Adult human height is one of the classical complex human traits. We searched for sequence variants that affect height by scanning the genomes of 25,174 Icelanders, 2,876 Dutch, 1,770 European ...Americans and 1,148 African Americans. We then combined these results with previously published results from the Diabetes Genetics Initiative on 3,024 Scandinavians and tested a selected subset of SNPs in 5,517 Danes. We identified 27 regions of the genome with one or more sequence variants showing significant association with height. The estimated effects per allele of these variants ranged between 0.3 and 0.6 cm and, taken together, they explain around 3.7% of the population variation in height. The genes neighboring the identified loci cluster in biological processes related to skeletal development and mitosis. Association to three previously reported loci are replicated in our analyses, and the strongest association was with SNPs in the ZBTB38 gene.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We aim to determine, in healthy high-risk adults, the association between subclinical coronary artery disease and white matter hyperintensity (WMH) volume and location, independent of atherosclerotic ...risk factors.
Seven hundred eighty-two asymptomatic first-degree relatives of index cases with early-onset coronary artery disease (<60 years old) from GeneSTAR (Genetic Study of Atherosclerosis Risk) with contemporaneous coronary computed tomography angiography and brain magnetic resonance imaging were analyzed. Multilevel mixed-effects linear regression models, accounting for family structure, evaluated the association of total WMH volume and 3 regions (deep WMH, periventricular WMH PVWMH, or borderzone cuff) with markers of coronary artery disease. Separate models were created for total WMH, deep WMH, PVWMH, and cuff volumes, each, as dependent variables, across coronary computed tomography angiography variables, adjusted for covariates.
Mean age was 51 years ±10, with 58% women and 39% African American people. Participants with any coronary plaque had 52% larger WMH volumes than those without plaque (95% CI, 0.24–0.59). Per 1% greater coronary plaque volume, total WMH volumes were 0.07% larger (95% CI, 0.04–0.10). Every 1% higher total coronary plaque volume was associated with 5.03% larger deep WMH volume (95% CI, 4.67–5.38), 5.10% PVWMH larger volume (95% CI, 4.72–5.48), and 2.74% larger cuff volume (95% CI, 2.38–3.09) with differences in this association when comparing deep WMH to PVWMH (P interaction, 0.001) or cuff (P interaction, <0.001), respectively.
In healthy, high-risk individuals, the presence and volume of coronary artery plaque are associated with larger WMH volumes, appearing the strongest for PVWMH. These findings in high-risk families suggest a disease relationship in 2 different vascular beds, beyond traditional risk factors, possibly due to genetic predisposition.
Platelet aggregation is heritable, and genome-wide association studies have detected strong associations with a common intronic variant of the platelet endothelial aggregation receptor1 (PEAR1) gene ...both in African American and European American individuals. In this study, we used a sequencing approach to identify additional exonic variants in PEAR1 that may also determine variability in platelet aggregation in the GeneSTAR Study. A 0.3 Mb targeted region on chromosome 1q23.1 including the entire PEAR1 gene was Sanger sequenced in 104 subjects (45% male, 49% African American, age = 52±13) selected on the basis of hyper- and hypo- aggregation across three different agonists (collagen, epinephrine, and adenosine diphosphate). Single-variant and multi-variant burden tests for association were performed. Of the 235 variants identified through sequencing, 61 were novel, and three of these were missense variants. More rare variants (MAF<5%) were noted in African Americans compared to European Americans (108 vs. 45). The common intronic GWAS-identified variant (rs12041331) demonstrated the most significant association signal in African Americans (p = 4.020×10(-4)); no association was seen for additional exonic variants in this group. In contrast, multi-variant burden tests indicated that exonic variants play a more significant role in European Americans (p = 0.0099 for the collective coding variants compared to p = 0.0565 for intronic variant rs12041331). Imputation of the individual exonic variants in the rest of the GeneSTAR European American cohort (N = 1,965) supports the results noted in the sequenced discovery sample: p = 3.56×10(-4), 2.27×10(-7), 5.20×10(-5) for coding synonymous variant rs56260937 and collagen, epinephrine and adenosine diphosphate induced platelet aggregation, respectively. Sequencing approaches confirm that a common intronic variant has the strongest association with platelet aggregation in African Americans, and show that exonic variants play an additional role in platelet aggregation in European Americans.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), ...both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 x 10(-7). This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
There is interest in deriving megakaryocytes (MKs) from pluripotent stem cells (iPSC) for biological studies. We previously found that genomic structural integrity and genotype concordance ...is maintained in iPSC‐derived MKs.
Objective
To establish a comprehensive dataset of genes and proteins expressed in iPSC‐derived MKs.
Methods
iPSCs were reprogrammed from peripheral blood mononuclear cells (MNCs) and MKs were derived from the iPSCs in 194 healthy European American and African American subjects. mRNA was isolated and gene expression measured by RNA sequencing. Protein expression was measured in 62 of the subjects using mass spectrometry.
Results and Conclusions
MKs expressed genes and proteins known to be important in MK and platelet function and demonstrated good agreement with previous studies in human MKs derived from CD34+ progenitor cells. The percent of cells expressing the MK markers CD41 and CD42a was consistent in biological replicates, but variable across subjects, suggesting that unidentified subject‐specific factors determine differentiation of MKs from iPSCs. Gene and protein sets important in platelet function were associated with increasing expression of CD41/42a, while those related to more basic cellular functions were associated with lower CD41/42a expression. There was differential gene expression by the sex and race (but not age) of the subject. Numerous genes and proteins were highly expressed in MKs but not known to play a role in MK or platelet function; these represent excellent candidates for future study of hematopoiesis, platelet formation, and/or platelet function.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Serum Lp(a) is a CAD risk factor in persons of European ancestry. Levels are 2-3 fold higher in African Americans (AA) but reported associations with coronary artery disease (CAD) have been ...inconsistent. The relationship of Lp(a) with the extent and severity of subclinical coronary plaque has not been described in African Americans. We screened 269 apparently healthy African Americans for risk factors and coronary plaque using advanced coronary computed tomographic angiography. Total coronary plaque (TCP), noncalcified plaque (NCP), and calcified plaque (CCP) volumes (mm3 ) were quantified using a validated automated method. Lp(a) was measured by ELISA. Multivariable modeling was performed with adjustment for traditional CAD risk factors and intrafamilial correlations. Mean age was 51±11 years and 64% were female. Plaque was present in 41%. Lp(a) was independently associated with total plaque volume log(TCP+1) (p=0.04), 3 vessel and/or left main involvement (p=0.04), and at least one stenosis >50% (p=0.006). Best fit regression analyses showed subjects with Lp(a)>40 mg/dl were 3-fold more likely to have 3-vessel and/or LM disease (95% CI:1.4-6.8, p=0.005) and 4-fold more likely to have stenosis >50% (95% CI: 1.3-15.0, p=0.02). In subjects with plaque (N=110), multivariable models showed Lp(a) level was significantly and independently associated with TCP (p=0.009), NCP (p=0.01), CCP (p=0.003), and affected vessel length (p=0.01). In conclusion, high Lp(a) is strongly associated with coronary plaque volumes, extent, and severity in apparently healthy AA. High levels of Lp(a) may be particularly important in the pathogenesis of CAD in AA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Background Little is known about symptoms and their burden in outpatients with chronic heart failure. Diverse symptoms may be associated with poor heart failure-related quality of life, and ...depression may be related to increased symptoms. Methods and Results The number of symptoms and symptom distress (physical symptoms on the Memorial Symptom Assessment Scale-Short Form), depression (Geriatric Depression Scale-Short Form), and heart failure-related quality of life (Kansas City Cardiomyopathy Questionnaire) were measured cross-sectionally in 60 patients with heart failure from two outpatient cardiology clinics. Patients experienced a mean of nine symptoms in the previous week. More than half reported shortness of breath, lack of energy, pain, feeling drowsy, or dry mouth. In unadjusted analyses, more severe depression was associated with a greater number of symptoms ( r = 0.51, P < .0001) and greater overall symptom distress ( r = 0.58, P < .0001). For each additional depression symptom, the number of symptoms reported increased by 0.6 after adjustment for age, race, and N-terminal pro-brain natriuretic peptide ( P = .01). The number of symptoms accounted for 32% of the variance in quality of life ( P < .0001). Conclusions Patients with heart failure report a large number of distressing symptoms. Depression in patients with heart failure is associated with a greater number of symptoms, which in turn is associated with a decrease in heart failure-related quality of life. Treatment of depression and the diverse symptoms reported by patients with heart failure might significantly improve quality of life.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background The periventricular white matter is more sensitive to the systemic hemodynamic alterations than the deep white matter because of differences in its vascular structure and systemic ...circulation relationship. We hypothesize that periventricular white matter hyperintensity (PVWMH) volume shows greater association than deep white matter hyperintensity (DWMH) volume with vascular properties (VPs) reflecting arterial stiffness and cardiovascular remodeling, indicators of the systemic circulation. Methods and Results A total of 426 participants (age, 59.0±6.1 years; 57.5% women; and 39.7% Black race) in the Genetic Study of Atherosclerosis Risk who were aged ≥50 years and had brain magnetic resonance imaging were studied. VPs included pulse pressure, hypertensive response to exercise, diastolic brachial artery diameter, diastolic common carotid artery diameter, common carotid artery distensibility coefficient, and left ventricular function. The relative associations of VPs with PVWMH and DWMH as multiple measures within the same individual were determined using multilevel linear models. We also determined if age modified the differences in VPs associations with PVWMH and DWMH. Our findings indicated that, within the same subject, PVWMH volume had greater association than DWMH volume with pulse pressure (
=0.002), hypertensive response to exercise (
=0.04), diastolic brachial artery diameter (
=0.012), and diastolic common carotid artery diameter (
=0.04), independent of age and cardiovascular risk factors. The differences of PVWMH versus DWMH associations with VPs did not differ at any age threshold. Conclusions We show, for the first time, that PVWMH has greater association than DWMH, independent of age, with vascular measurements of arterial stiffness and cardiovascular remodeling suggesting that changes in the systemic circulation affect the PVWMH and DWMH differently.
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