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1.  Genome-Wide Association Study Identifies Novel Loci Associated With Concentrations of Four Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway: Results from the CHARGE Consortium 
Background
Palmitic acid(16:0), stearic acid(18:0), palmitoleic acid(16:1n-7), and oleic acid(18:1n-9) are major saturated and mono-unsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis (DNL) and are the main saturated and mono-unsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes and coronary heart disease.
Methods and Results
Genome-wide association studies were conducted in 5 population-based cohorts comprising 8,961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these four fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of one or more of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0(P=2.7×10-11) and lower 18:0(P=2.2×10-18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7(P=6.6×10-13) and 18:1n-9(P=2.2×10-32), and lower 18:0(P =1.3×10-20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0(P=2.8×10-9). GCKR(glucokinase regulator, P =9.8×10-10) and HIF1AN(factor inhibiting hypoxia-inducible factor-1, P=5.7×10-9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1(polycystic kidney disease 2-like 1, P=5.7×10-15) and a locus on chromosome 2(not near known genes) were associated with lower 16:1n-7(P=4.1×10-8).
Conclusion
Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of four fatty acids in the DNL pathway. These results expand our knowledge of genetic factors relevant to DNL and fatty acid biology.
doi:10.1161/CIRCGENETICS.112.964619
PMCID: PMC3891054  PMID: 23362303
epidemiology; fatty acids; genome-wide association study
2.  Intake of Fruit Juice and Incidence of Type 2 Diabetes: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(3):e93471.
Background
Several prospective studies have been conducted to examine the relationship between fruit juice intake and risk of incident type 2 diabetes, but results have been mixed. In the present study, we aimed to estimate the association between fruit juice intake and risk of type 2 diabetes.
Methods
PubMed and Embase databases were searched up to December 2013. All prospective cohort studies of fruit juice intake with risk of type 2 diabetes were included. The pooled relative risks (RRs) with 95% confidence intervals (CIs) for highest vs. lowest category of fruit juice intake were estimated using a random-effects model.
Results
A total of four studies (191,686 participants, including 12,375 with type 2 diabetes) investigated the association between sugar-sweetened fruit juice and risk of incident type 2 diabetes, and four studies (137,663 participants and 4,906 cases) investigated the association between 100% fruit juice and risk of incident type 2 diabetes. A higher intake of sugar-sweetened fruit juice was significantly associated with risk of type 2 diabetes (RR = 1.28, 95%CI = 1.04–1.59, p = 0.02), while intake of 100% fruit juice was not associated with risk of developing type 2 diabetes (RR = 1.03, 95% CI = 0.91–1.18, p = 0.62).
Conclusions
Our findings support dietary recommendations to limit sugar-sweetened beverages, such as fruit juice with added sugar, to prevent the development of type 2 diabetes.
doi:10.1371/journal.pone.0093471
PMCID: PMC3969361  PMID: 24682091
3.  Association of SERPINA9 gene variants with carotid artery atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study 
The SNP rs11628722 in the SERPINA9 gene was previously associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. Centerin, the protein encoded by SERPINA9, is involved in maturation and maintenance of naïve B cells, which play a role in atherogenesis. We investigated whether 21 tag SNPs in the SERPINA9 gene are associated with features of carotid artery atherosclerotic plaque measured by magnetic resonance imaging (MRI). Carotid MRI data were obtained from 1,282 European Americans and 341 African Americans of the ARIC Carotid MRI study, which recruited participants from ARIC by a stratified sampling plan that over-sampled participants with carotid intima-media thickening. Five MRI measures, focused on carotid wall volume, wall thickness, and lipid core, were analyzed. Genetic associations between the MRI measurements and each of the 21 SNPs were analyzed in linear regression models with adjustment for sample weights and traditional risk factors. Rs11628722 was tested a priori. In African Americans, rs11628722 was significantly associated with carotid wall volume (p < 0.05). Among the other 20 SNPs, adjusted for multiple testing, rs4905204, which encodes an Ala to Val amino acid change, was significantly associated with maximum wall thickness (p < 0.000625) and suggestively associated with total wall volume (p < 0.0026) in European Americans. In conclusion, SNPs in the SERPINA9 gene showed race-specific associations with characteristics of carotid atherosclerotic plaques. Replications in other populations are needed to validate findings of this study and to establish the SERPINA9 gene as a candidate in the etiology of carotid atherosclerosis.
PMCID: PMC3852645  PMID: 24319541
SERPINA9 gene; carotid atherosclerosis; MRI; genetic association
4.  Effect of 9p21 genetic variation on coronary heart disease is not modified by other risk markers. The Atherosclerosis Risk in Communities (ARIC) Study 
Atherosclerosis  2012;224(2):435-439.
Objective
To determine whether the 9p21 SNP association with coronary heart disease is modified by other classical or novel risk markers.
Methods
The 9p21 SNP (rs10757274) and multiple risk markers were measured in the Atherosclerosis Risk in Communities Study, and incident coronary disease events were ascertained. Effect modification (interaction) of the 9p21 SNP with risk markers was tested in Cox proportional hazard regression models.
Results
The incidence rates of coronary heart disease per 1000 person-years were 14.4, 17.0, and 18.7 for AA, AG, and GG genotypes, yielding hazard ratios of 1.0, 1.20 (95% CI = 1.07-1.36), and 1.34 (95% CI = 1.16-1.53). There was no meaningful evidence of an interaction (all p-interaction > 0.04) between 9p21 SNP and any of 14 other risk markers for coronary heart disease. These included novel markers not previously explored for 9p21 interaction (e.g., cardiac troponin T and N-terminal pro-brain natriuretic peptide).
Conclusion
Our study extends evidence that the 9p21 SNP association with coronary heart disease is not modified by classical or novel risk markers. Our findings therefore rule out additional plausible pathways by which 9p21 might have increased coronary heart disease risk.
doi:10.1016/j.atherosclerosis.2012.08.007
PMCID: PMC3459136  PMID: 22935634
coronary disease; prospective study; 9p21 SNP
5.  Epistatic effects of ACE I/D and AGT gene variants on left ventricular mass in hypertensive patients: The HyperGEN Study 
Journal of human hypertension  2011;26(2):133-140.
Identifying predictors of left ventricular hypertrophy has been an active study topic because of its association with cardiovascular morbidity and mortality. We examined the epistatic effect (gene-gene interaction) of two genes (ACE I/D; AGT -6G-A, M235T, -20A-C) in the renin-angiotension system (RAS) on left ventricular mass (LVM) among hypertensive participants in the HyperGEN study.
Included were 2156 participants aged 20–87 years (60% women, 63% African American). We employed mixed linear regression models to assess main effects of four genetic variants on echocardigraphically determined LVM (indexed for height), and ACE-by-AGT epistatic effects. There was evidence that AGT -6G-A was associated with LVM among white participants: Adjusted mean LVM (g/m2.7) increased with ‘G’ allele copy number (‘AA’:41.2, ‘AG’:42.3, ‘GG’:44.0; p=0.03). There was also evidence of an ACE I/D-by-AGT -20A-C epistatic effect among white participants (interaction p=0.03): Among ACE ‘DD’ participants, AGT -20A-C ‘C’ allele carriers had lower mean LVM than ‘AA’ homozygotes (‘DD/CC’:39.2, ‘DD/AC’:39.9, ‘DD/AA’:43.9), with no similar significant effect among ACE ‘I’ allele carriers (‘ID/CC’:47.2, ‘ID/AC’:43.4, ‘ID/AA’:42.6; ‘II/CC’: NA, ‘II/AC’:41.3, ‘II/AA’:43.1).
These findings indicate that RAS variants in at least two genes may interact to modulate LVM.
doi:10.1038/jhh.2010.131
PMCID: PMC3775641  PMID: 21248783
Left ventricular mass; left ventricular hypertrophy; ACE gene; AGT gene; epistasis; hypertension
6.  Trends in prevalence, awareness, treatment, and control of hypertension among Chinese adults 1991–2009 
International Journal of Cardiology  2012;158(2):326-329.
doi:10.1016/j.ijcard.2012.04.140
PMCID: PMC3374129  PMID: 22626836
Hypertension; China; Prevalence; Awareness; Control; Trend
7.  Association of Genome-Wide Variation with Highly Sensitive Cardiac Troponin-T (hs-cTnT) Levels in European- and African-Americans: A Meta-Analysis from the Atherosclerosis Risk in Communities and the Cardiovascular Health Studies 
Background
High levels of cardiac troponin T measured by a highly sensitive assay (hs-cTnT) are strongly associated with incident coronary heart disease (CHD) and heart failure (HF). No large-scale genome-wide association study (GWAS) of hs-cTnT has been reported to date. We sought to identify novel genetic variants that are associated with hs-cTnT levels.
Methods and Results
We performed a GWAS in 9,491 European-Americans and 2,053 African-Americans free of CHD and HF from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS). GWASs were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum, and then across race strata to produce overall estimates and p-values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374, p = 9.06 × 10−9) near the nuclear receptor coactivator 2 (NCOA2) gene. Over-expression of NCOA2 can be detected in myoblasts An additional analysis using logistic regression and the clinically motivated 99th percentile cut-point detected a significant association at 1q32 (rs10091374, p = 9.06 × 10−8) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated SNPs were not associated with CHD in a large case-control study, but rs12564445 was significantly associated with incident HF in ARIC European-Americans (HR = 1.16, p-value = 0.004).
Conclusions
We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.
doi:10.1161/CIRCGENETICS.112.963058
PMCID: PMC3693561  PMID: 23247143
genetics; genome-wide association study; troponin
8.  Genetic variation in F3 (tissue factor) and the risk of incident venous thrombosis: meta-analysis of 8 studies 
doi:10.1111/j.1538-7836.2012.04665.x
PMCID: PMC3397243  PMID: 22340074
Venous thrombosis; tissue factor; F3; D-dimer; epidemiology; meta-analysis
9.  Pleiotropy and pathway analyses of genetic variants associated with both type 2 diabetes and prostate cancer 
Aims: Epidemiological evidence shows that diabetes is associated with a reduced risk of prostate cancer. The objective of this study was to identify genes that may contribute to both type 2 diabetes and prostate cancer outcomes and the biological pathways these diseases may share. Methods: The Atherosclerosis Risk in Communities (ARIC) Study is a population-based prospective cohort study in four U.S. communities that included a baseline examination in 1987-89 and three follow-up exams at three year intervals. Participants were 45-64 years old at baseline. We conducted a genomewide association (GWA) study of incident type 2 diabetes in males, summarized variation across genetic loci into a polygenic risk score, and determined if that diabetes risk score was also associated with incident prostate cancer in the same study population. Secondarily we conducted a separate GWA study of prostate cancer, performed a pathway analysis of both type 2 diabetes and prostate cancer, and qualitatively determined if any of the biochemical pathways identified were shared between the two outcomes. Results: We found that the polygenic risk score for type 2 diabetes was not statistically significantly associated with prostate cancer. The pathway analysis also found no overlap between pathways associated with type 2 diabetes and prostate cancer. However, it did find that the growth hormone signaling pathway was statistically significantly associated with type 2 diabetes (p=0.0001). Conclusion: The inability of this study to find an association between type 2 diabetes polygenic risk scores with prostate cancer or biological pathways in common suggests that shared genetic variants may not contribute significantly to explaining shared etiology.
PMCID: PMC3612454  PMID: 23565322
Type 2 diabetes; prostate cancer; polygenic risk score; pathway analysis
10.  Hemostatic markers are associated with the risk and prognosis of atrial fibrillation: the ARIC study 
International Journal of Cardiology  2010;155(2):217-222.
Background
Various hemostatic markers are associated with the risk of cardiovascular disease; however, limited information exists on their relationship with the occurrence and prognosis of atrial fibrillation (AF).
Objectives
To assess whether hemostatic markers are associated with the incidence and prognosis of AF.
Methods
We studied 14,858 men and women in the Atherosclerosis Risk in Communities cohort, aged 45–64 and free of AF at baseline (1987–1989). Fibrinogen, von Willebrand factor (vWf), factor VII activity (VIIc), factor VIII activity (VIIIc), protein C, antithrombin III (ATIII), and activated partial thromboplastin time (aPTT) were measured in blood samples at baseline. AF and other cardiovascular outcomes through 2005 were determined following standardized protocols.
Results
During a median follow-up of 16.8 years, 1209 cases of AF were identified. In multivariable Cox models, the hazard ratios (HR) and 95% confidence intervals (CI) of incident AF associated with a 1-standard deviation (SD) increase in each marker were 1.13 (1.07–1.20) for fibrinogen, 1.17 (1.11–1.23) for vWf, 1.17 (1.11–1.24) for factor VIIIc, 0.93 (0.88–1.00) for factor VIIc, 0.98 (0.92–1.04) for protein C, 1.00 (0.94–1.06) for aPTT and 1.00 (0.95–1.06) for ATIII. Greater factor VIIIc, fibrinogen and vWf were consistently associated with a higher risk of cardiovascular outcomes and mortality in those with and without incident AF, while greater protein C was associated with a lower risk of ischemic stroke.
Conclusion
Several hemostatic markers are associated with the incidence of AF independently of other cardiovascular risk factors. Their role in the risk stratification of AF patients should be further studied.
doi:10.1016/j.ijcard.2010.09.051
PMCID: PMC3025309  PMID: 20965585
atrial fibrillation; epidemiology; prognosis; fibrinogen; von Willebrand factor
11.  Relation of Lipid Gene Scores to Longitudinal Trends in Lipid Levels and Incidence of Abnormal Lipid Levels Among Individuals of European Ancestry: The Atherosclerosis Risk in Communities (ARIC) Study 
Background
Multiple genetic loci have been associated with blood lipid levels. We tested the hypothesis that people with an unfavorable lipid gene profile would experience a greater increase in lipid levels and a higher incidence of abnormal lipid levels, relative to those with more favorable lipid gene profiles.
Methods and Results
9,328 European-descent individuals in ARIC (ages 45–64 y) were followed for 9 years. Separate gene scores were created for each lipid phenotype based on 95 loci identified in a published GWAS of >100,000 European-descent individuals. Adjusted linear and survival models were used to estimate associations with lipid levels and incidence of lipid-lowering medication or abnormal lipid levels. Age and sex interactions were also explored. The cross-sectional difference (mg/dL) per one standard deviation (SD) was −1.89 for HDL-C, 9.5 for LDL-C, and 22.8 for triglycerides (p<5 × 10−34 for all). Longitudinally, overall triglyceride levels rose over time, and each SD greater triglyceride gene score was associated with an average increase in triglyceride levels of 0.3 mg/dL (p=0.003) over 3-years. The HDL-C, LDL-C and total cholesterol gene scores were not related to change. All lipid gene scores were positively related to incidence of abnormal lipid levels over follow-up (HRs per SD ranged from 1.15–1.36).
Conclusions
Associations of genetic variants with lipid levels over time are complex, with the triglyceride gene score positively related to change in triglycerides levels. Similar longitudinal results were not observed for LDL-C or HDL-C levels. Unfavorable gene scores were nevertheless related to higher incidence of abnormal levels.
doi:10.1161/CIRCGENETICS.111.959619
PMCID: PMC3288431  PMID: 22057756
lipids; longitudinal trends; gene score; Atherosclerosis Risk in Communities (ARIC)
12.  Effect of genetic variations in Syntaxin Binding Protein-5 and Syntaxin-2 on Von Willebrand Factor concentration and cardiovascular risk 
Background
Elevated von Willebrand Factor (VWF) plasma levels are associated with an increased risk of cardiovascular disease. A meta-analysis of genome wide association studies on VWF identified novel candidate genes, i.e. syntaxin-binding protein 5 (STXBP5) and syntaxin 2 (STX2), which are possibly involved in the secretion of VWF. We investigated whether VWF antigen levels (VWF:Ag), VWF collagen-binding activity (VWF:CB), and the risk of arterial thrombosis are affected by common genetic variations in these genes.
Methods and Results
In 463 young Caucasian subjects (males ≤ 45 years, females ≤ 55 years), who were included one to three months after a first event of arterial thrombosis, and 406 controls, we measured VWF:Ag and VWF:CB. Nine haplotype tagging SNPs of STXBP5 and STX2 were selected and subsequently analysed using linear regression with additive genetic models adjusted for age, sex and ABO blood group. The minor alleles of rs9399599 and rs1039084 in STXBP5 were associated with lower VWF plasma levels and activity, whereas the minor allele of rs7978987 in STX2 was associated with higher VWF plasma levels and activity. The minor alleles of the SNPs in STX2 were associated with a reduced risk of arterial thrombosis (rs1236:OR 0.73 [95%CI 0.59, 0.89], rs7978987:OR 0.81 [95%CI 0.65, 1.00], rs11061158:OR 0.69 [95%CI 0.55, 0.88]).
Conclusion
Genetic variability in STXBP5 and STX2 affects both VWF concentration and activity in young individuals with premature arterial thrombosis. Furthermore, in our study genetic variability in STX2 is associated with the risk of arterial thrombosis. However, at this point the underlying mechanism remains unclear.
doi:10.1161/CIRCGENETICS.110.957407
PMCID: PMC3511837  PMID: 21156930
Von Willebrand Factor; genetics; STX2; STXBP5; cardiovascular diseases
13.  Genetic association analysis highlights new loci that modulate hematological trait variation in Caucasians and African Americans 
Human genetics  2010;129(3):307-317.
Red blood cell, white blood cell, and platelet measures, including their count, sub-type and volume, are important diagnostic and prognostic clinical parameters for several human diseases. To identify novel loci associated with hematological traits, and compare the architecture of these phenotypes between ethnic groups, the CARe Project genotyped 49,094 single nucleotide polymorphisms (SNPs) that capture variation in ~2,100 candidate genes in DNA of 23,439 Caucasians and 7,112 African Americans from five population-based cohorts. We found strong novel associations between erythrocyte phenotypes and the glucose-6 phosphate dehydrogenase (G6PD) A-allele in African Americans (rs1050828, P < 2.0 × 10−13, T-allele associated with lower red blood cell count, hemoglobin, and hematocrit, and higher mean corpuscular volume), and between platelet count and a SNP at the tropomyosin-4 (TPM4) locus (rs8109288, P = 3.0 × 10−7 in Caucasians; P = 3.0 × 10−7 in African Americans, T-allele associated with lower platelet count). We strongly replicated many genetic associations to blood cell phenotypes previously established in Caucasians. A common variant of the α-globin (HBA2-HBA1) locus was associated with red blood cell traits in African Americans, but not in Caucasians (rs1211375, P < 7 × 10−8, A-allele associated with lower hemoglobin, mean corpuscular hemoglobin, and mean corpuscular volume). Our results show similarities but also differences in the genetic regulation of hematological traits in European- and African-derived populations, and highlight the role of natural selection in shaping these differences.
doi:10.1007/s00439-010-0925-1
PMCID: PMC3442357  PMID: 21153663
14.  A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium 
Human Molecular Genetics  2011;20(17):3525-3534.
Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50 000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2 000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16 324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12–13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.
doi:10.1093/hmg/ddr264
PMCID: PMC3153310  PMID: 21676895
15.  Longer legs are associated with greater risk of incident venous thromboembolism independent of total body height: The Longitudinal Study of Thromboembolism Etiology (LITE) 
Thrombosis and haemostasis  2011;106(1):113-120.
Several studies have reported that taller individuals are at greater risk of venous thromboembolism (VTE). We hypothesized that longer leg length would be positively associated with incident VTE, and would explain the height association. LITE ascertained VTE in a prospective population-based sample of 21,860 individuals aged 45 and older. Leg length was measured as standing height minus sitting height. Cox regression models were adjusted for age, race, sex, waist circumference, diabetes, and factor VIII. To evaluate whether leg length was associated with VTE risk independent of height we standardized leg length and height per 1 standard deviation (SD), and then included them simultaneously in Cox regression models. A total of 641 incident VTE cases accrued over a median follow-up of 16 yrs. Participants in the highest quintile of leg length were at 59% (95% CI: 22%-108%) greater risk of VTE, relative to the lowest quintile. For height, risk was 45% (12%-88%) greater for those in the highest quintile, compared to the lowest. When leg length and height were modeled simultaneously leg length remained associated with VTE risk (HR per 1 SD: 1.21 (1.04-1.40) while height was unrelated (HR per 1 SD: 1.00 (0.86-1.16). To conclude, participants with longer legs were at greater risk of incident VTE, and leg length explained the relation of height to VTE. It remains to be established whether this finding is due to greater venous surface area, a larger number of venous valves, or greater hydrostatic pressure among individuals with longer legs.
doi:10.1160/TH11-02-0100
PMCID: PMC3180885  PMID: 21655679
height; leg length; venous thromboembolism; Atherosclerosis Risk in Communities Study (ARIC); Cardiovascular Health Study (CHS)
16.  New gene functions in megakaryopoiesis and platelet formation 
Gieger, Christian | Radhakrishnan, Aparna | Cvejic, Ana | Tang, Weihong | Porcu, Eleonora | Pistis, Giorgio | Serbanovic-Canic, Jovana | Elling, Ulrich | Goodall, Alison H. | Labrune, Yann | Lopez, Lorna M. | Mägi, Reedik | Meacham, Stuart | Okada, Yukinori | Pirastu, Nicola | Sorice, Rossella | Teumer, Alexander | Voss, Katrin | Zhang, Weihua | Ramirez-Solis, Ramiro | Bis, Joshua C. | Ellinghaus, David | Gögele, Martin | Hottenga, Jouke-Jan | Langenberg, Claudia | Kovacs, Peter | O’Reilly, Paul F. | Shin, So-Youn | Esko, Tõnu | Hartiala, Jaana | Kanoni, Stavroula | Murgia, Federico | Parsa, Afshin | Stephens, Jonathan | van der Harst, Pim | van der Schoot, C. Ellen | Allayee, Hooman | Attwood, Antony | Balkau, Beverley | Bastardot, François | Basu, Saonli | Baumeister, Sebastian E. | Biino, Ginevra | Bomba, Lorenzo | Bonnefond, Amélie | Cambien, François | Chambers, John C. | Cucca, Francesco | D’Adamo, Pio | Davies, Gail | de Boer, Rudolf A. | de Geus, Eco J. C. | Döring, Angela | Elliott, Paul | Erdmann, Jeanette | Evans, David M. | Falchi, Mario | Feng, Wei | Folsom, Aaron R. | Frazer, Ian H. | Gibson, Quince D. | Glazer, Nicole L. | Hammond, Chris | Hartikainen, Anna-Liisa | Heckbert, Susan R. | Hengstenberg, Christian | Hersch, Micha | Illig, Thomas | Loos, Ruth J. F. | Jolley, Jennifer | Khaw, Kay Tee | Kühnel, Brigitte | Kyrtsonis, Marie-Christine | Lagou, Vasiliki | Lloyd-Jones, Heather | Lumley, Thomas | Mangino, Massimo | Maschio, Andrea | Leach, Irene Mateo | McKnight, Barbara | Memari, Yasin | Mitchell, Braxton D. | Montgomery, Grant W. | Nakamura, Yusuke | Nauck, Matthias | Navis, Gerjan | Nöthlings, Ute | Nolte, Ilja M. | Porteous, David J. | Pouta, Anneli | Pramstaller, Peter P. | Pullat, Janne | Ring, Susan M. | Rotter, Jerome I. | Ruggiero, Daniela | Ruokonen, Aimo | Sala, Cinzia | Samani, Nilesh J. | Sambrook, Jennifer | Schlessinger, David | Schreiber, Stefan | Schunkert, Heribert | Scott, James | Smith, Nicholas L. | Snieder, Harold | Starr, John M. | Stumvoll, Michael | Takahashi, Atsushi | Tang, W. H. Wilson | Taylor, Kent | Tenesa, Albert | Thein, Swee Lay | Tönjes, Anke | Uda, Manuela | Ulivi, Sheila | van Veldhuisen, Dirk J. | Visscher, Peter M. | Völker, Uwe | Wichmann, H.-Erich | Wiggins, Kerri L. | Willemsen, Gonneke | Yang, Tsun-Po | Zhao, Jing Hua | Zitting, Paavo | Bradley, John R. | Dedoussis, George V. | Gasparini, Paolo | Hazen, Stanley L. | Metspalu, Andres | Pirastu, Mario | Shuldiner, Alan R. | van Pelt, L. Joost | Zwaginga, Jaap-Jan | Boomsma, Dorret I. | Deary, Ian J. | Franke, Andre | Froguel, Philippe | Ganesh, Santhi K. | Jarvelin, Marjo-Riitta | Martin, Nicholas G. | Meisinger, Christa | Psaty, Bruce M. | Spector, Timothy D. | Wareham, Nicholas J. | Akkerman, Jan-Willem N. | Ciullo, Marina | Deloukas, Panos | Greinacher, Andreas | Jupe, Steve | Kamatani, Naoyuki | Khadake, Jyoti | Kooner, Jaspal S. | Penninger, Josef | Prokopenko, Inga | Stemple, Derek | Toniolo, Daniela | Wernisch, Lorenz | Sanna, Serena | Hicks, Andrew A. | Rendon, Augusto | Ferreira, Manuel A. | Ouwehand, Willem H. | Soranzo, Nicole
Nature  2011;480(7376):201-208.
Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
doi:10.1038/nature10659
PMCID: PMC3335296  PMID: 22139419
17.  Association of Left Ventricular Hypertrophy With Incident Hypertension: The Multi-Ethnic Study of Atherosclerosis 
American Journal of Epidemiology  2011;173(8):898-905.
Increased left ventricular (LV) mass and changes in LV geometry may precede hypertension onset. The authors examined the associations of LV mass and geometry, assessed by cardiac magnetic resonance imaging, with hypertension incidence in 2,567 normotensive participants enrolled in 2000–2002 in the Multi-Ethnic Study of Atherosclerosis, an ethnically diverse, population-based, US study. Over a median follow-up of 4.8 years, 745 (29%) participants developed hypertension. In a fully adjusted model including baseline blood pressure, the relative risks of incident hypertension from the lowest to highest LV mass quartile were 1.00 (referent), 1.13 (95% confidence interval (CI): 0.89, 1.43), 1.28 (95% CI: 1.00, 1.63), and 1.78 (95% CI: 1.38, 2.30) (P < 0.001 for linear trend). Higher levels of LV concentric geometry, defined by higher LV mass to end-diastolic volume quartiles, were associated with higher risk of incident hypertension in a fully adjusted model (P = 0.044 for linear trend). In a final model containing both quartiles of LV mass and LV mass/volume along with all covariates including baseline blood pressure, higher LV mass quartiles were associated with incident hypertension (P < 0.001 for linear trend), whereas higher LV mass/volume quartiles were not (P = 0.643 for linear trend). In this multiethnic cohort, alterations in LV mass preceded hypertension onset among normotensive individuals.
doi:10.1093/aje/kwq509
PMCID: PMC3105258  PMID: 21422061
hypertension; hypertrophy, left ventricular; magnetic resonance imaging; risk factors
18.  A Meta-Analysis and Genome-Wide Association Study of Platelet Count and Mean Platelet Volume in African Americans 
PLoS Genetics  2012;8(3):e1002491.
Several genetic variants associated with platelet count and mean platelet volume (MPV) were recently reported in people of European ancestry. In this meta-analysis of 7 genome-wide association studies (GWAS) enrolling African Americans, our aim was to identify novel genetic variants associated with platelet count and MPV. For all cohorts, GWAS analysis was performed using additive models after adjusting for age, sex, and population stratification. For both platelet phenotypes, meta-analyses were conducted using inverse-variance weighted fixed-effect models. Platelet aggregation assays in whole blood were performed in the participants of the GeneSTAR cohort. Genetic variants in ten independent regions were associated with platelet count (N = 16,388) with p<5×10−8 of which 5 have not been associated with platelet count in previous GWAS. The novel genetic variants associated with platelet count were in the following regions (the most significant SNP, closest gene, and p-value): 6p22 (rs12526480, LRRC16A, p = 9.1×10−9), 7q11 (rs13236689, CD36, p = 2.8×10−9), 10q21 (rs7896518, JMJD1C, p = 2.3×10−12), 11q13 (rs477895, BAD, p = 4.9×10−8), and 20q13 (rs151361, SLMO2, p = 9.4×10−9). Three of these loci (10q21, 11q13, and 20q13) were replicated in European Americans (N = 14,909) and one (11q13) in Hispanic Americans (N = 3,462). For MPV (N = 4,531), genetic variants in 3 regions were significant at p<5×10−8, two of which were also associated with platelet count. Previously reported regions that were also significant in this study were 6p21, 6q23, 7q22, 12q24, and 19p13 for platelet count and 7q22, 17q11, and 19p13 for MPV. The most significant SNP in 1 region was also associated with ADP-induced maximal platelet aggregation in whole blood (12q24). Thus through a meta-analysis of GWAS enrolling African Americans, we have identified 5 novel regions associated with platelet count of which 3 were replicated in other ethnic groups. In addition, we also found one region associated with platelet aggregation that may play a potential role in atherothrombosis.
Author Summary
The majority of the variation in platelet count and mean platelet volume between individuals is heritable. We performed genome-wide association studies in more than 16,000 African American participants from seven population-based cohorts to identify genetic variants that correlate with variation in platelet count and mean platelet volume. We observed statistically significant evidence (p-value<5×10−8) that 10 genomic regions were associated with platelet count and 3 were associated with mean platelet volume. Of the regions that were significantly associated, we found 5 novel regions that were not reported previously in other populations. Three of these 5 regions were also associated with platelet count in European Americans and Hispanic Americans. All these regions contain genes that are either known to have or potentially may have a role in determining platelet count and/or mean platelet volume. We further found that one of these regions was also associated with agonist-induced platelet aggregation. Further studies will determine the exact role played by these genomic regions in platelet biology. The knowledge generated by this and other studies will not only help us better understand platelet biology but can also lead us to the discovery of new anti-platelet drugs.
doi:10.1371/journal.pgen.1002491
PMCID: PMC3299192  PMID: 22423221
19.  Genetic Loci Associated with Plasma Phospholipid n-3 Fatty Acids: A Meta-Analysis of Genome-Wide Association Studies from the CHARGE Consortium 
PLoS Genetics  2011;7(7):e1002193.
Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3×10−64) and lower levels of eicosapentaenoic acid (EPA, p = 5×10−58) and docosapentaenoic acid (DPA, p = 4×10−154). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2×10−12) and DPA (p = 1×10−43) and lower docosahexaenoic acid (DHA, p = 1×10−15). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1×10−8). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.
Author Summary
Circulating long-chain n-3 polyunsaturated fatty acids (PUFAs) derive from fatty fish or from the conversion of the plant n-3 PUFA by elongation and desaturation. We looked for common genetic markers throughout the genome that might influence plasma phospholipid levels of the four major n-3 PUFAs in five large studies and pooled the results. We found that levels of all four n-3 PUFAs were associated with genetic markers in known desaturation and elongation genes. We also found evidence that conversion of the plant n-3 PUFA to longer chain n-3 PUFAs is less effective in people with certain desaturation-gene markers, which could be important for people who do not eat fish. We also found a marker in a gene involved in glucose metabolism, called the glucokinase regulator, to be associated with one intermediate n-3 PUFA. Some of these findings were seen across multiple race/ethnicities. Overall, these results have implications for how genes and the environment interact to influence circulating levels of fatty acids.
doi:10.1371/journal.pgen.1002193
PMCID: PMC3145614  PMID: 21829377
20.  Associations of Lipoprotein Lipase Gene Polymorphisms with Longitudinal Plasma Lipid Trends in Young Adults: the CARDIA Study 
Background
Genome-wide association studies (GWAS) in European Americans have reported several SNPs in the lipoprotein lipase (LPL) gene associated with plasma levels of HDL-C and triglycerides. However, the influences of the LPL SNPs on longitudinal changes of these lipids have not been systematically examined.
Methods and Results
Based on data from 2045 African American and 2116 European American young adults in the CARDIA Study, we investigated cross-sectional and longitudinal associations of lipids with 8 LPL SNPs, including two that have been reported in GWAS. Plasma levels of HDL-C and triglycerides were measured at seven examinations during 20 years of follow-up. In European Americans, rs328 (Ser447Stop), rs326 and rs13702 were significantly associated with cross-sectional interindividual variations in triglycerides and HDL-C (p<0.005) and with their longitudinal changes over time (p < 0.05). The minor alleles in rs326, rs328, and rs13702 that predispose an individual to lower triglycerides and higher HDL-C levels at young adulthood further slow down the trajectory increase in triglycerides and decrease in HDL-C during 20 years of follow-up. In African Americans, these 3 SNPs were significantly associated with triglycerides but only rs326 and rs13702 associated with HDL-C (p<0.008). Rs328 showed a stronger association in European Americans than African Americans and adjustment for it did not remove all of the associations for the other SNPs. Longitudinal changes in either trait did not differ significantly by SNP genotypes in African Americans.
Conclusions
Our data suggest that aging interacts with LPL gene variants to influence the longitudinal lipid variations and there is population-related heterogeneity in the longitudinal associations.
doi:10.1161/CIRCGENETICS.109.913426
PMCID: PMC3004750  PMID: 20150529
lipids; genetics; epidemiology; LPL gene
21.  NOVEL GENETIC VARIANTS CONTRIBUTING TO LEFT VENTRICULAR HYPERTROPHY: THE HYPERGEN STUDY 
Journal of hypertension  2009;27(8):1585-1593.
Objectives
To identify genes contributing to variation in echocardiographic left ventricular (LV) mass and related traits using linkage and linkage disequilibrium analysis in sibships ascertained on hypertension.
Methods
The HyperGEN Study of LV hypertrophy characterized LV mass, relative wall thickness (RWT), and aortic root diameter (ARD) with echocardiograms collected using a standardized protocol at four HyperGEN field centers. A high-throughput scanning fluorescence detector system genotyped 387 polymorphisms distributed throughout the genome. Linkage analyses were conducted once genotyping results became available for 885 siblings from 382 sibships.
Results
Although single LOD score peaks ≥ 1.2 were found on chromosomes 1, 4, 5, 6, 7, 8, 9, 10, 12, 14, 17, and 21, we observed a broad band of peaks in both ethnic groups (white and black) on chromosome 4 and selected candidate genes (NPY1R, NPY2R, NPY5R, SFPR2, CPE, IL15, EDNRA) from this region. Using cases and controls from extremes of the LV mass index, RWT, and ARD distributions, we assessed associations with these phenotypes and haplotype-tagging single nucleotide polymorphisms (SNPs) in the candidates. Among blacks, SNPs in IL15, NPY2R, and NPY5R showed strong evidence for association (p < 0.005); all candidates except EDNRA showed suggestive association (p < 0.05). In whites, NPY2R, NPY5R, and SFRP2 SNPs offered suggestive evidence of association with one or more traits (p < 0.05).
Conclusions
Genetic variation in NPY1R, NPY2R, NPY5R, CPE, IL15, and SFRP2, detected using linkage analysis in hypertensive siblings, was associated with LV phenotypes in blacks and/or whites.
doi:10.1097/HJH.0b013e32832be612
PMCID: PMC2868312  PMID: 19593212
left ventricular hypertrophy; genetics; echocardiography
22.  Association of Novel Genetic Loci with Circulating Fibrinogen Levels: A Genome-Wide Association Study in Six Population-Based Cohorts 
Background
Fibrinogen is both central to blood coagulation and an acute phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels.
Methods and Results
We conducted a genome-wide association analysis on six population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the MONICA/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22,096 participants of European ancestry. Four loci were marked by one or more single nucleotide polymorphisms (SNPs) that demonstrated genome-wide significance (p<5.0×10−8). These included a SNP located in the fibrinogen β chain (FGB) gene and three SNPs representing newly identified loci. The high-signal SNPs were rs1800789 in exon 7 of FGB (p=1.8×10−30), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (p= 1.3×10−15), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (p= 5.9×10−10), and rs1539019 on the NLR family, pyrin domain containing 3 isoforms (NLRP3) gene (p = 1.04×10−8).
Conclusions
Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.
doi:10.1161/CIRCGENETICS.108.825224
PMCID: PMC2764985  PMID: 20031576
genome-wide association; fibrinogen; gene; FGB; IRF1; PCCB; NLRP3
23.  Factor Relationships of Metabolic Syndrome and Echocardiographic Phenotypes in the HyperGEN Study 
Journal of hypertension  2008;26(7):1360-1366.
Metabolic Syndrome (MetS) and its risk factors are predictors of cardiovascular events. MetS is also directly associated with echocardiographic (ECHO) phenotypes. The current study is the first to investigate factors associated with both MetS risk factors and echocardiographic phenotypes and to assess their heritability. Multivariate factor analysis (FA) was performed on 15 traits in 1,393 African Americans and 1,133 Caucasians, as well as stratified by type 2 diabetes mellitus (DM) status. FA with Varimax rotation established four to five latent factors across ethnicities and DM stratifications. Among MetS risk factors, BP was most highly correlated with cardiac traits. The factor domains, ordered by the proportion of variance explained, were “LV wall thickness,” “LV geometry,” “BP,” “body mass index-insulin,” and “lipid-insulin.” FA without any rotation identified special (cross domain) MetS-ECHO factors, “BP-LV geometry” and “BP-LV dimension-wall thickness” in Caucasians. Of the total original risk factors variance, 50%–57% of it was explained by the latent factors. Heritabilities were highest for body mass index-insulin (37–53%), lowest for “BP” factors (15–27%) and intermediate for MetS-ECHO factors. These identified latent factors can be utilized as summary phenotypes in epidemiological, linkage and association studies.
doi:10.1097/HJH.0b013e3282ffdc80
PMCID: PMC2663576  PMID: 18551011
Metabolic syndrome; echocardiography; heritability; factor analysis
24.  Genome-wide association study identifies single-nucleotide polymorphism in KCNB1 associated with left ventricular mass in humans: The HyperGEN Study 
BMC Medical Genetics  2009;10:43.
Background
We conducted a genome-wide association study (GWAS) and validation study for left ventricular (LV) mass in the Family Blood Pressure Program – HyperGEN population. LV mass is a sensitive predictor of cardiovascular mortality and morbidity in all genders, races, and ages. Polymorphisms of candidate genes in diverse pathways have been associated with LV mass. However, subsequent studies have often failed to replicate these associations. Genome-wide association studies have unprecedented power to identify potential genes with modest effects on left LV mass. We describe here a GWAS for LV mass in Caucasians using the Affymetrix GeneChip Human Mapping 100 k Set. Cases (N = 101) and controls (N = 101) were selected from extreme tails of the LV mass index distribution from 906 individuals in the HyperGEN study. Eleven of 12 promising (Q < 0.8) single-nucleotide polymorphisms (SNPs) from the genome-wide study were successfully genotyped using quantitative real time PCR in a validation study.
Results
Despite the relatively small sample, we identified 12 promising SNPs in the GWAS. Eleven SNPs were successfully genotyped in the validation study of 704 Caucasians and 1467 African Americans; 5 SNPs on chromosomes 5, 12, and 20 were significantly (P ≤ 0.05) associated with LV mass after correction for multiple testing. One SNP (rs756529) is intragenic within KCNB1, which is dephosphorylated by calcineurin, a previously reported candidate gene for LV hypertrophy within this population.
Conclusion
These findings suggest KCNB1 may be involved in the development of LV hypertrophy in humans.
doi:10.1186/1471-2350-10-43
PMCID: PMC2692849  PMID: 19454037
25.  Identification of a pleiotropic locus on chromosome 7q for a composite left ventricular wall thickness factor and body mass index: the HyperGEN Study 
BMC Medical Genetics  2009;10:40.
Background
Left ventricular (LV) mass and wall thickness are closely associated with measures of body size and blood pressure and also correlated with systolic and diastolic function, suggesting a contribution of common physiologic mechanisms, including pleiotropic genes, to their covariation.
Methods
Doppler echocardiography was performed in 434 African-American (1344 individuals) and 284 white families (1119 individuals). We conducted a genome-wide linkage scan for LV mass, LV structure and function, and composite factors derived from a factor analysis of LV structure and function in the HyperGEN Study population.
Results
Factor analysis identified (i) a LV wall thickness factor correlated strongly with interventricular septal thickness (IVSTd) and posterior wall thickness (PWTd) and (ii) a LV diastolic filling factor strongly correlated with early and atrial phase peak transmitral filling velocities. The LV phenotypes and composite factor scores were analyzed in multipoint variance components linkage model implemented in SOLAR with 387 microsatellite markers. In whites, the two highest LODs were 3.42 for LV atrial phase peak filling velocity at 144 cM on chromosome 1 and 3.12 for the LV wall thickness factor at 160 cM on chromosome 7. The peak LODs of the component traits (IVSTd and PWTd) clustered at the same region as the composite factor. Adjusting the factor score for body mass index (BMI) substantially reduced the peak LOD at this region (LOD = 1.92). Bivariate linkage analysis of the composite factor with BMI improved LOD to 3.42 at 158 cM. Also in whites, suggestive linkage was observed on chromosomes 2 and 4 for LV mass, chromosomes 3, 5, 10, and 17 for LV atrial phase peak filling velocity, and chromosome 10 for LV diastolic filling factor. In African Americans, suggestive linkage was observed on chromosome 12 for LV mass, chromosome 21 for IVSTd, and chromosome 3 for LV internal diameter at end-diastole.
Conclusion
Our study suggests that a region on chromosome 7 contains pleiotropic genes contributing to the variations of both LV wall thickness and BMI in whites.
doi:10.1186/1471-2350-10-40
PMCID: PMC2692848  PMID: 19426520

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