Lipoprotein associated phospholipase A2 activity, apolipoprotein C3 loss-of-function variants and cardiovascular disease: The Atherosclerosis Risk In Communities Study

Lipoprotein-associated phospholipase A2 (LpPLA2) activity was associated with higher CHD risk in a meta-analysis, which was partly dependent on circulating lipid levels. Apolipoprotein C3 loss-of-function (ApoC3 LOF) mutations were related with reduced postprandial lipemia and CHD risk. However, the association of LpPLA2 activity with ApoC3 LOF is not known

Association of Exome Sequences With Cardiovascular Traits among Blacks in the Jackson Heart Study

The correlation of null alleles with human phenotypes can provide insight into gene function in humans. In individuals of African ancestry, we set out to identify null and damaging missense variants, and test these variants for association with a range of cardiovascular phenotypes

Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis

(The American Journal of Human Genetics 99, 481–488; August 4, 2016

Genetic Discovery and Risk Characterization in Type 2 Diabetes across Diverse Populations

Genomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in th

Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors

Large-scale exome-wide association analysis identifies loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3 UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases

Discovering the spectrum of genetic architecture influencing coronary artery calcification

Coronary artery calcification (CAC) is directly correlated to the amount of atherosclerotic plaque with atherosclerosis being a major cause of coronary heart disease. The development of CAC is influenced by both genetic and non-genetic risk factors. This work tested for the genetic variants influencing the extent of CAC via three approaches including the interaction with an environmental variable, smoking, as well as testing for common and rare variants. Three sources of genetic data were analyzed in European American participants from the Genetic Epidemiology Network of Arteriopathy (GENOA). The three aims of the study were 1) identify gene by smoking (GxS) interactions associated with the extent of CAC in sibships (N=915) in Genome-Wide Association studies in GENOA and attempt replication in the Framingham Heart Study (N=1025), 2) determine the association of CAC with the oxidative stress pathway by testing common and rare variants in 40 candidate genes and 5 gene families obtained by targeted sequencing (N=270), and 3) identify novel and known associations with CAC in the extreme tails of the distribution (N=228) in common and rare variants of the exome chip array. Analysis of the GxS GWAS utilized a generalized estimating equations (GEE) model to account for the correlation within sibships with interaction tested via cigarette smoking status stratification followed by a t test of the differences between strata. Replication was attempted by identifying gene concordance between suggested genome-wide significant discovery SNPs of GENOA and followed up within a +/- 250 kb window in the Framingham sample, then corrected for multiple testing by the number of linkage disequilibrium blocks within a region. To test associations with genes in the oxidative stress pathway, a suite of rare variant tests were conducted to determine associations of particular gene families as well as if several rare variant tests consistently provided similar results in candidate genes. Finally, participants selected from the extreme tails of the CAC distribution were analyzed with SCORE-Seq for common and rare variants available on the exome chip. Results from GxS GWAS interaction replicated genes included TBC1D4 (p=6.9x10-5) and ADAMTS9 (p=7.1x10 -5). SNPs/genes associated with oxidative stress were a common variant in FBG (p=6.43x10-4) and gene-based tests of rare variants were consistent for NOS1AP (Madsen-Browning Weighted Sum Test p=9.50x10-5) of the nitric oxide synthase family as well as the peroxidase genes (Madsen-Browning Weighted Sum Test p=1.02x10-4). The exome chip results yielded a common SNP in PNPLA2 (p=5.06x10-6) and gene-based tests of rare variants yielded ATP6AP1 (EREC test p=1.53x10 -3). Genetic differences in smokers and nonsmokers may help target associations with the extent of CAC unique to a subgroup. In addition, analyses of rare variants may provide novel insights into disease mechanism. Genes involved in inflammatory pathways were associated with CAC and as smoking induces inflammation, it follows that CAC development has inflammatory mediators. To establish causation, future functional studies would be necessary. Genes of the NF-κB axis influencing the OPG/RANKL signaling pathway of bone regulation are promising drug targets for future treatment to reduce CAC, especially in targeted groups with increased risk of cardiovascular disease, type 2 diabetes, rheumatoid arthritis, and chronic kidney disease

Lipoprotein-associated phospholipase A2 and risk of incident peripheral arterial disease: Findings from The Atherosclerosis Risk in Communities study (ARIC)

Background and aimsResults from prospective studies evaluating the relationship between elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and incident peripheral arterial disease (PAD) have been mixed. We investigated whether higher Lp-PLA2 levels are associated with increased risk of incident PAD and whether PLA2G7 gene variants, which result in lower Lp-PLA2 levels, are associated with reduced risk of incident PAD.MethodsOur analysis included 9922 participants (56% female; 21% African-American; mean age 63 years) without baseline PAD at ARIC Visit 4 (1996-1998), who had Lp-PLA2 activity measured and were subsequently followed for the development of PAD, defined by occurrence of a PAD-related hospitalization, through 2012. Cox proportional hazard models were performed to determine the association of Lp-PLA2 levels and PLA2G7 gene variants with incident PAD.ResultsDuring a median follow-up of 14.9 years, we identified 756 incident cases of PAD. In analyses adjusting for age, race, and sex, each standard deviation increment in Lp-PLA2 activity (62 nmol/ml/min) was associated with a higher risk of developing PAD (hazard ratio (HR) 1.17; 95% confidence interval (CI) 1.09, 1.26). This association remained significant after additional adjustment for risk factors, other cardiovascular disease, and medication use, but was strongly attenuated (HR: 1.09; 95% CI 1.00, 1.20). PLA2G7 variants were not associated with a lower risk of PAD in both white carriers (HR: 1.21; 95% CI: 0.17-8.56) and African-American carriers (HR: 0.83; 95% CI: 0.41-1.67), although statistical power was quite limited for this analysis, particularly in whites.ConclusionsWhile higher Lp-PLA2 activity was associated with an increased risk for incident PAD, it is likely a risk marker largely represented by traditional risk factors

Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome

Abstract To comprehensively evaluate a European-American child with severe hypertension, whole-exome sequencing (WES) was performed on the child and parents, which identified causal variation of the proband's early-onset disease. The proband's hypertension was resistant to treatment, requiring a multiple drug regimen including amiloride, spironolactone, and hydrochlorothiazide. We suspected a monogenic form of hypertension because of the persistent hypokalemia with low plasma levels of renin and aldosterone. To address this, we focused on rare functional variants and indels, and performed gene-based tests incorporating linkage scores and allele frequency and filtered on deleterious functional mutations. Drawing upon clinical presentation, 27 genes were selected evidenced to cause monogenic hypertension and matched to the gene-based results. This resulted in the identification of a stop-gain mutation in an epithelial sodium channel (ENaC), SCNN1B, an established Liddle syndrome gene, shared by the child and her father. Interestingly, the father also harbored a missense mutation (p.Trp552Arg) in the α-subunit of the ENaC trimer, SCNN1A, possibly pointing to pseudohypoaldosteronism type I. This case is unique in that we present the early-onset disease and treatment response caused by a canonical stop-gain mutation (p.Arg566 * ) as well as ENaC digenic hits in the father, emphasizing the utility of WES informing precision medicine