| 11. |
- Fourier, C, et al.
(författare)
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A genetic CLOCK variant associated with cluster headache causing increased mRNA levels
- 2018
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Ingår i: Cephalalgia : an international journal of headache. - : SAGE Publications. - 1468-2982. ; 38:3, s. 496-502
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Tidskriftsartikel (refereegranskat)abstract
- Cluster headache is characterized by recurrent unilateral headache attacks of severe intensity. One of the main features in a majority of patients is a striking rhythmicity of attacks. The CLOCK ( Circadian Locomotor Output Cycles Kaput) gene encodes a transcription factor that serves as a basic driving force for circadian rhythm in humans and is therefore particularly interesting as a candidate gene for cluster headache. Methods We performed an association study on a large Swedish cluster headache case-control sample (449 patients and 677 controls) screening for three single nucleotide polymorphisms (SNPs) in the CLOCK gene implicated in diurnal preference (rs1801260) or sleep duration (rs11932595 and rs12649507), respectively. We further wanted to investigate the effect of identified associated SNPs on CLOCK gene expression. Results We found a significant association with rs12649507 and cluster headache ( p = 0.0069) and this data was strengthened when stratifying for reported diurnal rhythmicity of attacks ( p = 0.0009). We investigated the effect of rs12649507 on CLOCK gene expression in human primary fibroblast cultures and identified a significant increase in CLOCK mRNA expression ( p = 0.0232). Conclusions Our results strengthen the hypothesis of the involvement of circadian rhythm in cluster headache.
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| 17. |
- Fourier, C, et al.
(författare)
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The molecular clock gene cryptochrome 1 (CRY1) and its role in cluster headache
- 2021
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Ingår i: Cephalalgia : an international journal of headache. - : SAGE Publications. - 1468-2982. ; 41:13, s. 1374-1381
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Tidskriftsartikel (refereegranskat)abstract
- Cluster headache is a severe primary headache disorder commonly featuring a strikingly distinct circadian attack pattern. Therefore, the circadian system has been suggested to play a crucial role in the pathophysiology of cluster headache. Cryptochromes are key components of the molecular clock generating circadian rhythms and have previously been shown to be associated with several psychiatric disorders, including seasonal affective disorder, bipolar disorder, and depression. Methods In this case-control study, we investigated the role of cryptochrome ( CRY) genes in cluster headache by screening 628 cluster headache patients and 681 controls from Sweden for four known genetic variants in the CRY1 (rs2287161 and rs8192440) and CRY2 (rs10838524 and rs1554338) genes. In addition, we analyzed CRY1 gene expression in primary fibroblast cell lines from eleven patients and ten controls. Results The exonic CRY1 variant rs8192440 was associated with cluster headache on allelic level ( p=0.02) and this association was even more pronounced in a subgroup of patients with reported diurnal rhythmicity of attacks ( p=0.002). We found a small significant difference in CRY1 gene expression between cluster headache patients and control individuals ( p=0.04), but we could not identify an effect of the associated variant rs8192440 on CRY1 expression. Conclusions We discovered a disease-associated variant in the CRY1 gene and slightly increased CRY1 gene expression in tissue from cluster headache patients, strengthening the hypothesis of circadian dysregulation in cluster headache. How this gene variant may contribute to the pathophysiology of the disease remains subject to further studies.
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| 18. |
- McMurray, J. J. V., et al.
(författare)
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Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction
- 2019
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 381:21, s. 1995-2008
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.METHODS In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.RESULTS Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.CONCLUSIONS Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.
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