7 research outputs found
Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor BlockerāInduced Angioedema
Angioedema occurring in the head and neck region is a rare and sometimes lifeāthreatening adverse reaction to angiotensināconverting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEIāinduced angioedema (ACEIāAE) or ARBāinduced angioedema (ARBāAE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEIāAE, ARBāAE, and 658 controls) was performed using exomeāenriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEIāAE and ARBāAE (odds ratio: 2.85, 95% confidence interval (CI), 1.89ā4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEIāAE or ARBāAE, P = 2.09 Ć 10ā3. A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49ā3.27, P = 6.30 Ć 10ā9) times the odds of having ACEIāAE or ARBāAE. The increased risk due to the common Leiden allele was confirmed in a genomeāwide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defectācausing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEIāAE or ARBāAE
CKM Glu83Gly Is Associated With Blunted Creatine Kinase Variation, but Not With Myalgia
To test the association of a recently reported variant in the creatine kinase (CK) muscle gene, CKM Glu83Gly (rs11559024) with constitutive creatine phosphokinase (CK) levels, CK variation, and inducibility. Given the diagnostic importance of CK in determining muscle damage, we tested the association of the variant with myalgia. Meta-analysis between longitudinal cohort GoDARTS (Genetics of Diabetes Audit and Research, Tayside Scotland), minor allele frequency (=0.02), and randomized clinical trial (JUPITER [Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin], minor allele frequency=0.018) was used to replicate the association with baseline CK measures. GoDARTS was used to study the relationship with CK variability. Myalgia was studied in JUPITER trial participants. Baseline and SDs of CK were on average 18% (P value=6Ć10-63) and 24% (P value=2Ć10-5) lower for carriers of the variant, respectively. The variant was not associated with myalgia (odds ratio, 0.84; 95% confidence interval, 0.52-1.38). This study highlights that a genetic factor known to be associated with constitutive CK levels is also associated with CK variability and inducibility. This is discussed in the context of evidence to suggest that the variant has an impact on inducibility of CK by trauma through a previously reported case of a homozygous carrier. However, the lack of association between the variant and myalgia suggests that it cannot reliably be used as a biomarker for muscle symptom
Leucocyte immunoglobulin-like receptor subfamily-B5 (LILRB5) genetic variation and statin-associated muscle symptoms: another piece in a puzzling puzzle
Determinants of angiotensin-converting enzyme inhibitor (ACEI) intolerance and angioedema in the UK Clinical Practice Research Datalink
AIM: The aim of the present study was to describe the occurrence and determinants of angiotensin-converting enzyme (ACE) inhibitor (ACEI) intolerance and angioedema (AE) among patients initiating ACEI therapy in a real-world primary care population. METHODS: Two nested case-control studies were conducted in a cohort of 276ā977 patients aged ā„45 years initiating ACEIs from 2007 to 2014 in the UK Clinical Practice Research Datalink (CPRD). Cases of AE occurring for the first time during ACEI therapy (n = 416) were matched with AE-free controls (n = 4335) on the duration of ACEI treatment. Documented switches to angiotensin-II receptor blockers in the prescription records were used to identify ACEI-intolerance cases (n = 24ā709), and these were matched with continuous ACEI users (n = 84ā238) on the duration of ACEI therapy. Conditional logistic regression was used to assess the associations of demographic factors, comorbidities and comedication with AE and ACEI intolerance. RESULTS: AE during ACEI therapy was associated with age over 65 years [odds ratio (OR) 1.36, 95% confidence interval (CI) 1.07, 1.73], history of allergy (OR 1.53, 95% CI 1.19, 1.96), use of calcium channel blockers (OR 1.57, 95% CI 1.23; 2.01), use of antihistamines (OR 21.25, 95% CI 16.44, 27.46) and use of systemic corticosteroids (OR 4.52, 95% CI 3.26, 6.27). ACEI intolerance was significantly associated with more comorbidities and comedication compared with AE, including allergy (OR 2.02, 95% CI 1.96, 2.09), use of antiasthmatic drugs (OR 1.51, 95% CI 1.42, 1.61) and use of antihistamines (OR 1.53, 95% CI 1.43, 1.63). CONCLUSIONS: Among ACEI users developing AE or ACEI intolerance, several comorbidities and comedication classes were significantly more prevalent compared with ACEI users not developing these adverse reactions
Determinants of angiotensin-converting enzyme inhibitor (ACEI) intolerance and angioedema in the UK Clinical Practice Research Datalink
AimThe aim of the present study was to describe the occurrence and determinants of angiotensin-converting enzyme (ACE) inhibitor (ACEI) intolerance and angioedema (AE) among patients initiating ACEI therapy in a real-world primary care population. MethodsTwo nested case-control studies were conducted in a cohort of 276977 patients aged 45years initiating ACEIs from 2007 to 2014 in the UK Clinical Practice Research Datalink (CPRD). Cases of AE occurring for the first time during ACEI therapy (n = 416) were matched with AE-free controls (n = 4335) on the duration of ACEI treatment. Documented switches to angiotensin-II receptor blockers in the prescription records were used to identify ACEI-intolerance cases (n = 24709), and these were matched with continuous ACEI users (n = 84238) on the duration of ACEI therapy. Conditional logistic regression was used to assess the associations of demographic factors, comorbidities and comedication with AE and ACEI intolerance. ResultsAE during ACEI therapy was associated with age over 65years [odds ratio (OR) 1.36, 95% confidence interval (CI) 1.07, 1.73], history of allergy (OR 1.53, 95% CI 1.19, 1.96), use of calcium channel blockers (OR 1.57, 95% CI 1.23; 2.01), use of antihistamines (OR 21.25, 95% CI 16.44, 27.46) and use of systemic corticosteroids (OR 4.52, 95% CI 3.26, 6.27). ACEI intolerance was significantly associated with more comorbidities and comedication compared with AE, including allergy (OR 2.02, 95% CI 1.96, 2.09), use of antiasthmatic drugs (OR 1.51, 95% CI 1.42, 1.61) and use of antihistamines (OR 1.53, 95% CI 1.43, 1.63). ConclusionsAmong ACEI users developing AE or ACEI intolerance, several comorbidities and comedication classes were significantly more prevalent compared with ACEI users not developing these adverse reaction
Meta-analysis of genome-wide association studies on the intolerance of angiotensin-converting enzyme inhibitors
Objectives To identify single nucleotide polymorphisms (SNPs) associated with switching from an angiotensin-converting enzyme (ACE)-inhibitor to an angiotensin receptor blocker. Methods Two cohorts of patients starting ACE-inhibitors were identified within the Rotterdam Study in the Netherlands and the Genetics of Diabetes Audit and Research in Tayside Scotland study in Scotland. Cases were intolerant patients who switched from an ACE-inhibitor to an angiotensin receptor blocker and controls were individuals who used ACE-inhibitors continuously for at least 2 years and did not switch. Genome-wide association study (GWAS) using an additive model was run in these sets and the results were meta-analysed using Genome-Wide Association Meta Analysis software. Results A total of 972 cases out of 5161 ACE-inhibitor starters were identified. Eight SNPs within four genes reached the genome-wide association study significance level (
A common missense variant of LILRB5 is associated with statin intolerance and myalgia
Aims: A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366: Tā>āC: Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study. Methods and results: In the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy [odds ratio (OR) 1.81; 95% confidence interval (CI): 1.34-2.45] and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36; 95% CI: 1.07-1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48; 95% CI: 1.05-2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35, 95% CI: 1.10-1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34; 95% CI: 1.16-1.54). Conclusion: This study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins