Dataset Information

Analysis of NOS Gene Polymorphisms in Relation to Cluster Headache and Predisposing Factors in Sweden.

ABSTRACT: Cluster headache is characterized by activation of the autonomic-trigeminal reflex. Nitric oxide can trigger headaches in patients, and nitric oxide signaling is known to be affected in cluster headache. Based on the hypothesis of nitric oxide being involved in cluster headache pathophysiology we investigated nitric oxide synthases as potential candidate genes for cluster headache. We analyzed eight variants in the three forms of nitric oxide synthase (NOS) genes, inducible NOS (iNOS), endothelial NOS (eNOS) and neuronal NOS (nNOS), and tested for association with cluster headache. Swedish cluster headache patients (n = 542) and controls (n = 581) were genotyped using TaqMan^® assays on an Applied Biosystems 7500 qPCR cycler. This is the largest performed genetic study on NOS involvement in cluster headache so far. We found an association between cluster headache and one iNOS haplotype consisting of the minor alleles of rs2297518 and rs2779249 (p = 0.022). In addition, one of the analyzed nNOS variants, rs2682826, was associated with reported triptan use (p = 0.039). Our data suggest that genetic variants in NOS genes do not have a strong influence on cluster headache pathophysiology, but that certain combinations of genetic variants in NOS genes may influence the risk of developing the disorder or triptan use.

SUBMITTER: Ran C

PROVIDER: S-EPMC7824326 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Analysis of NOS Gene Polymorphisms in Relation to Cluster Headache and Predisposing Factors in Sweden.

Ran Caroline C Michalska Julia M JM Fourier Carmen C Sjöstrand Christina C Waldenlind Elisabet E Steinberg Anna A Belin Andrea C AC

Brain sciences 20201231 1

Cluster headache is characterized by activation of the autonomic-trigeminal reflex. Nitric oxide can trigger headaches in patients, and nitric oxide signaling is known to be affected in cluster headache. Based on the hypothesis of nitric oxide being involved in cluster headache pathophysiology we investigated nitric oxide synthases as potential candidate genes for cluster headache. We analyzed eight variants in the three forms of nitric oxide synthase (<i>NOS</i>) genes, inducible <i>NOS</i> (<i ...[more]

PMID: 33396232

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Project description:ObjectiveThe purpose of this study was to investigate the HCRTR2 gene variants rs3122156, rs2653342, and rs2653349 in a large homogenous Swedish case-control cohort in order to further evaluate the possible contribution of HCRTR2 to cluster headache.BackgroundCluster headache is a severe neurovascular disorder and the pathophysiology is not yet fully understood. Due to striking circadian and circannual patterns of this disease, the hypothalamus has been a research focus in cluster headache. Several studies with many different cohorts from Europe have investigated the hypocretin receptor 2 (HCRTR2) gene, which is expressed in the hypothalamus. In particular, one HCRTR2 single nucleotide polymorphism, rs2653349, has been subject to a number of genetic association studies on cluster headache, with conflicting results. Two other HCRTR2 gene variants, rs2653342 and rs2653349, have been reported to be linked to cluster headache in an Italian study.MethodsWe genotyped a total of 517 patients diagnosed with cluster headache and 581 controls, representing a general Swedish population, for rs3122156, rs2653342, and rs2653349 using quantitative real-time PCR. Statistical analyses of genotype, allele, and haplotype frequencies for the 3 gene variants were performed comparing patients and controls.ResultsFor rs3122156, the minor allele frequency in patients was 25.9% compared to 29.9% in controls (P = .0421). However, this significance did not hold after correction for multiple testing. The minor allele frequencies for rs2653342 (14.7% vs 14.7%) and rs2653349 (19.5% vs 18.8%) were similar for patients and controls. Furthermore, we found one haplotype that was significantly less common in patients than controls (P = .0264). This haplotype included the minor allele for rs3122156 and the major alleles for rs2653342 and rs2653349. Significance did not hold after applying a permutation test.ConclusionsOur data show a trend for association between cluster headache and the HCRTR2 polymorphism rs3122156, where the minor allele seems to be a protective factor. However, the other 2 HCRTR2 gene variants, including the previously reported rs2653349, were not associated with cluster headache in our Swedish material. A comparison with previous studies points to variance in genotype and allele frequencies among the different populations, which most likely contributes to the opposing results regarding rs2653349. Although the results from this study do not strongly support an association, HCRTR2 remains an interesting candidate gene for involvement in the pathophysiology of cluster headache.

Project description:ObjectiveTo investigate the possible subgroups of patients with Cluster Headache (CH) by using K-means cluster analysis.MethodsA total of 209 individuals (mean (SD) age: 39.8 (11.3) years), diagnosed with CH by headache experts, participated in this cross-sectional multi-center study. All patients completed a semi-structured survey either face to face, preferably, or through phone interviews with a physician. The survey was composed of questions that addressed sociodemographic characteristics as well as detailed clinical features and treatment experiences.ResultsCluster analysis revealed two subgroups. Cluster one patients (n = 81) had younger age at diagnosis (31.04 (9.68) vs. 35.05 (11.02) years; p = 0.009), a higher number of autonomic symptoms (3.28 (1.16) vs. 1.99(0.95); p < 0.001), and showed a better response to triptans (50.00% vs. 28.00; p < 0.001) during attacks, compared with the cluster two subgroup (n = 122). Cluster two patients had higher rates of current smoking (76.0 vs. 33.0%; p=0.002), higher rates of smoking at diagnosis (78.0 vs. 32.0%; p=0.006), higher rates of parental smoking/tobacco exposure during childhood (72.0 vs. 33.0%; p = 0.010), longer duration of attacks with (44.21 (34.44) min. vs. 34.51 (24.97) min; p=0.005) and without (97.50 (63.58) min. vs. (83.95 (49.07) min; p = 0.035) treatment and higher rates of emergency department visits in the last year (81.0 vs. 26.0%; p< 0.001).ConclusionsCluster one and cluster two patients had different phenotypic features, possibly indicating different underlying genetic mechanisms. The cluster 1 phenotype may suggest a genetic or biology-based etiology, whereas the cluster two phenotype may be related to epigenetic mechanisms. Toxic exposure to cigarettes, either personally or secondarily, seems to be an important factor in the cluster two subgroup, inducing drug resistance and longer attacks. We need more studies to elaborate the causal relationship and the missing links of neurobiological pathways of cigarette smoking regarding the identified distinct phenotypic classes of patients with CH.

Project description:BackgroundThe pneumococcal conjugate vaccine PCV7 was introduced in Southwest Sweden in the child vaccination program in 2009, followed by PCV13 in 2010 and PCV10 in 2015. In this retrospective cohort study we assessed the pneumococcal serotype distribution in relation to predisposing factors, clinical manifestations and outcome during seven years after PCV introduction.MethodsClinical data from 1278 patients with 1304 episodes of invasive pneumococcal disease (IPD) between January 2009 and December 2015 in Region Västra Götaland, Sweden, were retrospectively collected from medical records. Pneumococcal isolates were serotyped by gel diffusion and/or Quellung reactions performed at the Public Health Agency in Sweden. Associations between serotypes and clinical characteristics were statistically evaluated by use of Fisher's exact test, Mann-Whitney U test and Logistic regression analysis, whereas IPD episodes caused by serotypes over time were analyzed by Mantel-Haenszel chi-square test.ResultsWith the exception of serotype 3, the prevalence of PCV13 serotypes decreased during the study period, from 76% (n = 157) of all IPD episodes in 2009 to 25% (n = 42) in 2015 (p < 0.001) while non-PCV13 serotypes increased, mainly among patients ≥65 years and in patients with predisposing factors, including cardiovascular disease, pulmonary disease and malignancy (p < 0.001 for all). Patients with predisposing factors, including those with malignancy, immune deficiency or renal disease, were more likely to have IPD caused by a serotype not included in PCV13 rather than a vaccine-included serotype. Serotype 3 was associated with intensive care unit admissions while serotype 1 and 7F caused IPD among healthier and younger patients. PCV13 serotypes were associated with invasive pneumonia, and non-PCV13 serotypes were associated with bacteremia with unknown focus and with manifestations other than pneumonia or meningitis.ConclusionsNon-PCV13 serotypes caused the majority of IPD cases in Southwest Sweden, especially in patients ≥65 years and in patients with predisposing factors. Serotype 3, included in PCV13, was prevalent and often caused severe disease.

Project description:BackgroundThe glutamatergic neurotransmission has important role in the pathomechanism of primary headache disorders. The kynurenine metabolites derived from catabolism of tryptophan (Trp) have significant involvement not only in glutamatergic processes, but also in the neuroinflammation, the oxidative stress and the mitochondrial dysfunctions. Previously we identified a depressed peripheral Trp metabolism in interictal period of episodic migraineurs, which prompted us to examine this pathway in patients with episodic cluster headache (CH) as well. Our aims were to compare the concentrations of compounds both in headache-free and attack periods, and to find correlations between Trp metabolism and the clinical features of CH. Levels of 11 molecules were determined in peripheral blood plasma of healthy controls (n = 22) and interbout/ictal periods of CH patients (n = 24) by neurochemical measurements.FindingsSignificantly decreased L-kynurenine (KYN, p < 0.01), while increased quinolinic acid (QUINA, p < 0.005) plasma concentrations were detected in the interbout period of CH patients compared to healthy subjects. The levels of KYN are further reduced during the ictal period compared to the controls (p < 0.006). There was a moderate, negative correlation between disease duration and interbout QUINA levels (p < 0.048, R = - 0.459); and between the total number of CH attacks experienced during the lifetime of patients and the interbout KYN concentrations (p < 0.024, R = - 0.516). Linear regression models revealed negative associations between age and levels of Trp, kynurenic acid, 3-hdyroxyanthranilic acid and QUINA in healthy control subjects, as well as between age and ictal level of anthranilic acid.ConclusionsOur results refer to a specifically altered Trp metabolism in CH patients. The onset of metabolic imbalance can be attributed to the interbout period, where the decreased KYN level is unable to perform its protective functions, while the concentration of QUINA, as a toxic compound, increases. These processes can trigger CH attacks, which may be associated with glutamate excess induced neurotoxicity, neuroinflammation and oxidative stress. Further studies are needed to elucidate the exact functions of these molecular alterations that can contribute to identify new, potential biomarkers in the therapy of CH.

Dataset Information

Analysis of NOS Gene Polymorphisms in Relation to Cluster Headache and Predisposing Factors in Sweden.

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Analysis of NOS Gene Polymorphisms in Relation to Cluster Headache and Predisposing Factors in Sweden.

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