👤 Sadia M Din

Lipoprotein(a) (Lp[a]) can refine atherosclerotic cardiovascular disease risk assessment and guide lipid-lowering therapy intensification (LLTI). However, the association between Lp(a) testing and LLTI across large health systems is not well characterized. Using Veterans Affairs electronic health record data, we conducted a retrospective cohort study of veterans undergoing lipid testing from January 1, 2017, to June 30, 2024. We first compared a 1:1 propensity-matched cohort with concurrent low-density lipoprotein cholesterol (LDL-C) and Lp(a) testing with those with LDL-C testing alone. We then compared veterans with elevated versus nonelevated Lp(a) (>50 versus <50 mg/dL). The primary outcome was LLTI within 12 months, defined as therapy initiation, dose escalation, or addition of another lipid-lowering agent. LDL-C goal attainment (<100 mg/dL primary prevention; <70 mg/dL secondary prevention) was assessed within 12 months. Multivariable logistic regression adjusted for sociodemographic and clinical factors. Among 6 941 840 veterans with LDL-C testing, 10 384 (0.1%) underwent Lp(a) testing. The propensity-matched cohort included 20 768 veterans (mean±SD age, 58.4±15.3 years; 12.4% women; 19.2% Black individuals). Elevated Lp(a) (>50 mg/dL) was present in 25% (n=2562). Lp(a) testing was associated with greater LLTI (odds ratio [OR], 2.11 [95% CI, 1.95-2.29]), LDL-C testing (OR, 1.27 [95% CI, 1.19-1.36]), and LDL-C goal attainment (OR, 1.22 [95% CI, 1.12-1.33]). Compared with Lp(a) <50 mg/dL, Lp(a) >50 mg/dL was associated with increased LLTI (OR, 1.73 [95% CI, 1.55-1.94]). Lp(a) >100 mg/dL was associated with lower LDL-C goal attainment (OR, 0.68 [95% CI, 0.56-0.84]). Lp(a) testing was associated with increased LLTI and LDL-C goal attainment. Elevated Lp(a) identified individuals more likely to undergo LLTI, suggesting testing may motivate preventive treatment optimization. Show less

Monogenic forms of obesity have been identified in ≤10% of severely obese European patients. However, the overall spectrum of deleterious variants (point mutations and structural variants) responsible for childhood severe obesity remains elusive. In this study, we genetically screened 225 severely obese children from consanguineous Pakistani families through a combination of techniques, including an in-house-developed augmented whole-exome sequencing method (CoDE-seq) that enables simultaneous detection of whole-exome copy number variations (CNVs) and point mutations in coding regions. We identified 110 (49%) probands carrying 55 different pathogenic point mutations and CNVs in 13 genes/loci responsible for nonsyndromic and syndromic monofactorial obesity. CoDE-seq also identified 28 rare or novel CNVs associated with intellectual disability in 22 additional obese subjects (10%). Additionally, we highlight variants in candidate genes for obesity warranting further investigation. Altogether, 59% of cases in the studied cohort are likely to have a discrete genetic cause, with 13% of these as a result of CNVs, demonstrating a remarkably higher prevalence of monofactorial obesity than hitherto reported and a plausible overlapping of obesity and intellectual disabilities in several cases. Finally, inbred populations with a high prevalence of obesity provide unique, genetically enriched material in the quest of new genes/variants influencing energy balance. Show less