👤 Afshin Parsa

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

Insulin resistance (IR) contributes to atherogenic dyslipidemia and elevated ASCVD risk. Apolipoprotein A1 (ApoA1)-associated lipoproteins have diverse anti-atherogenic functions, but it is unclear whether IR drives adverse changes in their proteomic composition. We hypothesized that IR is associated with an atherogenic ApoA1 proteome and that insulin-sensitizing interventions would improve its composition. We studied 861 participants without diabetes (age 47 ± 12 years, 65.5% female). IR was directly measured using the steady-state plasma glucose (SSPG) concentration via the insulin suppression test. ApoA1-associated proteins were quantified by mass spectrometry. A subset underwent interventions for 3 months (N total 108): pioglitazone, PIO Show less

This review aims to explore the epidemiology of lipoprotein(a) [Lp(a)] by its structural and genetic make-up variation amongst ancestry groups. Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein particle, causally implicated in atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). Given its genetic basis, studies have shown marked ancestry-related differences in different races and ethnicities. Lp(a) plasma concentrations vary by more than 100-fold among individuals, primarily due to LPA gene polymorphisms and the number of kringle-IV type 2 (KIV2) repeats, which define apolipoprotein(a) [apo(a)] isoform size. Individuals of African descent have the highest median concentrations, followed by South Asians, with Hispanics/Latinos and East Asians having lower levels. Admixed populations display heterogeneity reflecting genetic ancestry. Despite differences in absolute levels, the relative ASCVD risk per unit increase in Lp(a) is consistent across groups, highlighting the universal atherogenicity of elevated Lp(a). Small apo(a) isoforms are associated with higher Lp(a) concentrations and risk, though isoform size is mainly a surrogate for Lp(a) burden. Despite a strong genetic basis and disproportionate burden in some populations, ancestry-specific testing guidelines are limited and testing rates remain low. Therapies targeting LPA transcription are in development, with outcome trials underway. Integrating ancestry-informed perspectives with universal risk principles is essential for equitable prevention and treatment. Routine, one-time Lp(a) testing enables cost-effective early risk stratification as Lp(a)-directed therapies emerge. Show less

Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of White individuals. Here, we conducted a GWAS of 537 blood metabolites measured in the Chronic Renal Insufficiency Cohort (CRIC) Study, with separate analyses in 822 White and 687 Black study participants. Trans-ethnic meta-analysis was then applied to improve fine-mapping of potential causal variants. Mean estimated glomerular filtration rate was 44.4 and 41.5 mL/min/1.73m Show less

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD. Show less

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney. Show less