Genetic Testing in Patients with High Lipoprotein(a): Experience from the UCSD Lipoprotein(a) Specialty Clinic†

Abstract

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis Lipoprotein(a) (Lp(a)) is an inherited and likely causal risk factor for cardiovascular disease (CVD) and aortic stenosis. LPA variants rs10455872 and rs3798220 are present in ∼15% and ∼3% of Caucasians, respectively, and are associated with elevated Lp(a) levels. Genetic testing in clinical practice is emerging as a tool for personalizing risk assessment and treatment decisions [1-3]. Objective/Purpose To explore the role of genetic testing for LPA SNPs and other genetic mutations in patients with elevated Lp(a). Methods In the UC San Diego Lipoprotein(a) Specialty Clinic, next-generation DNA sequencing was performed using the GBinsight Comprehensive Dyslipidemia Panel (GB Lifesciences, San Diego, CA, USA) in 26 patients with Lp(a) ³ 50 mg/dL, evaluating 327 exons and selected single-nucleotide polymorphisms (SNPs) in 129 genes known or suspected to be associated with CVD. Known LPA SNPs and high impact variants in other genes associated with lipid abnormalities were reported as pathogenic/likely pathogenic. Given non-normality, Lp(a) values were compared using a Mann-Whitney U test. Results Among the 26 patients (mean age 61 yrs, 50% women), 14 (53.8%) had LPA SNPs that have been shown to be associated with elevated Lp(a): rs10455872 (minor allele frequency (MAF) 2.2%) occurred in 9 patients (34.6%), and rs3798220 (MAF 5.1%) occurred in 7 patients (26.9%). Two patients (7.7%) had both rs10455872 and rs3798220 LPA SNPs. LPA SNP rs41272112 (MAF 2.2%) was present in 1 patient (3.8%), and rs186696265 (MAF 0.3%) was present in 4 patients (15.4%). Thus, 12 patients (46.2%) with elevated Lp(a) had no known LPA SNPs. Three of those 12 patients had other potential genetic explanations for elevated Lp(a) (compound heterozygote LDLR, APOE e4 homozygote, and a heterozygous likely pathogenic variant in LDLRAP1) (Table). Patients with elevated Lp(a) and at least 1 LPA variant had Lp(a) 166 +/- 92 mg/dL (mean+/-SD) (131.5, 106.75-243 mg/dL (median, IQR)), and those with elevated Lp(a) but without an LPA variant had Lp(a) 105.9 +/- 46 mg/dL (mean+/-SD) (100.5, 65.5-127.25 mg/dL (median, IQR) (p=0.08)). Conclusions Real-world testing for LPA SNPs in a referral Lp(a) specialty practice demonstrates genetic associations of elevated Lp(a) in approximately half of the patients, which is substantially higher than the general population. However, a significant proportion of patients have no known LPA SNPs despite highly elevated Lp(a), suggesting they harbor small apo(a) isoforms. The role of genetic testing at the bedside in such patients is evolving. A dedicated Lp(a) specialty clinic may allow optimal evaluation and management of patients with elevated Lp(a). Nothing to disclose.