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When indicated, guidelines recommend measurement of lipoprotein(a) for cardiovascular risk assessment. However, temporal variability in lipoprotein(a) is not well understood, and it is unclear if repeat testing may help refine risk prediction of coronary artery disease (CAD).The authors examined the stability of repeat lipoprotein(a) measurements and the association between instability in lipoprotein(a) molar concentration with incident CAD.The authors assessed the correlation between baseline and first follow-up measurements of lipoprotein(a) in the UK Biobank (n = 16,017 unrelated individuals). The association between change in lipoprotein(a) molar concentration and incident CAD was assessed among 15,432 participants using Cox proportional hazards models.Baseline and follow-up lipoprotein(a) molar concentration were significantly correlated over a median of 4.42 years (IQR: 3.69-4.93 years; Spearman rho = 0.96; P 0.0001). The correlation between baseline and follow-up lipoprotein(a) molar concentration were stable across time between measurements of 3 (rho = 0.96), 3-4 (rho = 0.97), 4-5 (rho = 0.96), and5 years (rho = 0.96). Although there were negligible-to-modest associations between statin use and changes in lipoprotein(a) molar concentration, statin usage was associated with a significant increase in lipoprotein(a) among individuals with baseline levels ≥70 nmol/L. Follow-up lipoprotein(a) molar concentration was significantly associated with risk of incident CAD (HR per 120 nmol/L: 1.32 [95% CI: 1.16-1.50]; P = 0.0002). However, the delta between follow-up and baseline lipoprotein(a) molar concentration was not significantly associated with incident CAD independent of follow-up lipoprotein(a) (P = 0.98).These findings suggest that, in the absence of therapies substantially altering lipoprotein(a), a single accurate measurement of lipoprotein(a) molar concentration is an efficient method to inform CAD risk.

Background and AimsThe genetic basis and clinical relevance of the classical Fredrickson-Levy-Lees (FLL) dyslipoproteinemia classifications has not been studied in general population-based cohorts. We aimed to evaluate the phenotypic and genetic characteristics of FLL disorders.MethodsAmong UK Biobank participants free of prevalent coronary artery disease (CAD), we used blood lipids and apolipoprotein B concentrations to infer FLL classes (Types I, IIa, IIb, III, IV, and V). For each FLL class, Cox proportional hazards regression estimated risk of incident CAD. Phenome-wide association testing was performed. GWAS were performed, followed by in silico causal gene prioritization and heritability analyses. Prevalence of disruptive Mendelian lipid variants was assessed from whole exome sequencing.ResultsOf 450,636 individuals, 259,289 (57.5%) met criteria for a FLL dyslipoproteinemia: 63 (0.01%) type I; 40,005 (8.9%) type IIa; 94,785 (21.0%) type IIb; 13,998 (3.1%) type III; 110,389 (24.5%) type IV; and 49 (0.01%) type V. Over median 11.1 years follow-up, compared to normolipidemics the type IIb pattern conferred the highest hazard of incident CAD overall (HR 1.92, 95% CI 1.84-2.01, PConclusionsFLL classes have distinct genetic architectures yielding new insights for cardiometabolic disease beyond single lipid analyses.

Coronary artery disease (CAD) remains the leading cause of death despite scientific advances. Elucidating shared CAD/pneumonia pathways may reveal novel insights regarding CAD pathways. We performed genome-wide pleiotropy analyses of CAD and pneumonia, examined the causal effects of the expression of genes near independently replicated SNPs and interacting genes with CAD and pneumonia, and tested interactions between disruptive coding mutations of each pleiotropic gene and smoking status on CAD and pneumonia risks. Identified pleiotropic SNPs were annotated to ADAMTS7 and IL6R . Increased ADAMTS7 expression across tissues consistently showed decreased risk for CAD and increased risk for pneumonia; increased IL6R expression showed increased risk for CAD and decreased risk for pneumonia. We similarly observed opposing CAD/pneumonia effects for NLRP3 . Reduced ADAMTS7 expression conferred a reduced CAD risk without increased pneumonia risk only among never-smokers. Genetic immune-inflammatory axes of CAD linked to respiratory infections implicate ADAMTS7 and IL6R , and related genes.

Introduction: Increased triglycerides (TG) frequently accompanies type 2 diabetes (T2D) mellitus and poor glycemic control. The extent to which genetics influences triglycerides differently in individuals with T2D is not well understood. Methods: We conducted a genome-wide association study (GWAS) of log(TG) stratified by T2D using imputed UKB genotypes with minor allele count>20. We used linear regression model with a leave-one-out cross-validation using REGENIE adjusted for PC1-10, age, age 2 , gender, array-type, and race. We assessed the heterogeneity (I 2 ) between the effects of TG in T2D and non-T2D individuals. We sought replication in the Mass General Brigham Biobank (MGBB). Results: Among 21,176 T2D and 402,944 non-T2D samples, stratified GWAS identified 17 and 45 loci significantly associated with TG levels, respectively. Only one loci exhibited significant genome-wide heterogeneity (I 2 =98.4%; p heterogeneity =2x10 -15 ). The most significantly heterogenous variant was an intronic variant of the HLA-DQB1 gene, where the major allele (frequency 91.3%) was associated with increased TGs among those with T2D but not non-T2D (T2D group: beta=0.066, p-value=3.9x10 -15 ; non-T2D group: beta=-0.002, p-value=0.21). Among 25,136 participants (6,951 T2D cases) of MGBB, we replicated this finding (p heterogeneity =0.01). Conclusions: An intronic variant at HLA-DQB1 significantly associates with increased TGs only in those with T2D.

Introduction: Pneumonia correlates strongly with coronary artery disease (CAD) risk, and influenza vaccination reduces CAD risk in trials. Elucidating shared pathways may elucidate novel insights regarding residual CAD risk. Hypothesis: Genetic alleles exhibit pleiotropy for pneumonia and CAD, and may be leveraged for causal inference. Methods: We performed genome-wide pleiotropy analyses CAD and pneumonia with the PLACO method using summary statistics from CARDIoGRAMplusC4D (CAD) and FinnGen v4 (pneumonia). For genes near independently replicated SNPs (in UK and Mass General Brigham Biobanks) and expressed in GTEx v8 tissues, we examined the causal effects of index and interacting (by STRING) gene expression with CAD and pneumonia through Mendelian randomization (MR). Lastly, we examined for interactions between prioritized SNPs and smoking status on incident CAD and pneumonia risks. Results: Among 115 SNPs with significant genetic pleiotropy between CAD and pneumonia, 90 of them were replicated, and nearby genes ( ADAMTS7 , IL6R ) showed heritable gene expression. Across tissues, increased ADAMTS7 expression consistently showed decreased risk for CAD and increased risk for pneumonia, and increased IL6R expression showed increased risk for CAD and decreased risk for pneumonia. Among genes that interacted closely with ADAMTS7 and IL6R , NLRP3 similarly demonstrated significant causal effects on CAD and pneumonia in the same directions as that of ADAMTS7 . Sensitivity analysis using multiple MR methods yielded consistent results. The presence of ADAMTS7 p.Ser214Pro conferred a significantly reduced risk of CAD among non-smokers but not those who ever smoked ( P interaction 0.01) and a significantly increased risk of pneumonia only among those who ever smoked ( P interaction 0.0003). Conclusions: Genetic immune-inflammatory axes of CAD linked to respiratory infections implicate ADAMTS7 and IL6R , and related genes.

Coronary artery disease (CAD) remains the leading cause of death despite scientific advances. Elucidating shared CAD/pneumonia pathways may reveal novel insights regarding CAD pathways. We performed genome-wide pleiotropy analyses of CAD and pneumonia, examined the causal effects of the expression of genes near independently replicated SNPs and interacting genes with CAD and pneumonia, and tested interactions between disruptive coding mutations of each pleiotropic gene and smoking status on CAD and pneumonia risks. Identified pleiotropic SNPs were annotated to ADAMTS7 and IL6R. Increased ADAMTS7 expression across tissues consistently showed decreased risk for CAD and increased risk for pneumonia; increased IL6R expression showed increased risk for CAD and decreased risk for pneumonia. We similarly observed opposing CAD/pneumonia effects for NLRP3. Reduced ADAMTS7 expression conferred a reduced CAD risk without increased pneumonia risk only among never-smokers. Genetic immune-inflammatory axes of CAD linked to respiratory infections implicate ADAMTS7 and IL6R, and related genes.

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