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

Examining the Incidence of Human Papillomavirus-Associated Head and Neck Cancers by Race and Ethnicity in the U.S., 1995–2005

Background: Head and neck cancer (HNC) incidence, mortality and survival rates vary by sex and race, with men and African Americans disproportionately affected. Risk factors for HNC include tobacco and alcohol exposure, with a recent implication of human papillomavirus (HPV) in the pathogenesis of HNC. This study describes the epidemiology of HNC in the United States, examining variation of rates by age, sex, race/ethnicity and potential HPV-association. Methods: We used the North American Association of Central Cancer Registries (NAACCR) Cancer in North America (CINA) Deluxe Analytic Data to analyze HNC incidence for 1995–2005 from forty population-based cancer registries. We calculated age-adjusted incidence rates and incidence trends using annual percent change by age, sex, race/ethnicity and HPVassociation. Results: Males and Non-Hispanic Blacks experienced greater HNC incidence compared to women and other race/ethnicity groupings. A significant overall increase in HNC incidence was observed among HPV-associated sites during 1995–2005, while non HPV-associated sites experienced a significant decline in HNC incidence. Overall, younger age groups, Non-Hispanic Whites and Hispanics experienced greater increases in incidence for HPV-associated sites, while HNC incidence declined for Non-Hispanic Blacks independent of HPV-association. In particular, for HPV-associated sites, HNC incidence for Non-Hispanic White males aged 45–54 increased at the greatest rate, with an APC of 6.28 % (p,0.05). Among non HPVassociated sites, Non-Hispanic Black males aged 0–44 years experienced the greatest reduction in incidence (APC, 28.17%

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

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

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

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

Annual percent change for age-adjusted HNC incidence rates by age, sex and race/ethnicity for Non HPV-associated sites, 1995–2005.

<p>AAIR: age-adjusted incidence rate; HNC: head and neck cancer; HPV: human papillomavirus; APC: annual percent change; NHW: Non-Hispanic Whites; NHB: Non-Hispanic Blacks. *Rates are significantly different from zero (p<0.05). Rates are per 100,000 and age-adjusted to the 2000 US Standard Population (19 age groups – Census P25-1130). Annual percent change was calculated using the least squares method. Only registries contributing data to the entire 1995–2005 period were used in the analysis.</p