Lack of association of endothelial nitric oxide synthase polymorphisms and migraine

Objective.— The aim of this study was to evaluate if 2 functional endothelial nitric oxide synthase (eNOS) gene polymorphisms might be risk factors for migraine.
Background.— Nitric oxide synthase promotes the synthesis of nitric oxide (NO). NO is a potent vasodilator and mediates several processes involved in migraine pathophysiology. Only one study has suggested an association with migraine with aura.
Methods.— We performed a sex- and age-matched case-control study using 2 eNOS polymorphisms (rs1800779 and rs1799983), which are in linkage disequilibrium. Genotypes were obtained with allele-specific probes in a real-time polymerase chain reaction assay. Genotypic and allelic distributions were compared with χ² method. We also estimated the reconstructed haplotypes and calculated ORs for individual haplotypes.
Results.— A total of 337 migraine patients (188 with aura) and 341 healthy controls were recruited. We found no significant differences in the distribution of genotypes and alleles for either polymorphism among clinical subgroups. Neither rs1800779 nor rs1799983 polymorphisms increased the risk for suffering from migraine aura.
Conclusions.— As others have previously reported, we failed to demonstrate genetic association of the eNOS gene with migraine.     

Potential neurogenic and vascular roles of nitric oxide in migraine headache and aura

It has long been known that nitrate and nitrite medications consistently cause significant headache as a side effect. Classical research has shown that cerebral vasodilation accompanies the use of these medications. More modern studies suggest that these vasodilators exert their action on blood vessels via nitric oxide and its second messenger, cyclic guanosine monophosphate. This paper reviews research studies and theoretical articles which address the concept that nitric oxide plays a major role in the vasodilation associated with the headache phase of migraine with aura. A brief discussion of nitric oxide biochemistry and pharmacology follows.
In addition, there is a review of evidence examining the possible contributions of nitric oxide to the neurogenic and vascular events associated with spreading cortical depression, an animal model of migraine aura. The paradoxical hypotheses that nitric oxide may contribute to both the propagation of spreading cortical depression and its limitation are presented. Finally, a rationale for the experimental use of nitric oxide agonists and antagonists in the abortion of migraine aura is introduced.     

冠心病合并抑郁患者内皮型一氧化氮合酶基因G894T多态性分析

目的探讨冠心病合并抑郁与内皮型一氧化氮合酶基因G894T位点多态性的关系。方法冠心病患者217例,分为冠心病合并抑郁组39例和冠心病组178例,选择同期抑郁症患者45例(抑郁症组)与健康体检者85名(对照组)。检测4组内皮型一氧化氮合酶基因G894T位点多态性,并分析4组间差异。结果 4组内皮型一氧化氮合酶基因G894T位点GT杂合基因型和T等位基因频率分布两两比较差异均无统计学意义(P>0.05)。结论冠心病合并抑郁与一氧化氮合酶基因G894T位点多态性无明显相关性。     

Migraine with aura and migraine without aura: an epidemiological study

In a cross-sectional study of headache disorders in a representative general population of 1,000 persons the epidemiology of migraine with aura (MA) and migraine without aura (MO) was analysed in relation to sex and age distribution, symptomatology and precipitants. The headache disorders were classified on the basis of a clinical interview as well as a physical and a neurological examination using the operational diagnostic criteria of the International Headache Society (IHS). Lifetime prevalence of MA was 5%, male:female ratio 1:2. Lifetime prevalence of MO was 8%, M:F ratio 1:7. Women, but not men, were significantly more likely to have MO than MA. Neither MA nor MO showed correlation to age in the studied age interval (25-64 years). Premonitory symptoms occurred in 16% of subjects with MA and in 12% with MO. One or more precipitating factor was present in 61% with MA and in 90% with MO. In both MA and MO the most conspicuous precipitating factor was stress and mental tension. Visual disturbances were the most common aura phenomenon occurring in 90% of subjects with MA. Aura symptoms of sensory, motor or speech disturbances rarely occurred without coexisting visual disturbances. The pain phase of MA fulfilled the criteria for MO of the IHS. Headache was, however, less severe and shorter lasting in MA than in MO. Onset at menarche, menstrual precipitation, menstrual problems, influence of pregnancy and use of oral contraceptives all showed some relationship with the presence of MO and less with MA. The present findings suggest that MA and MO share the pain phase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of association of the Glu298Asp polymorphism of endothelial nitric oxide synthase with manifest coronary artery disease,carotid atherosclerosis and forearm vascular reactivity in two Austrian populations

OBJECTIVE: Conflicting data exists about the possible contribution of the homozygous Asp/Asp genotype of the Glu298Asp polymorphism of endothelial nitric oxide synthase to human atherosclerotic vascular disease. We investigated the polymorphism in two independent study populations: a case-control study including patients with angiographically verified coronary artery disease (CAD) on the one hand and a cross-sectional epidemiological study on the other hand. METHODS: The Glu298Asp polymorphism was determined by PCR-RFLP as established. In the case-control study (240 patients and 248 controls) a possible association between the polymorphism and CAD, and age of onset of CAD and myocardial infarction was investigated. In the cross-sectional epidemiological study (932 subjects) intima-media thickness (IMT) of the carotid artery as well as morphological plaque burden and forearm vascular reactivity (peak postischemic reactive hyperaemia, determined by venous occlusion plethysmography) were measured. RESULTS: In the case-control study genotype distribution (Glu/Glu; Glu/Asp; Asp/Asp) was not different between the CAD patients (43/46/11%) and the controls (49/41/10%, P = NS). No association of the polymorphism with age of onset of CAD or myocardial infarction was found. In the epidemiological study no influence of the genetic variant on IMT was observed after correction for classical determinants of IMT (average IMT: Asp/ Asp: 0.077 +/- 0.011 mm; Glu/Glu and Glu/Asp: 0.080 +/- 0.012 mm, P = NS). Forearm vascular reactivity was also not different between homozygous Asp/Asp subjects and Glu/Glu and Glu/Asp subjects (peak-reactive hyperaemia 20.1 +/- 7.3 mL min-1 100 mL-1 vs. 20.0 +/- 6.5 mL min-1 100 mL-1, P = NS). CONCLUSIONS: Our results suggest that there is no association of the Glu298Asp polymorphism with coronary or carotid atherosclerosis or forearm vascular reactivity in these populations recruited in a country with a rather high risk for atherosclerosis. We suggest additional investigations to be performed in populations at different risk for coronary events to further elucidate the possible contribution of this polymorphism to vascular disease.     

Endothelial nitric oxide synthase (NOS) is upregulated in rapid progressive pulmonary hypertension of the newborn

Objective To provide evidence for the upregulation of endothelial nitric oxide synthase (eNOS) or inducible nitric oxide synthase (iNOS) in the assumed imbalance in the pathophysiology of rapid progressive pulmonary hypertension of the newborn (RPPHN), which is characterized by abnormal hypertrophy of the pulmonary arterioles and arteries leading to increased pulmonary vascular resistance. Furthermore, to determine the cellular source and topographic distribution of eNOS and iNOS.Material and Methods Lung biopsies were taken from two term neonates with clinical and echocardiographic evidence of RPPH and of three controls. Biopsies were obtained at an early stage of the disease as well as at post mortem and examined immunohistochemically for the presence of eNOS, iNOS and nitrotyrosine.Results The endothelial cells of pulmonary arterioles stained significantly for eNOS protein in RPPHN patients. This was not the case in the control infants. There were no differences for nitrotyrosine or iNOS between RPPHN patients and controls.Conclusion Rapid progressive pulmonary hypertension of the newborn leads to compensatory induction of eNOS synthesis specifically in endothelial cells of the pulmonary arterioles. This mechanism of compensation can lead to delayed presentation of RPPHN during the late neonatal period. Exogenous inhaled nitric oxide therapy does not lead to suppression of the endogenous synthesis of nitric oxide.     

Preventing disturbing migraine aura with lamotrigine: an open study

BACKGROUND: Lamotrigine has been suggested as possibly effective for preventing migraine aura. OBJECTIVE: To describe our experience with a series of patients with disturbing migraine aura treated with lamotrigine. METHODS: The members of the Headache Group of the Spanish Society of Neurology were sent an ad hoc questionnaire to collect patients treated with lamotrigine due to disturbing migraine aura. The main outcome parameter ("response") was a >50% reduction in the mean frequency of migraine auras at 3 to 6 months of treatment. RESULTS: A total of 47 patients had been treated with lamotrigine due to severe migraine aura. Three could not complete the protocol as a result of developing skin rashes. Thirty (68%) patients responded. These were 21 females and 9 males whose ages ranged from 19 to 71 years. Eight suffered from migraine with "prolonged" aura, 8 typical aura with migraine headache (but had frequent episodes including speech symptoms), 6 basilar-type migraine, 6 typical aura without headache, and 2 hemiplegic migraine. Fifteen had been previously treated, without response, with other preventatives. The mean monthly frequency of migraine auras in these 30 patients changed from 4.2 (range: 1 to 15) to 0.7 (range: 0 to 6). Response was considered as excellent (>75% reduction) in 21 cases (70% of responders). Auras reappeared in 2 months in 9 out of 13 patients where lamotrigine was stopped, and ceased as soon as this drug was reintroduced. CONCLUSIONS: Lamotrigine should be considered in clinical practice for the preventive treatment of selected patients with disturbing migraine auras. Lamotrigine seems worthy of a controlled trial as prophylaxis of migraine aura.     

Endothelial nitric oxide synthase Glu(298)-->Asp polymorphism, carotid atherosclerosis and intima-media thickness in a general population sample

The Glu(298)-->Asp (E298D; 894G-->T) polymorphism of eNOS (endothelial nitric oxide synthase) has been related with cardiovascular disease. In the present study, we investigated the association of Glu(298)-->Asp with atherosclerotic plaques in different carotid vessel segments and with carotid IMT (intima-media thickness). The Glu(298)-->Asp eNOS polymorphism was determined by 5'-exonuclease assay among 2448 participants of the SHIP (Study of Health in Pomerania). Mean and maximum common carotid IMT, as well as carotid atherosclerosis, were measured by high-resolution ultrasound. The Asp/Asp(298) genotype was associated with an increased risk of atherosclerotic plaques at the level of the common carotid arteries [multivariate odds ratio, 1.57 and 95% CI (confidence interval), 1.05-2.34; P=0.025], but not in the carotid bifurcations or internal or external carotid arteries. Glu(298)-->Asp genotype was not associated with carotid IMT in the whole sample. However, the Asp/Asp(298) genotype was independently associated with both higher mean [adjusted increase by 0.046 mm (95% CI, 0.013-0.078); P=0.006] and maximum carotid IMT [0.137 mm (95% CI, 0.064-0.209); P<0.001] in the low-risk group of subjects without carotid atherosclerosis. In conclusion, the Asp/Asp(298) genotype is associated with atherosclerosis in the common carotid arteries and, in a low-risk group, also with carotid IMT. This suggests that the association of the Glu(298)-->Asp genotype with atherosclerosis in the carotid arteries is site-specific and is modified by overall cardiovascular risk.     

The 1246G-->A polymorphism of the HCRTR2 gene is not associated with migraine

Studies in experimental animals have suggested that the hypocretin/orexin system may be involved in migraine pathophysiology. Using a case-control design study, we genotyped 246 migraine patients and 239 healthy controls for the 1246G-->A polymorphism of the hypocretin receptor 2 (HCRTR2) gene. Genotypic and allelic frequencies of the examined polymorphism were similarly distributed between cases and controls (chi2 = 2.22, P = 0.14 and chi2 = 2.45, P = 0.29, respectively). When different migraine subgroups were compared (migraine with aura vs. migraine without aura and episodic vs. chronic migraine) no significant difference was found. Comparison of the clinical features of the disease with the 1246G-->A genotypes showed no significant difference. Our data suggest that the HCRTR2 gene is not a genetic risk factor in migraine.     

大鼠创伤性脑水肿一氧化氮及其合成酶的变化

目的：探讨脑损伤后一氧化氮（ＮＯ）及一氧化氮合酶（ＮＯＳ）与脑水肿的关系。方法：建立大鼠创伤性脑水肿模型,按不同时间点处死动物,测定其脑含水量及静脉血ＮＯ 和脑组织中ＮＯＳ。结果：脑创伤后脑含水量随静脉血ＮＯ的增加而增加,组织ＮＯＳ则随ＮＯ 的增加而下降。结论：创伤性脑水肿与血ＮＯ 有密切相关性,组织中ＮＯＳ则是该过程的可能催化剂     

Glu298Asp and NOS4ab polymorphisms in diabetic nephropathy

Background and aims. The risk of diabetic nephropathy (DN) increases with increase in intraglomerular pressure, which may partly be regulated by nitric oxide (NO). NO‐production can be affected by polymorphisms in the endothelial NO‐synthase gene (NOS3), hyperglycaemia and smoking. We therefore studied association between DN and two polymorphisms in NOS3, Glu298Asp and NOS4ab, in Caucasian type 1 diabetes (T1D) patients.

Patients and methods. A total of 1510 Finnish and Swedish T1D patients were included in a cross‐sectional case‐control study. Incipient DN was defined as an albumin excretion rate (AER) of 20–200?µg/min (n = 336). Overt DN = AER>200?µg/min or renal replacement therapy (n = 619). All patients with DN were considered as cases. The controls were T1D patients with diabetes duration ?20 years, AER<20?µg/min and without antihypertensive treatment (n = 555). The genetic markers studied were a 27?bp repeat (NOS4ab) and Glu298Asp (rs1799983).

Results. Age at onset of diabetes, male sex, duration of diabetes, HbA1c, blood pressure and smoking were assessed as possible confounders in the logistic regression analysis, which showed that homozygosity for the Glu‐allele of the Glu298Asp‐polymorphism was independently associated with increased risk of DN (OR = 1.46; 95% CI = 1.12–1.91). The variables smoking (OR = 2.13; 95% CI = 1.63–2.78), male sex (OR = 1.61; 95% CI = 1.23–2.10), HbA1c (OR per % increase above upper limit of the normal reference range = 1.02; 95% CI = 1.02–1.03), systolic (OR = 1.05; 95% CI = 1.04–1.06) and diastolic blood pressure (OR = 1.04; 95% CI = 1.02–1.05) also significantly and independently increased the risk of DN when taking age at diabetes onset and diabetes duration into account. The NOS4 a‐allele was not associated with DN.

Conclusions. The Glu/Glu‐genotype of the NOS3 Glu298Asp polymorphism may increase the risk of developing DN independently of other known risk factors.     

Migraine with aura after administration of sublingual nitroglycerin tablets

As a nitric oxide donor, nitroglycerin can trigger migraine in migraineurs. The headache is not characteristically accompanied by an aura. A patient with no personal or family history of migraine reported the development of a typical visual aura and a throbbing headache while using nitroglycerin for angina pectoris. The possible mechanisms are discussed.     

Daily migraine with visual aura associated with an occipital arteriovenous malformation

A 51-year-old woman with daily attacks of migraine with visual aura is described. The aura always occurred on the right and the headache always on the left side of the head, suggesting a structural lesion in the left occipital lobe. The lesion appeared to be an arteriovenous malformation of which almost full obliteration resulted in a decrease in frequency of the aura and in intensity of the headache. Subsequent treatment of borderline hypothyroidism with levothyroxine brought about a dramatic improvement in frequency of both the aura and the headache. The case is discussed in the light of our present understanding of the pathogenesis of the migraine attack.     

Arterial supersensitivity to nitric oxide (nitroglycerin) in migraine sufferers

The sensitivity to nitroglycerin-induced dilatation of large intracranial arteries was studied in 17 patients with migraine without aura, 17 age and sex-matched healthy subjects and 9 patients with episodic tension-type headache. Nitroglycerin in the doses of 0.015, 0.03, 0.25 and 0.5 μg/kg/min was successively infused for 15 min per dose. Blood velocity (V_mean) in the middle cerebral artery (MCA) was recorded with transcranial Doppler before and at the end of every infusion period, and 30 and 60 min after end of the last infusion. In all three groups V_mean decreased with increasing doses (p < 0.001). The response was more pronounced in migraine patients at the two higher doses (p < 0.05). Since nitroglycerin acts as an exogenous source of nitric oxide (NO), these data support that NO supersensitivity may be an important molecular mechanism of migraine pain.     

Impact of endothelial nitric oxide synthase gene polymorphism on severity of enterovirus 71-infection in Chinese children

Objectives

Genetic polymorphism G894T on the endothelial nitric oxide synthase (eNOS) gene has been reported as a susceptibility factor in a number of diseases, but evidence of its effect on enterovirus 71 (EV71) infection is lacking. This study investigated the possible association between this polymorphism (rs1799983) and disease severity in Chinese children with EV71 infection.

Design and methods

185 children with EV71 infection (83 with severe and 102 with mild disease) and 234 control healthy children underwent testing with polymerase chain reaction–restriction fragment length polymorphism (PCR–RLFP) to detect G894T polymorphism. In addition, plasma levels of nitric oxide (NO), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) and serum eNOS activity were measured according to genotype.

Results

The presence of GT + TT genotypes and T allele were associated with severe cases compared to genotype GG (OR 2.5, 95% CI 1.2–5.3, P = 0.017) and G (OR 2.4, 95% CI 1.2–4.8, P = 0.011). Furthermore, in EV71 encephalitis, GT + TT genotype and T allele were also more frequent than GG and G (P < 0.05). The NO level and eNOS activity in T carriers (GT + TT) (84.3 ± 2.5 μmol/L and 14.4 ± 1.8 U/mL) were significantly less compared to in G carriers (GG) (92.0 ± 1.5 μmol/L and 19.1 ± 1.7 U/mL, P < 0.001). But T carriers had higher plasma levels of IL-1β, IL-6, and TNF-α than people without a T allele (P < 0.001), and a significant negative correlation was observed between NO and cytokine levels.

Conclusion

The results indicate that carrying the T allele of the eNOS G894T gene polymorphism was associated with EV71 infection, and could be a susceptibility factor in the development of EV71 infection in Chinese children.     

诱导型一氧化氮合酶基因启动子区微卫星多态与急性冠状动脉综合征

目的:研究中国汉族人群诱导型一氧化氮合酶(NOS2A)基因启动子区-2.5kb微卫星CCTTT串联重复序列多态与急性冠状动脉综合征(ACS)的相关性。方法:应用微卫星分析技术,检测CCTTT微卫星多态在117例ACS患者和125名健康对照者中的频率分布。结果:根据CCTTT微卫星多态对NOS2A基因转录水平的影响,将CCTTT串联重复序列分为S(重复次数≤13)和L(重复次数>13)2类,基因型分布在ACS组(S/S=48,S/L=64,L/L=5)和对照组(S/S=56,S/L=49,L/L=20)间存在显著差异(χ2=11.354,P=0.003)。对照组的L/L基因型频率显著高于ACS组,r为0.234(95%CI=0.085～0.647,P=0.003),可能具有保护性作用。分层研究发现,女性ACS与对照组相比,基因型分布存在显著差异(χ2=8.134,P=0.017)。结论:NOS2A基因启动子区CCTTT微卫星多态可能与中国汉族ACS,尤其与女性患者的遗传易感性有关。     

Frequency of factor V Leiden in juvenile migraine with aura

Patients with migraine are known to be at risk for stroke. It has been reported that in a group of patients with cerebral ischemia and the Leiden mutation of factor V, 67% had classical migraine. We have studied the frequency of this mutation in a group of Italian children and adolescents affected by migraine with aura. The Leiden mutation was detected in 2 (3.5%) of 57 patients and in 8 (3.7%) of 219 controls. The 2 patients carrying the mutation had no peculiar characteristics as compared with the rest of the migrainous population. In our study, the frequency of the Leiden mutation in patients was not different from that of controls. These data contrast with those collected in the Finnish population and in a group of northwestern Italian adult patients, but agree with results previously reported from The Netherlands.     

Gender specific association of endothelial nitric oxide synthase gene (Glu298Asp) polymorphism with essential hypertension in a south Indian population

BACKGROUND: Endothelial derived nitric oxide (NO) plays a major role in blood pressure regulation. The role of missense variant eNOS-Glu298Asp has been demonstrated by many studies with conflicting results. Our objective was to investigate the association of eNOS gene polymorphism with essential hypertension in a south Indian population. METHODS: We carried out a case control study in 438 hypertensive patients and 444 healthy control subjects in a homogenous population. Genotyping was done by PCR-RFLP method. Multiple logistic regression analysis was used to detect the association between genotype and hypertension. RESULTS: The homozygous variant genotype Asp298Asp was significantly associated with hypertension (odds ratio 2.4; 95% CI, 1.23-5.0, p<0.01). Gender specific analysis showed both the heterozygous (odds ratio, 2.0; 95% CI, 1.3-2.9, p<0.01) and homozygous variants (odds ratio, 7.9; 95% CI, 2.0-4.1, p<0.001) were positively associated with hypertension in females. The variant allele Asp was higher in female hypertensives when compared to male hypertensive cases (22% vs. 16%). CONCLUSION: The eNOS gene polymorphism is a candidate gene for hypertension and the association to be gender specific with respect to females in a south Indian Tamilian population.