraine with aura. The first degree relatives of probands with migraine with aura had nearly four times the risk of migraine with aura and no increased risk of migraine without aura. The first degree relatives of probands who had never had migraine had no increased risk of migraine either with or without aura. Spouses of probands with migraine without aura had 1.4 times the risk of migraine without aura whereas spouses of probands with migraine with aura had no increased risk of migraine with aura.
結論	前兆のある片頭痛と前兆のない片頭痛とでは家族の発症者のパターンが異なっており，両者における発症機序が異なることが推察される．前兆のない片頭痛は遺伝因子と環境因子が重なって発症するのに対し，前兆のある片頭痛は遺伝因子の関与が非常に大きいことが予測される．
コメント	Danish Central Person Registryというコホート集団の40歳の男性3000人，女性1000人において，第一度近親者や配偶者にも直接インタヴューを試みている．λs は前兆のある片頭痛では3.35，前兆のない片頭痛で1.95という結果が得られている．しかし，probandの男女比（男：女＝3：1）に差がありすぎる点は問題と思われる．
備考	MeSH Terms: 　 Adolescent 　 Adult 　 Aged 　 Child 　 Child, Preschool 　 Denmark/epidemiology 　 Female 　 Human 　 Infant 　 Infant, Newborn 　 Male 　 Middle Aged 　 Migraine/epidemiology 　 Migraine/etiology 　 Migraine/genetics* 　 Pedigree 　 Prevalence 　 Risk Factors 　 Support, Non-U.S. Gov't
作成者	百瀬義雄

2) Ulrich V, Gervil M, Kyvik KO, Olesen J, Russell MB . Evidence of a 　 genetic factor in migraine with aura: a population-based Danish twin 　 study.Ann Neurol. 1999 Feb;45(2):242-6.
論文抄録	We studied the genetic influence on cause of migraine with aura (MA) by analyzing a twin population. The twin sample consisted of 2,026 monozygotic (MZ) twins and 3,334 same-sex dizygotic (DZ) twins, born from 1953 to 1960, from the population-based New Danish Twin Register. A validated questionnaire was used to screen for migraine, the response rate being 87%, and similar among MZ and DZ twins. All twin pairs with at least 1 twin with possible MA were interviewed by a physician experienced in headache diagnoses. The answers from the questionnaire as well as the zygosity of the twins were blinded for the interviewer. A total of 211 twin pairs were identified, of whom 77 pairs were MZ and 134 pairs were DZ. The lifetime prevalence of MA was 7% and with a male-to-female ratio of 1:1.1. The pairwise concordance rates were significantly higher in MZ (34%) than in DZ twin pairs (12%), emphasizing the importance of genetic factors in MA. However, environmental factors are also important, as the pairwise concordance rate was less than 100% in MZ twin pairs. The recurrence risk of MA was 50% in MZ and 21% in DZ twin pairs. In nontwin siblings, the recurrence risk of MA is 27%, which is similar to the recurrence risk in DZ twins. This indicates that MA is not developed due to specific environmental factors shared by the twins.
文献 Pubmed-ID	PMID: 9989627
エビデンスレベル	VI
文献タイトル（日本語）	前兆のある頭痛における遺伝因子の証拠：集団を基盤としたデンマーク双子研究
雑誌名，出版年　巻：頁	Ann Neurol. 1999 Feb;45(2):242-6.
目的	前兆のある頭痛における遺伝因子の存在の有無を明らかにする
研究デザイン	疫学双子調査
研究施設	Department of Neurology, Glostrup Hospital , University of Copenhagen , Glostrup , Denmark .
研究期間
対象患者	2680組の双子（1013組は一卵性，1667組は同性の二卵性）
介入	質問用紙の郵送及び電話による追跡調査
主要評価項目とそれに用いた統計学的手法	（１）前兆のある片頭痛の有無： pairwise concordance rateとprobandwise concordance rateの算出，（２）痛みの部位，性状，誘発因子，強さ，随伴症状の一致率：Fisher's exact test，（３）（２）の各項目の一卵性と二卵性の比較：Wilcoxon signed rank test
結果	（１） pairwise concordance rateは一卵性では34％，二卵性では12％．
結論	一致率は二卵性より一卵性のほうが高く，前兆のある頭痛には遺伝因子が存在することが示唆された．しかし一致率は 100%ではなく，環境因子もまた存在することが示唆され，片頭痛が多因子疾患であることが示された．
コメント	コホート集団を対象にした疫学調査．片頭痛の診断には一卵性か二卵性か知らされていない 2人の医師の判定を用い，kappa 統計量も算定し，バイアスなく，正確性の高い診断であることが確認されている．
備考	MeSH Terms: 　 Adult 　 Age Distribution 　 Denmark/epidemiology 　 Diseases in Twins/epidemiology* 　 Diseases in Twins/genetics* 　 Female 　 Human 　 Male 　 Migraine/epidemiology* 　 Migraine/genetics* 　 Registries 　 Support, Non-U.S. Gov't
作成者	百瀬義雄

3) Gervil M, Ulrich V, Kyvik KO, Olesen J, Russell MB. Migraine without 　 aura: A population-based twin study . Ann Neurol. 1999 Oct;46(4):606- 　 11.
論文抄録	To investigate the importance of genetic and environmental factors to the etiology of migraine without aura and to compare the symptomatology of migraine without aura in monozygotic and dizygotic twins, 2,680 twin pairs were recruited from the population-based Danish Twin Registry. Monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs, where at least one twin had self-reported migraine or self-reported severe headache with accompanying symptoms, were telephone interviewed by a physician. The participation rate in the telephone interview was 90%. The pairwise concordance rate was significantly higher in MZ than in DZ twin pairs (28% vs 18%). The probandwise concordance rate was 40% (95% CI, 33-48%) in MZ and 28% (95% CI, 23-33%) in DZ twin pairs. The pairwise concordance rates for the different pain characteristics and accompanying symptoms were not significantly different in MZ and DZ twin pairs. However, comparing all of the pairwise concordance rates of pain characteristics and accompanying symptoms together, MZ twin pairs were significantly more concordant than DZ twin pairs. Our data demonstrate a significant genetic factor in migraine without aura. The size of this factor is modest and the demonstration of susceptibility genes is predicted to be laborious and difficult.
文献 Pubmed-ID	PMID: 10514097
エビデンスレベル	IV
文献タイトル（日本語）	前兆のない頭痛：集団を基にした双子研究
目的	前兆のない頭痛における遺伝因子の存在の有無を明らかにする
研究デザイン	疫学双子調査
研究施設	Department of Neurology, Glostrup Hospital , University of Copenhagen , Glostrup , Denmark .
研究期間
対象患者	2680組の双子（1013組は一卵性，1667組は同性の二卵性）
介入	質問用紙の郵送及び電話による追跡調査
主要評価項目とそれに用いた統計学的手法	（１）前兆のない片頭痛の有無： pairwise concordance rateとprobandwise concordance rateの算出，（２）痛みの部位，性状，誘発因子，強さ，随伴症状の一致率：Fisher's exact test，（３）　（２）の各項目の一卵性と二卵性の比較：Wilcoxonの符号順位検定
結果	（１） pairwise concordance rateは一卵性では28％，二卵性では18％．proband concordance rateは一卵性では40％，二卵性では28％．（２）痛みの特徴や随伴症状は一卵性と二卵性を比較すると差はなかったが，（３）双子内での一致率は一卵性のほうが二卵性よりも有意に高かった．
結論	一致率は一卵性のほうが有意に高く，前兆のない頭痛には遺伝因子が存在することが示唆された
コメント	片頭痛に関する双子研究は多いが，ある集団を基盤として biasを除去しようと試みた点，前兆の有無をきちんと分けて検討した点から他のstudyより信頼性が高いと言える．
備考	MeSH Terms: Diseases in Twins* Female Human Male Migraine/etiology Migraine/genetics* Migraine/physiopathology* Risk Factors Support, Non-U.S. Gov't
作成者	百瀬義雄

4) Noble-Topham SE, Cader MZ, Dyment DA, Rice GP, Brown JD, Ebers 　 GC. Genetic loading in familial migraine with aura. J Neurol Neurosurg 　 Psychiatry. 2003 Aug;74(8):1128-30.
論文抄録	Migraine with aura (MA) arises from a combination of genetic and environmental factors. The sibling risk, age at onset, and aura type were compared in 54 MA probands categorised by family history of MA. Three family types were ascertained each having an MA proband and: (1) an MA parent and MA offspring (three generation; n=15), (2) either an MA parent or an MA offspring (two generation; n=20), and (3) neither an MA parent nor an MA offspring (one generation; n=19). The crude recurrence risk to siblings of probands was 2.7-fold higher in three generation compared with two generation MA families (chi (2) =6.24, p=0.0125) and 4.8-fold higher in three generation compared with one generation MA families (chi (2) =9.95, p<0.002). The mean age at onset decreased with an increase in genetic load. The MA probands from three generation families were significantly younger than probands from the one generation families (F=5.14, p=0.030). MA probands from three generation families were more likely to report more than one type of aura than MA probands from two generation families (chi(2)=4.44, p=0.035). The significant difference in genetic loading and the earlier age at onset in the three generation families add further evidence for a genetic basis for MA and the difference in sibling risks demonstrates that the MA population is heterogeneous.
文献 Pubmed-ID	PMID: 12876251
エビデンスレベル	VI
文献タイトル（日本語）	家族歴を有する前兆のある頭痛における遺伝的負荷
目的	片頭痛の遺伝学的研究において前兆のある片頭痛の家族を選択することについての妥当性を確立する
研究デザイン	横断研究
研究施設	Lawson Health Research Institute, London Health Sciences Centre, London , Ontario , Canada .
研究期間
対象患者	230人の前兆のある頭痛患者（MA）のうち，39人は協力拒否，45人は所在不明，38人は関連する他の病気と判定．残り108人のうち親世代，子世代の情報が得られた54人を最終的にエントリー．
介入	電話調査．半構造化された質問紙を使用．
主要評価項目とそれに用いた統計学的手法	(1)親も子もMA（15名），（２）親か子，どちらかのみMA（20名），（３）親も子もMAではない（19名），の3群に分け，兄弟の発症リスク，視覚以外の前兆についてχ 2 乗検定で，発症年齢，についてはANOVAで統計処理．
結果	兄弟の発症リスクが三世代発症者は二世代発症者の 2.7倍（χ 2 =6.24, p=0.0125），一世代発症者の4.8倍（χ2=9.95, p<0.002）であった．発症年齢は三世代発症者のほうが一世代発症者より若く（F=5.14, P=0.030），視覚以外の前兆に関して三世代発症者は二世代発症者よりも多かった（χ2=4.44, p=0.035）．
結論	三世代発症者ほど発症年齢が低いことは， MAにおける遺伝因子の存在の証拠となる．また3群において兄弟の発症リスクが異なることはMAがheterogeneousであることを示している．
コメント	（１）母集団のサイズがやや小さい点，（２） 38名が関連する他の病気とされ除外された点，（３）視覚以外の前兆に関する検討で三世代発症と一世代発症では統計学的有意差がなかった点はやや問題があるが，本研究により前兆のある片頭痛発症に遺伝因子が存在する可能性は示唆できると思われる．
備考	MeSH Terms: Adult Anticipation, Genetic/genetics Classic Migraine/diagnosis Classic Migraine/genetics* England Female Genetic Load* Genetic Predisposition to Disease/genetics Human Male Middle Aged Pedigree Risk
作成者	百瀬義雄

5) Stewart WF, Staffa J, Lipton RB, Ottman R. Familial risk of migraine: a 　 population-based study. Ann Neurol. 1997 Feb;41(2):166-72.
論文抄録	Estimates of familial aggregation of migraine have varied considerably due, in part, to methodological differences among studies. We concluded a population-based study of 73 clinically confirmed probands with migraine, 72 matched control probands, and 511 of their first-degree relatives, all of whom were directly interviewed. The risk of migraine was 50% more likely in relatives of migraine probands than in relatives of controls. Migraine risk was considerably higher among relatives of probands with disabling migraine compared with relatives of probands with minimal disability. Moreover, for probands with minimal disability, no excess risk of migraine in female relatives was observed. Finally, in relatives of male migraine probands, there appears to be an excess risk of migraine with aura. A borderline significant relative risk of 4.04 was observed. No excess risk was observed among relatives of male probands who had migraine without aura. This study suggests that familial factors (environment related to the family or genetic factors) account for less than one-half of all migraine cases in the population. Degree of disability in the proband appears to influence familial risk. These results suggest that the development of migraine is determined by complex genetic as well as environmental factors.
文献 Pubmed-ID	PMID: 9029065
エビデンスレベル	IV
文献タイトル（日本語）	片頭痛の家族内発症リスク：集団を基盤とした研究
目的	片頭痛の家族内発症リスクを明らかにする
研究デザイン	横断研究
研究施設	Department of Epidemiology, the Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205, USA.
研究期間	1992年8月～1993年5月
対象患者	73名の片頭痛患者と72名の性と年齢をマッチさせた対照者73名を選び，彼らの第一度近親者511名
介入	メリーランド州ボルチモアで Walksburg random digit dialing methodを用いて，1928戸の家庭に電話をかけ，20歳以上50歳未満で片頭痛のある者，ない者を抽出．そこから73名の片頭痛患者と72名の性と年齢をマッチさせた対照者73名を選び，彼らの第一度近親者511名にも電話をかけ，HIS診断基準を用いて片頭痛の有無を聴取した．さらに随伴症状や重症度も確認した．
主要評価項目とそれに用いた統計学的手法	relative riskをCox proportional hazards modelにより算出
結果	片頭痛患者の第一度近親者の相対危険度は対照者の第一度近親者の 1.5倍であり，特に学業や職業に支障を来たすような重症患者ほど家族集積性が高かった．しかし軽症者の場合，第一度近親者が女性でもリスクが高くなるということはなかった．男性患者の場合，前兆がある場合は第一度近親者の発症リスクも高くなるが，前兆がない場合は高くなかった．
結論	片頭痛の発症は環境要因だけでなく，複雑な遺伝要因によっても規定されている．
コメント	バイアスを極力取り除くように設計された studyではあるが，電話調査が主で，実際に患者や対照者を診察できたのは一部である点は問題．
備考	MeSH Terms: Adult Female Human Male Middle Aged Migraine/epidemiology Migraine/etiology* Migraine/genetics Risk Factors Support, Non-U.S. Gov't
作成者	百瀬義雄

6)　McCarthy LC, Hosford DA, Riley JH, Bird MI, White NJ, 　　 Hewett DR, Peroutka SJ,Griffiths LR, Boyd PR, Lea RA, Bhatti SM, 　　 Hosking LK, Hood CM, Jones KW, Handley AR, Rallan R, 　　 Lewis KF, Yeo AJ, Williams PM, Priest RC, Khan P, Donnelly C, 　　 Lumsden SM, O'Sullivan J, See CG, Smart DH, Shaw-Hawkins S, 　　 Patel J, Langrish TC, Feniuk W, Knowles RG, Thomas M, Libri V, 　　 Montgomery DS, Manasco PK, Xu CF, Dykes C, Humphrey PP, 　　 Roses AD, Purvis IJ. 　　 Single-nucleotide polymorphism alleles in the insulin receptor gene 　　 are associated with typical migraine. Genomics 2002 　　 Feb;79(2):271.
論文抄録	We have identified a migraine locus on chromosome 19p13.3/2 using linkage and association analysis. We isolated 48 single-nucleotide polymorphisms within the locus, of which we genotyped 24 in a Caucasian population comprising 827unrelated cases and 765 controls. Five single-nucleotide polymorphisms within the insulin receptor gene showed significant association with migraine. This association was independently replicated in a case-control population collected separately. We used experiments with insulin receptor RNA and protein to investigate functionality for the migraine-associated single-nucleotide polymorphisms. We suggest possible functions for the insulin receptor in migraine pathogenesis.
文献 Pubmed-ID	PMID: 11735220
エビデンスレベル	VI
文献タイトル（日本語）	インスリン受容体の一塩基多型アリルは典型的片頭痛に関連がある
目的	片頭痛の疾患感受性遺伝子を明らかにする
研究施設	GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road , Stevenage SG1 2NY , UK .
研究期間	未記載
対象患者	片頭痛患者 827名と正常対照者765名
主要評価項目とそれに用いた統計学的手法	chi-squared test
結果	インスリン受容体の一塩基多型で有意差が確認された。しかし、この多型によって発現レベルや alternative splicing、インスリン受容体への結合能が変化することはなかった。
結論	インスリン受容体遺伝子は片頭痛発症に何らかの影響を及ぼしている可能性がある。
コメント	マスコミで発表された時はかなり注目されたが、いざ発表されると関連があるはずの多型によっても functionalな変化がないということが判り、結果には疑問が呈された。その後否定的な結果の報告はあるが、肯定的な追試結果は出ていない。CACNA1Aと約6Mb離れたい位置に存在するが、ノイズを拾ったのであろうか？
作成者	百瀬義雄

7)　Colson NJ , Lea RA, Quinlan S, MacMillan J, Griffiths LR. 　　The estrogen receptor 1 G594A polymorphism is associated with 　　migraine susceptibility in two independent case/control groups. 　　Neurogenetics. 2004 Jun;5(2):129-33.
論文抄録	Migraine is a painful and debilitating disorder with a significant genetic component. Steroid hormones, in particular estrogen, have long been considered to play a role in migraine, as variations in hormone levels are associated with migraine onset in many sufferers of the disorder. Steroid hormones mediate their activity via hormone receptors, which have a wide tissue distribution. Estrogen receptors have been localized to the brain in regions considered to be involved in migraine pathogenesis. Hence it is possible that genetic variation in the estrogen receptor gene may play a role in migraine susceptibility. This study thus examined the estrogen receptor 1 (ESRalpha) gene for a potential role in migraine pathogenesis and susceptibility. A population-based cohort of 224 migraine sufferers and 224 matched controls were genotyped for the G594A polymorphism located in exon 8 of the ESR1 gene. Statistical analysis indicated a significant difference between migraineurs and non-migraineurs in both the allele frequencies (P=0.003) and genotype distributions (P=0.008) in this sample. An independent follow-up study was then undertaken using this marker in an additional population-based cohort of 260 migraine sufferers and 260 matched controls. This resulted in a significant association between the two groups with regard to allele frequencies (P=8 x 10(-6)) and genotype distributions (P=4 x 10(-5)). Our findings support the hypothesis that genetic variation in hormone receptors, in particular the ESR1 gene, may play a role in migraine.
文献 Pubmed-ID	PMID: 15133719
エビデンスレベル	VI
文献タイトル（日本語）	エストロゲン受容体 1型遺伝子のG594A多型は二つの独立したケース/コントロール群において片頭痛の易罹患性と関連している
目的	エストロゲン受容体 1型遺伝子のG594A多型が片頭痛の易罹患性と関連しているかどうかを明らかにする
研究デザイン	2つの独立した集団における患者対照関連解析
研究施設	Genomics Research Centre, School of Health Science, Griffith University , Gold Coast , Queensland , Australia .
研究期間	未記載
対象患者	（１）患者 224人対正常対照224人、（２）患者260人対正常対照260人
主要評価項目とそれに用いた統計学的手法	chi-squared analysis
結果	第一集団ではアリル頻度で P=0.03, 遺伝子型でP=0.008で有意、第二集団ではアリル頻度でP=8X10 -6 , 遺伝子型でP=4X10 -5 で有意あった。
結論	エストロゲン受容体 1型遺伝子のG594A多型は片頭痛の易罹患性と関連している
コメント	片頭痛の頻度には明らかに男女差があり、女性が有意に多い。このため女性ホルモンが発症に何らかの影響を与えている可能性は以前より示唆されていた。本研究では二つの独立した集団において有意差を認めており、信頼性は高い。ただし両集団とも Caucasianであり、もし他人種でも証明されれば、さらに結果に対する信憑性は高まると思われる。
作成者	百瀬義雄

8)　Tzourio C, El Amrani M, Poirier O, Nicaud V, Bousser MG, 　　 Alperovitch A. Association between migraine and endothelin type 　　 A receptor (ETA -231 A/G) gene polymorphism. Neurology. 2001 　　 May 22;56(10):1273-7.
論文抄録	BACKGROUND: Previous studies have described an association between migraine and endothelin, a potent vasoconstrictor. OBJECTIVE: To test the association between migraine and gene polymorphisms of the endothelin system. METHODS: A population-based study of elderly individuals (n = 1,188) in Nantes (western France ) was conducted. Lifetime migraine was defined according to the International Headache Society criteria, after an interview with a headache specialist. Five polymorphisms in genes encoding endothelin 1, endothelin type A (ET(A)), and type B receptors were determined in more than 90% of the sample. RESULTS Migraine was diagnosed in 140 participants (11.9%). The ETA (-231 A/G) polymorphism was the only polymorphism significantly associated with migraine. There was a trend of decreasing prevalence of migraine with number of copies of the G allele (AA genotype: 15.7% of participants with migraine, AG: 9.7%, GG: 2.9%; p < 0.001). Carrying the G allele was associated with a sex- and age-adjusted odds ratio of 0.50 (95% CI, 0.34 to 0.74). The association was observed in both sexes and was stronger in participants with a family history of severe headaches than in those without. CONCLUSIONS: A variant of the ET(A) receptor gene modulates the risk for migraine. These results offer new insights into the pathophysiology of the vascular component of migraine.
文献 Pubmed-ID	PMID: 11376172
エビデンスレベル	VI
文献タイトル（日本語）	片頭痛とエンドセリン A型受容体多型（ETA -231 A/G）との関連
目的	片頭痛とエンドセリンシステムの遺伝子多型との関連を検討する
研究デザイン	関連解析
研究施設	INSERM U 360, Salpetriere Hospital , Paris , France .
研究期間	未記載
対象患者	A population-based study of elderly individuals (n = 1,188) in Nantes (western France )
主要評価項目とそれに用いた統計学的手法	chi-squared test
結果	Migraine was diagnosed in 140 participants (11.9%). The ETA (-231 A/G) polymorphism was the only polymorphism significantly associated with migraine. There was a trend of decreasing prevalence of migraine with number of copies of the G allele (AA genotype: 15.7% of participants with migraine, AG: 9.7%, GG: 2.9%; p < 0.001). Carrying the G allele was associated with a sex- and age-adjusted odds ratio of 0.50 (95% CI, 0.34 to 0.74). The association was observed in both sexes and was stronger in participants with a family history of severe headaches than in those without.
結論	A variant of the ET(A) receptor gene modulates the risk for migraine. These results offer new insights into the pathophysiology of the vascular component of migraine.
コメント	フランス西部のコホート集団を用いていることが特徴。その点では他の関連解析より信頼性は高い。ただし、追試の報告は今のところ存在しない。
作成者	百瀬義雄

9) Kowa H, Yasui K, Takeshima T, Urakami K, Sakai F, Nakashima K. The 　 homozygous C677T mutation in the methylenetetrahydrofolate 　 reductase gene is a genetic risk factor for migraine. Am J Med Genet. 　 2000; 96(6): 762-4.
論文抄録	Increased homocysteine levels are associated with various pathological conditions in humans, including stroke and cardiovascular disorders. Homocysteine acts as an excitatory amino acid in vivo and may influence the threshold of migraine headache. Frosst et al. [1995] reported an association between the homozygous C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and serum homocysteine levels. This study was designed to determine the prevalence of the MTHFR mutation in Japanese patients with migraine and tension-type headache (TH). Seventy-four patients with migraine headaches (22 with aura and 52 without aura), 47 with THs, and 261 normal controls were recruited. Genotyping of MTHFR C677T polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism. We detected that the incidence of the homozygous transition (T/T) in migraine sufferers (20.3%) was significantly higher than that in controls (9.6%). Moreover, the frequency of the T/T genotype in individuals with migraine headaches with aura was remarkably high (40.9%). The MTHFR T allele was more frequent in the migraine group than in the control group. Our results support the conclusion that the MTHFR gene, causing mild hyperhomocysteinemia may be a genetic risk factor for migraine.
文献 Pubmed-ID	PMID: 11121176
エビデンスレベル	VI
文献タイトル（日本語）	メチレンテトラヒドロ葉酸還元酵素遺伝子の C677Tホモ接合変異は片頭痛の遺伝的危険因子である
研究デザイン	患者対照関連解析
研究施設	Division of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University , Yonago , Japan .
対象患者	前兆のある片頭痛患者 22名，前兆のない片頭痛患者52名，緊張型頭痛47名，正常対照261名
主要評価項目とそれに用いた統計学的手法	chi-squared test
結論	高ホモシステイン血症を生じる MTHFR 遺伝子のホモ多型は片頭痛発症の危険因子となる．
コメント	MTHFRが片頭痛の疾患感受性遺伝子となる可能性を指摘した世界初の報告．
作成者	古和久典