Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker–Induced Angioedema

Angioedema occurring in the head and neck region is a rare and sometimes life‐threatening adverse reaction to angiotensin‐converting 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 ACEI‐induced angioedema (ACEI‐AE) or ARB‐induced angioedema (ARB‐AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI‐AE, ARB‐AE, and 658 controls) was performed using exome‐enriched 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 ACEI‐AE and ARB‐AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89–4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEI‐AE or ARB‐AE, P = 2.09 × 10−3. 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, 1.49–3.27, P = 6.30 × 10−9) times the odds of having ACEI‐AE or ARB‐AE. The increased risk due to the common Leiden allele was confirmed in a genome‐wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect‐causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI‐AE or ARB‐AE

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=6×10-63) and 24% (P value=2×10-5) 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

Secular trends in the prevalence of diabetes and prediabetes among the rural population of South India

Objective This study aimed to assess the secular trends in the prevalence of diabetes and pre-diabetes from two cross-sectional studies done 11 years apart, in rural Tamil Nadu. Methods The Telemedicine PRoject for screENing Diabetes and its complications in rural Tamil Nadu(TREND) study is a cross-sectional survey that screened 14,117 individuals aged ≥ 18 years between 2018–2021. TREND was conducted in 30 villages of Chengalpattu/Kancheepuram districts of Tamil Nadu in Southern India. The prevalence of diabetes and prediabetes was compared with an earlier study the Chunampet Rural Diabetes Prevention Project(CRDPP) which screened 23,380 individuals aged ≥ 20 years between 2006–2010 using similar methodology, in 42 villages in the same area. Diabetes and prediabetes were diagnosed using the WHO criteria. Results Individuals screened in TREND were significantly older (43.7 ± 14.5 vs.40.5 ± 15.2 years) and had higher BMI (23 ± 5 vs.21.4 ± 4.1) compared to CRDPP participants. The age and gender adjusted prevalence of diabetes increased from 5.3% to 13.7% (158.5% increase) during this 11-year period. There was a significant increase in prevalence of both self-reported diabetes (3.8% to 9.7%) and newly diagnosed diabetes (1.5% to 4.0%), but a decrease in prevalence of prediabetes from 16.7% to 8.4% (49.7% decrease) during the 11-year period. Age, male sex, BMI, formal education, occupations other than agriculture, family history of diabetes, and systolic blood pressure were significant predictors of diabetes. Conclusions The prevalence of diabetes among adults in rural south India has dramatically increased while that of prediabetes, has decreased, over a 11-year period. The decrease in prevalence of prediabetes might suggest a future slowing down of the epidemic