Analysis of causal effect of APOA5 variants on premature coronary artery disease.

Apolipoprotein A5 (APOA5) regulates the metabolisms of triglyceride and HDL. APOA5 variants have been linked to coronary artery disease (CAD), but their causal roles are not well studied yet. This study aims to identify the causal effects of APOA5 variants on premature CAD. Sequencing analysis of APOA5 in 128 premature, familiar CAD patients from GeneQuest identified 11 genomic variants, including p.S19W (rs3135506). SKAT analysis showed that all sequenced variants, in aggregate, significantly increased the risk of premature CAD (P-skat = 0.037). Individually, the p.S19W variant was significantly associated with risk of premature CAD (OR = 2.30, P = 0.008) in an independent set of 342 premature CAD patients and 537 controls after adjusting for covariates of sex, age, hypertension, body mass index, triglycerides (TGs), and total, LDL-, and HDL-cholesterol levels. Meanwhile, p.S19W significantly correlated with HDL-C levels (P = 0.048) and TG levels (P = 0.025). Mediation analysis yielded a mediation effect of p.S19W on risk of premature CAD through HDL-C (OR = 0.98, P = 0.040) and TG (OR = 0.98, P = 0.042), suggesting a causal relationship between p.S19W and premature CAD partially through its effects on HDL-C and TG levels. These results suggest that APOA5 variation regulates TG and HDL levels, thus displaying a causal role in the development of CAD.

Acceleration of Preexisting Aortic Stenosis After Teriparatide Initiation.

Background/Objective: Teriparatide, an osteoanabolic agent similar to parathyroid hormone in properties, is used to manage severe osteoporosis. Aortic valve stenosis is a common valve condition observed in the elderly. Its natural history includes gradual progression toward severity. We present a case of a patient who had rapidly progressive aortic stenosis after teriparatide initiation. Case Report: An 84-year-old woman who was diagnosed with osteoporosis was treated with oral bisphosphonates. When she had spinal compression fractures, she was found to have primary hyperparathyroidism. She underwent parathyroidectomy and was treated with denosumab infusions every 6 months. However, after she experienced bilateral atypical femoral fractures, she was switched to teriparatide daily injections. Her laboratory test results showed a calcium level of 10 mg/dL (reference range, 8.5-10.2 mg/dL), 25-hydroxyvitamin D level of 38.2 ng/mL (reference range, 31.0-80.0 ng/mL), and phosphorus level of 3.3 mg/dL (reference, range, 2.7-4.8 mg/dL). On reviewing echocardiograms before and after teriparatide initiation, we found a rapid progression of her aortic stenosis from moderate to severe based on the mean gradients (23 to 40 mm Hg) and peak velocities (3.09 to 4 m/s), over a span of 10 months. She eventually required valve replacement. Discussion: Natural progression of mild to severe aortic stenosis typically occurs at the rate of 3 to 7 mm Hg per year over several years. Chronic exposure of human valvular endothelial cells to parathyroid hormone can trigger endothelial dysfunction and valvular calcification. Conclusion: In patients with preexisting aortic stenosis, coordination of care with cardiology and echocardiographic monitoring while on therapy may be considered.

Genome-Wide Linkage Analysis of Large Multiple Multigenerational Families Identifies Novel Genetic Loci for Coronary Artery Disease.

Coronary artery disease (CAD) is the leading cause of death, and genetic factors contribute significantly to risk of CAD. This study aims to identify new CAD genetic loci through a large-scale linkage analysis of 24 large and multigenerational families with 433 family members (GeneQuest II). All family members were genotyped with markers spaced by every 10 cM and a model-free nonparametric linkage (NPL-all) analysis was carried out. Two highly significant CAD loci were identified on chromosome 17q21.2 (NPL score of 6.20) and 7p22.2 (NPL score of 5.19). We also identified four loci with significant NPL scores between 4.09 and 4.99 on 2q33.3, 3q29, 5q13.2 and 9q22.33. Similar analyses in individual families confirmed the six significant CAD loci and identified seven new highly significant linkages on 9p24.2, 9q34.2, 12q13.13, 15q26.1, 17q22, 20p12.3, and 22q12.1, and two significant loci on 2q11.2 and 11q14.1. Two loci on 3q29 and 9q22.33 were also successfully replicated in our previous linkage analysis of 428 nuclear families. Moreover, two published risk variants, SNP rs46522 in UBE2Z and SNP rs6725887 in WDR12 by GWAS, were found within the 17q21.2 and 2q33.3 loci. These studies lay a foundation for future identification of causative variants and genes for CAD.