Dataset Information

ADRA2A and IRX1 are putative risk genes for Raynaud's phenomenon.

ABSTRACT: Raynaud's phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers, but despite its high reported heritability, no causal genes have been robustly identified. We conducted a genome-wide association study including 5,147 RP cases and 439,294 controls, based on diagnoses from electronic health records, and identified three unreported genomic regions associated with the risk of RP (p < 5 × 10^-8). We prioritized ADRA2A (rs7090046, odds ratio (OR) per allele: 1.26; 95%-CI: 1.20-1.31; p < 9.6 × 10^-27) and IRX1 (rs12653958, OR: 1.17; 95%-CI: 1.12-1.22, p < 4.8 × 10^-13) as candidate causal genes through integration of gene expression in disease relevant tissues. We further identified a likely causal detrimental effect of low fasting glucose levels on RP risk (r_G = -0.21; p-value = 2.3 × 10^-3), and systematically highlighted drug repurposing opportunities, like the antidepressant mirtazapine. Our results provide the first robust evidence for a strong genetic contribution to RP and highlight a so far underrated role of α_2A-adrenoreceptor signalling, encoded at ADRA2A, as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms.

SUBMITTER: Hartmann S

PROVIDER: S-EPMC10570309 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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ADRA2A and IRX1 are putative risk genes for Raynaud's phenomenon.

Hartmann Sylvia S Yasmeen Summaira S Jacobs Benjamin M BM Denaxas Spiros S Pirmohamed Munir M Gamazon Eric R ER Caulfield Mark J MJ Hemingway Harry H Pietzner Maik M Langenberg Claudia C

Nature communications 20231012 1

Raynaud's phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers, but despite its high reported heritability, no causal genes have been robustly identified. We conducted a genome-wide association study including 5,147 RP cases and 439,294 controls, based on diagnoses from electronic health records, and identified three unreported genomic regions associated with the risk of RP (p < 5 × 10<sup>-8</sup>). We prioritized ADRA2A (rs7090046, odds ratio (OR) per allele: 1.2 ...[more]

PMID: 37828025

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Project description:BackgroundMany different drugs have been suggested for the symptomatic treatment of primary Raynaud's phenomenon. Apart from calcium channel blockers, which are considered the drugs of choice, the evidence of the effects of alternative pharmacological treatments is limited. This is an update of a review first published in 2008.ObjectivesTo assess the effects of various drugs with vasodilator actions on primary Raynaud's phenomenon.Search methodsFor this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched 14 May 2012), CENTRAL (Issue 4, 2012) and clinical trials databases. We contacted one pharmaceutical company and one trial author for additional information. In addition, the reference lists of relevant studies were searched for additional citations. There were no language restrictions.Selection criteriaRandomised controlled trials evaluating the effects of oral formulations of any drug with vasodilator effects on subjective symptoms in primary Raynaud's phenomenon. Treatment with, or comparison with, calcium channel blockers was not assessed in this review.Data collection and analysisTwo members of the review team independently assessed the trials for inclusion and their quality and extracted the data. Data extraction included adverse events. We contacted trial authors for missing data.Main resultsEight studies involving 290 participants were included. Two trials examined the effects of captopril, the rest were single trials on single drugs. All comparisons were with placebo. The methodological quality of most trials was poor.Enalapril was associated with a small increase in the frequency of attacks per week (difference in means 0.8; 95% CI 0.43 to 1.17). The difference between the intervention groups on a subjective improvement score was non-significant. There was a significant effect of buflomedil on the frequency of attacks per week (weighted mean difference (WMD) -8.8; 95% CI -17.55 to -0.09), but there was no evidence of effect on the severity score. The proportion with fewer attacks was significantly higher on moxisylyte than on placebo (relative risk (RR) 4.33; 95% CI 1.36 to 13.81). For captopril, beraprost, dazoxiben and ketanserin there was no evidence of an effect on the frequency, severity or duration of attacks. Beraprost and moxisylyte gave significantly more adverse effects than placebo.Authors' conclusionsPoor methodological quality, small sample sizes and the limited data available resulted in low precision of the statistical results and limited value of the overall results .The overall results show that there is no evidence for an effect of vasodilator drugs on primary Raynaud's phenomenon.

Project description:ObjectiveThe aim at the current study was to investigate the clinical characteristics and risk factors of Raynaud's phenomenon (RP) in patients with primary Sjögren's syndrome (pSS).MethodsRetrospective analysis of the medical records of 333 new-onset pSS patients was performed. Demographic, clinical, and serological data were compared between individuals with and without RP. Logistic regression analysis was used to identify risk factors.ResultsRP was present in 11.41% of the pSS patients. pSS-RP patients were younger (49.74±14.56 years vs. 54.46±13.20 years, p=0.04) and exhibited higher disease activity (11 [5.75-15] vs. 7 [4-12], p=0.03) than those without. The prevalence of lung involvement was significantly higher in pSS patients with RP (60.53% vs. 17.29%; p<0.001). A significantly higher proportion of patients with pSS-RP tested positive about antinuclear (ANA), anti-RNP, and anti-centromere antibodies (ACA) compared to those without (p=0.003, <0.001, and 0.01, respectively). Multivariate analysis identified lung involvement (odds ratio [OR]=8.81, 95% confidence interval [CI] 2.02-38.47; p=0.04), anti-RNP positive status (OR=79.41, 95% CI 12.57-501.78; p<0.0001), as well as ACA (OR=13.17, 95% CI 2.60-66.72; p=0.002) as prognostic factors for pSS-RP.ConclusionThe presence of RP defined a subset of pSS with a unique phenotype, manifesting as increased lung involvement and a higher frequency of anti-RNP antibodies and ACA, as well as greater disease activity. These results suggest that RP has clinical and prognostic value of pSS patients. Further prospective studies with a larger number of subjects are warranted to confirm our findings and assess the prognostic and treatment implications of RP in pSS patients. Key Points • Raynaud's phenomenon (RP) was present in 38 (11.41%) of 333 patients with primary Sjögren's syndrome (pSS), with patients with RP exhibiting a younger age and higher disease activity. • The presence of RP indicates a subset of pSS with a unique phenotype, with manifestations including increased lung involvement and a higher frequency of anti-RNP antibodies and anti-centromere antibodies. • Patients with pSS and RP need close follow-up and long-term observation (including assessment of microangiopathy), with specific attention paid to the possible development of clinical features of systemic sclerosis.

Project description:ObjectiveTo determine if having Raynaud's phenomenon (RP) affects the work ability, job retainment, or occurrence of sick leave.MethodsSurveys on the working-age general population of northern Sweden were conducted in 2015 and 2021, gathering data on RP, occupation and sick leave. Work ability was assessed using the Work Ability Score.ResultsThe study population consisted of 2,703 women and 2,314 men, among which 390 women and 290 men reported RP at follow-up. For women, the mean [standard deviation (SD)] Work Ability Score was 8.02 (2.24) for subjects reporting RP and 7.68 (2.46) for those without RP. For men, the corresponding numbers were 7.37 (2.03) and 7.61 (2.14), respectively. Multiple linear regression did not show an association between RP status and work ability (p = 0.459 for women and p = 0.254 for men), after adjusting for age, body mass index, physical workload, cardiovascular disease, and perceived stress. Having retained the same main livelihood since baseline was reported by 227 (58.5%) women with RP, 1,163 (51.2%) women without RP, 152 (52.6%) men with RP, and 1,075 (54.1%) men without RP (p = 0.002 for women and p = 0.127 for men). At follow-up, any occurrence of sick leave during the last year was reported by 80 (21.4%) women with RP, 410 (18.6%) women without RP, 48 (17.1%) men with RP, and 268 (13.7%) men without RP (p = 0.208 for women and p = 0.133 for men). Among those reporting sick leave, the mean (SD) duration in months was 2.93 (3.76) for women with RP, 3.00 (4.64) for women without RP, 2.77 (3.79) for men with RP, and 2.91 (12.45) for men without RP (p = 0.849 for women and p = 0.367 for men).ConclusionFor neither women nor men was there a significant effect of having RP on work ability. Women with RP reported a slightly higher job retainment compared to those without the condition, while there was no difference in job retainment among men. For neither gender did the presence of RP influence the occurrence of recent sick leave, nor did it affect the length of time away from work.

Dataset Information

ADRA2A and IRX1 are putative risk genes for Raynaud's phenomenon.

Publications

ADRA2A and IRX1 are putative risk genes for Raynaud's phenomenon.

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