Epigenetic Connection of the Calcitonin Gene-Related Peptide and Its Potential in Migraine

Fila, Michał; Sobczuk, Anna; Pawłowska, Elżbieta; Błasiak, Janusz

doi:10.3390/ijms23116151

Cited by 19 publications

(17 citation statements)

References 136 publications

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“…The CGRP gene (CALCA) expression can be modified in several ways (DNA methylation, histone modifications, and noncoding RNAs), and the CGRP might, in turn, trigger regulatory mechanisms in neuronal and glial cells. 22 In the present study, we sought to determine the characteristics of headaches from a semiological point of view in Mennonites, comparing them with Brazilian non-Mennonites, subject to a similar environment (epigenetic factors).…”

Section: Introductionmentioning

confidence: 99%

Clinical characteristics of headaches in an urban Mennonite group in South Brazil

Dück,

Utiumi,

Boldt

et al. 2023

Arq Neuropsiquiatr

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Background Genetic variants play a pathophysiological role in headaches, especially in migraine. The Mennonite group (MG) has been geographically and genetically isolated throughout its history, harboring a distinctive distribution of diseases. Objective To determine the characteristics of headaches in a group with direct Mennonite ancestry contrasting with other urban community members (control group [CG]). Methods Subjects with headaches were asked to complete a questionnaire covering: the type of headache, presence of aura, frequency and duration of attacks, pain location and severity, analgesic consumption, premonitory and postdromic manifestations, Depressive Thoughts Scale, Epworth Sleepiness Scale (ESS), General Anxiety Disorder-7, Patient Health Questionnaire-9 (PHQ-9), Migraine Disability Assessment, and Composite Autonomic System Score. Results We included 103 participants (CG: 45, Mennonite group [MG]: 58). Migraine was the most common headache (CG: 91.1%; MG: 81.0%; p = 0.172), followed by tension-type headache (CG: 8.9%; MG: 15.5%; p = 0.381). Aura was identified by 44.4% and 39.7% in the CG and MG, respectively (p = 0.689). The groups differed only concerning the frequency of retro-orbital pain (CG: 55.6%; MG: 32.8%; p = 0.027), PHQ-9 (CG: median 7, range 0 to 22; MG: median 5, range 0 to 19; p = 0.031) and ESS (CG: median 0, range 0 to 270; MG: median 0, range 0 to 108; p = 0.048) scores. Conclusion There were no major differences in the prevalence and clinical characterization of headaches between the MG and the CG. However, the latter showed more diffuse pain, sleepiness, and depressive symptoms. Specific genetic or epigenetic variants in Mennonite descendants might account for these differences.

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Section: Introductionmentioning

confidence: 99%

Clinical characteristics of headaches in an urban Mennonite group in South Brazil

Dück,

Utiumi,

Boldt

et al. 2023

Arq Neuropsiquiatr

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“…[9][10][11] Monoclonal antibodies are the first agents specifically designed for migraine, targeting the calcitonin gene-related peptide pathway, representing an effective new treatment modality in migraine prophylaxis and treatment. 12 This agent class has shown excellent efficacy and tolerability in clinical trials and real-world studies.…”

Section: Introductionmentioning

confidence: 99%

“…Oral agents are generally not migraine‐specific but rather re‐purposed from other indications, 9 and are often ineffective or poorly tolerated, leading to poor treatment adherence and treatment discontinuation 9–11 . Monoclonal antibodies are the first agents specifically designed for migraine, targeting the calcitonin gene‐related peptide pathway, representing an effective new treatment modality in migraine prophylaxis and treatment 12 . This agent class has shown excellent efficacy and tolerability in clinical trials and real‐world studies.…”

Section: Introductionmentioning

confidence: 99%

Improved quality of life with fremanezumab in Japanese and Korean patients with episodic and chronic migraine: Results of two multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group clinical trials

Matsumori,

Ishida,

Iba

et al. 2023

Headache

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ObjectiveTo evaluate quality of life (QoL) endpoints from two 12‐week trials investigating fremanezumab efficacy and safety in Japanese/Korean patients with chronic (CM) or episodic (EM) migraine.BackgroundMigraine is a leading cause of disability and affects QoL considerably, interfering with work and daily activities, social and family life, and emotional wellbeing.MethodsThis planned exploratory analysis used data from two multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group studies in which Migraine‐Specific QoL (MSQoL; Role Function‐Restrictive [RR], Role Function‐Preventive [RP], and Emotional Function [EF] domains) scores and Patient Global Impression of Change (PGIC) scores were pre‐specified QoL outcomes in individuals receiving monthly or quarterly fremanezumab or placebo. In both trials, MSQoL was assessed at baseline, and MSQoL and PGIC at Weeks 4, 8, and 12. PGIC responders had a score of ≥5 points, indicating significant improvement.ResultsMean baseline MSQoL scores were similar across groups in both CM (N = 565; RR, 60.3–61.5; RP, 78.5–80.0; EF, 69.0–71.4) and EM (N = 353; RR, 68.6–71.1; RP, 83.1–85.7; EF, 76.7–81.9) trials. In the CM trial, all three MSQoL domains improved in both fremanezumab groups at 12 weeks compared with placebo: least squares mean (LSM) and standard error (SE) change from baseline, p versus placebo (quarterly; monthly; placebo): RR 14.9 (1.3), p = 0.030; 15.1 (1.4), p = 0.020; 11.6 (1.3); RP 8.9 (1.1), p = 0.007; 8.6 (1.1), p = 0.013; 5.4 (1.1); EF 13.3 (1.5), p < 0.001; 12.5 (1.5), p = 0.003; 7.5 (1.5). In the EM trial, RR/EF domains improved in both fremanezumab groups compared with placebo: LSM change from baseline, p versus placebo (quarterly; monthly; placebo): RR 16.3 (1.4), p = 0.003; 16.4 (1.3), p = 0.002; 11.6 (1.4); EF 13.0 (1.3), p < 0.001; 11.5 (1.2), p = 0.004; 7.4 (1.3); RP improved in the quarterly group RP 8.6 (1.1), p = 0.010; 7.6 (1.1), p = 0.066; 5.4 (1.1). The proportion of PGIC responders at Week 12 was greater in the monthly and quarterly fremanezumab groups compared with the placebo group in the CM (96/182 [52.7%] and 98/180 [54.4%] vs. 68/179 [38.0%]; p < 0.05) and EM trial (81/118 [68.6%] and 86/113 [76.1%] vs. 38/111 [34.2%]; p < 0.001).ConclusionPatients with EM/CM receiving monthly or quarterly fremanezumab, for a duration of 12 weeks, showed significant improvements in their QoL.

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“…Recently, response to erenumab was associated with older migraineonset age, fewer previously tried preventives (without response), and higher Migraine Disability Assessment (MIDAS) scores, 46 while response to galcanezumab, fremanezumab, and erenumab in patients with high-frequency episodic migraine (HFEM) or chronic migraine (CM) was positively associated with unilateral pain, unilateral cranial autonomic symptoms, and allodynia. 47 Factors that may influence response include different mechanisms of action in medications targeting CGRP or its receptors, 48 epigenetic modifications at the CGRP gene CALCA, 49 and genetic variation. 46,50,51 Because a migraine polygenic risk score (PRS) has been associated with triptan responsiveness, 52 a related PRS may be associated with CGRP medication responsiveness.…”

Section: Introductionmentioning

confidence: 99%

Characteristics associated with response to subcutaneously administered anti‐CGRP monoclonal antibody medications in a real‐world community cohort of persons living with migraine: A retrospective clinical and genetic study

Chase,

Semenov,

Rubin

et al. 2023

Headache

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ObjectiveTo evaluate response to anti‐calcitonin gene–related peptide (CGRP) migraine preventives in a real‐world community cohort of persons living with migraine and to identify clinical and genetic characteristics associated with efficacious response.BackgroundErenumab‐aooeb, fremanezumab‐vrfm, and galcanezumab‐gnlm target CGRP or its receptor; however, many patients are non‐responsive.MethodsIn this retrospective clinical and genetic study, we identified 1077 adult patients who satisfied the International Classification of Headache Disorders, 3rd edition, criteria for migraine without aura, migraine with aura, or chronic migraine and who were prescribed an anti‐CGRP migraine preventive between May 2018 and May 2021. Screening of 558 patients identified 289 with data at baseline and first follow‐up visits; data were available for 161 patients at a second follow‐up visit. The primary outcome was migraine days per month (MDM). In 198 genotyped patients, we evaluated associations between responders (i.e., patients with ≥50% reduction in MDM at follow‐up) and genes involved in CGRP signaling or pharmacological response, and genetic and polygenic risk scores.ResultsThe median time to first follow‐up was 4.4 (0.9–22) months after preventive start. At the second follow‐up, 5.7 (0.9–13) months later, 145 patients had continued on the same preventive. Preventives had strong, persistent effects in reducing MDM in responders (follow‐up 1: η2 = 0.26, follow‐up 2: η2 = 0.22). At the first but not second follow‐up: galcanezumab had a larger effect than erenumab, while no difference was seen at either follow‐up between galcanezumab and fremanezumab or fremanezumab and erenumab. The decrease in MDM at follow‐up was generally proportional to baseline MDM, larger in females, and increased with months on medication. At the first follow‐up only, patients with prior hospitalization for migraine or who had not responded to more preventive regimens had a smaller decrease in MDM. Reasons for stopping or switching a preventive varied between medications and were often related to cost and insurance coverage. At both follow‐ups, patient tolerance (1: 92.2% [262/284]; 2: 95.2% [141/145]) and continued use (1: 77.5% [224/289]; 2: 80.6% [116/145]) were high and similar across preventives. Response consistency (always non‐responders: 31.7% [46/145]; always responders: 56.5% [82/145], and one‐time only responders: 11.7% [17/145]) was also similar across preventives. Non‐responder status had nominally significant associations with rs12615320‐G in RAMP1 (odds ratio [95% confidence interval]: 4.7 [1.5, 14.7]), and rs4680‐A in COMT (0.6[0.4, 0.9]). Non‐responders had a lower mean genetic risk score than responders (1.0 vs. 1.1; t(df) = −1.75(174.84), p = 0.041), and the fraction of responders increased with genetic and polygenic risk score percentile.ConclusionsIn this real‐world setting, anti‐CGRP preventives reduced MDM persistently and had similar and large effect sizes on MDM reduction; however, clinical and genetic factors influenced response.

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Epigenetic Connection of the Calcitonin Gene-Related Peptide and Its Potential in Migraine

Cited by 19 publications

References 136 publications

Clinical characteristics of headaches in an urban Mennonite group in South Brazil

Clinical characteristics of headaches in an urban Mennonite group in South Brazil

Improved quality of life with fremanezumab in Japanese and Korean patients with episodic and chronic migraine: Results of two multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group clinical trials

Characteristics associated with response to subcutaneously administered anti‐CGRP monoclonal antibody medications in a real‐world community cohort of persons living with migraine: A retrospective clinical and genetic study

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