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Karin Hek,
Ayse Demirkan,
Jari Lahti,
Antonio Terracciano,
Alexander Teumer,
Marilyn C Cornelis,
Najaf Amin,
Erin Bakshis,
Jens Baumert, Jingzhong Ding, [......],
Katri Räikkönen,
Toshiko Tanaka,
Cornelia M van Duijn,
Hans J Grabe,
Lenore J Launer,
Kathryn L Lunetta,
Thomas H Mosley,
Anne B Newman,
Henning Tiemeier,
Joanne Murabito
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ABSTRACT: BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258). CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
Biological psychiatry 01/2013; · 8.93 Impact Factor
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Daniel I Chasman,
Christian Fuchsberger,
Cristian Pattaro,
Alexander Teumer,
Carsten A Böger,
Karlhans Endlich,
Matthias Olden,
Ming-Huei Chen,
Adrienne Tin,
Daniel Taliun, [......],
Cinzia Sala,
Paul Mitchell,
Marina Ciullo,
Stuart K Kim,
Peter Vollenweider,
Olli Raitakari,
Andres Metspalu,
Colin Palmer,
Paolo Gasparini,
Mario Pirastu
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Nora Franceschini,
Frank J A van Rooij,
Bram P Prins,
Mary F Feitosa,
Mahir Karakas,
John H Eckfeldt,
Aaron R Folsom,
Jeffrey Kopp,
Ahmad Vaez,
Jeanette S Andrews, [......],
Alan F Wright,
Qingyu Wu,
Yongmei Liu,
Nancy S Jenny,
Kari E North,
Janine F Felix,
Behrooz Z Alizadeh,
L Adrienne Cupples,
John R B Perry,
Andrew P Morris
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ABSTRACT: Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.
The American Journal of Human Genetics 09/2012; 91(4):744-753. · 10.60 Impact Factor
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Jie Huang,
Maria Sabater-Lleal,
Folkert W Asselbergs,
David Tregouet,
So-Youn Shin, Jingzhong Ding,
Jens Baumert,
Tiphaine Oudot-Mellakh,
Lasse Folkersen,
Andrew D Johnson, [......],
Per Eriksson,
Francois Cambien,
Cardiogenics Consortium,
Pierre-Emmanuel Morange,
Wolfgang Koenig,
Nicole Soranzo,
Pim van der Harst,
Yongmei Liu,
Christopher J O'Donnell,
Anders Hamsten
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ABSTRACT: We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19,599 subjects, followed by replication analysis of genome-wide significant (P<5x10(-8)) single nucleotide polymorphisms (SNPs) in 10,796 independent samples. We further examined associations with type 2 diabetes (T2D) and coronary artery disease (CAD), assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P=3.4x10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P=3.0x10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P=2.9x10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with T2D and CAD at ARNTL (P<0.05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL, and a SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.
Blood 09/2012; · 9.90 Impact Factor
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Daniel I Chasman,
Christian Fuchsberger,
Cristian Pattaro,
Alexander Teumer,
Carsten A Böger,
Karlhans Endlich,
Matthias Olden,
Ming-Huei Chen,
Adrienne Tin,
Daniel Taliun, [......],
Inga Prokopenko,
Jacqueline Witteman,
Caroline Hayward,
Paul M Ridker,
Afshin Parsa,
Murielle Bochud,
Iris M Heid,
W H Linda Kao,
Caroline S Fox,
Anna Köttgen
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ABSTRACT: In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
Human Molecular Genetics 09/2012; · 7.64 Impact Factor
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ABSTRACT: Associations of adiponectin and leptin and their ratio with body mass index (BMI) and homeostasis model assessment of insulin resistance (HOMA-IR) have been investigated in different ethnic groups but variability in both assays and statistical methods have made cross-study comparisons difficult. We examined associations among these variables across four ethnic groups in a single study.
Adiponectin and leptin were measured in a subset of participants from the Multi-Ethnic Study of Atherosclerosis study. We calculated associations (using both partial correlations and adjusted linear regression) in each ethnic group and then compared the magnitude of these associations across groups.
After we excluded individuals with type 2 diabetes, there were 714 white, 219 Chinese, 332 African-American, and 405 Hispanic subjects in the study sample. Associations of BMI with adiponectin and leptin differed significantly (P < .05) across the ethnic groups in regression analyses, whereas associations of HOMA-IR with adiponectin and leptin did not differ across ethnic groups. The leptin-to-adiponectin ratio was not associated with a greater amount of adiposity or HOMA-IR variance than leptin or adiponectin in any ethnic group.
Given the consistency of HOMA-IR and adipokine associations, the differing means of adiponectin and leptin across ethnic groups may help to explain ethnic differences in mean insulin resistance.
Annals of epidemiology 08/2012; 22(10):705-9. · 2.95 Impact Factor
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Qibin Qi,
Claudia Menzaghi,
Shelly Smith,
Liming Liang,
Nathalie de Rekeneire,
Melissa E Garcia,
Kurt K Lohman,
Iva Miljkovic,
Elsa S Strotmeyer,
Steve R Cummings,
Alka M Kanaya,
Frances A Tylavsky,
Suzanne Satterfield, Jingzhong Ding,
Eric B Rimm,
Vincenzo Trischitta,
Frank B Hu,
Yongmei Liu,
Lu Qi
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ABSTRACT: Resistin is a polypeptide hormone that was reported to be associated with insulin resistance, inflammation and risk of type 2 diabetes and cardiovascular disease. We conducted a genome-wide association (GWA) study on circulating resistin levels in individuals of European ancestry drawn from the two independent studies: the Nurses' Health Study (n = 1590) and the Health, Aging and Body Composition Study (n = 1658). Single-nucleotide polymorphisms (SNPs) identified in the GWA analysis were replicated in an independent cohort of Europeans: the Gargano Family Study (n = 659). We confirmed the association with a previously known locus, the RETN gene (19p13.2), and identified two novel loci near the TYW3/CRYZ gene (1p31) and the NDST4 gene (4q25), associated with resistin levels at a genome-wide significant level, best represented by SNP rs3931020 (P = 6.37 × 10(-12)) and SNP rs13144478 (P = 6.19 × 10(-18)), respectively. Gene expression quantitative trait loci analyses showed a significant cis association between the SNP rs3931020 and CRYZ gene expression levels (P = 3.68 × 10(-7)). We also found that both of these two SNPs were significantly associated with resistin gene (RETN) mRNA levels in white blood cells from 68 subjects with type 2 diabetes (both P = 0.02). In addition, the resistin-rising allele of the TYW3/CRYZ SNP rs3931020, but not the NDST4 SNP rs13144478, showed a consistent association with increased coronary heart disease risk [odds ratio = 1.18 (95% CI, 1.03-1.34); P = 0.01]. Our results suggest that genetic variants in TYW3/CRYZ and NDST4 loci may be involved in the regulation of circulating resistin levels. More studies are needed to verify the associations of the SNP rs13144478 with NDST4 gene expression and resistin-related disease.
Human Molecular Genetics 07/2012; 21(21):4774-80. · 7.64 Impact Factor
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Caroline S Fox,
Charles C White,
Kurt Lohman,
Nancy Heard-Costa,
Paul Cohen,
Yingying Zhang,
Andrew D Johnson,
Valur Emilsson,
Ching-Ti Liu,
Y-D Ida Chen,
Kent D Taylor,
Matthew Allison,
Matthew Budoff,
Jerome I Rotter,
J Jeffrey Carr,
Udo Hoffmann, Jingzhong Ding,
L Adrienne Cupples,
Yongmei Liu
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ABSTRACT: Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. We hypothesized that genetic loci would be associated with pericardial fat independent of other body fat depots. Pericardial fat was quantified in 5,487 individuals of European ancestry from the Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of pericardial fat adjusted for age, sex, weight, and height. A weighted z-score meta-analysis was conducted, and validation was obtained in an additional 3,602 multi-ethnic individuals from the MESA study. We identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7 × 10(-08)). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38), although we observed direction-consistent, nominal significance with visceral fat adjusted for BMI (p = 0.01) in the Framingham Heart Study. Our findings were robust among African ancestry (n = 1,442, p = 0.001), Hispanic (n = 1,399, p = 0.004), and Chinese (n = 761, p = 0.007) participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution.
PLoS Genetics 05/2012; 8(5):e1002705. · 8.69 Impact Factor
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Patrick T Ellinor,
Kathryn L Lunetta,
Christine M Albert,
Nicole L Glazer,
Marylyn D Ritchie,
Albert V Smith,
Dan E Arking,
Martina Müller-Nurasyid,
Bouwe P Krijthe,
Steven A Lubitz, [......],
Bruno H Ch Stricker,
Stephan B Felix,
Alvaro Alonso,
Dawood Darbar,
John Barnard,
Daniel I Chasman,
Susan R Heckbert,
Emelia J Benjamin,
Vilmundur Gudnason,
Stefan Kääb
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ABSTRACT: Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
Nature Genetics 04/2012; 44(6):670-5. · 35.53 Impact Factor
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[show abstract]
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ABSTRACT: Maintaining cognitive function protects older adults from developing functional decline. This study aims to identify the neuroimaging correlates of maintenance of higher global cognition as measured by the Modified Mini Mental State Test (3 MS) score.
Repeated 3 MS measures from 1997-98 through 2006-07 and magnetic resonance imaging with diffusion tensor in 2006-07 were obtained in a biracial cohort of 258 adults free from dementia (mean age 82.9 years, 56% women, 42% blacks). Participants were classified as having shown either maintenance (3 MS slope>0) or decline (3 MS slope<1 SD below the mean) of cognition using linear mixed models. Measures of interest were white matter hyperintensity volume (WMHv) from total brain, volume of the gray matter (GMv) and microstructure (mean diffusivity, MD) for total brain and for brain areas known to be related to memory and executive control function: medial temporal area (hippocampus, parahippocampus and entorhinal cortex), cingulate cortex, dorsolateral prefrontal and posterior parietal cortex.
Differences between cognitive maintainers (n=153) and non-maintainers (n=107) were significant for GMv of the medial temporal area (35.8%, p=0.004) and lower MD of the cingulate cortex (37.9%, p=0.008), but not for other neuroimaging markers. In multivariable regression models adjusted for age, race, WMHv and GMV from the total brain and vascular conditions, each standard deviation of GMv of the medial temporal area and each standard deviation of MD of the cingulate cortex were associated with a nearly 4 times greater probability (odds ratio [standard deviation]: 3.80 [1.16, 12.44]) and a 34% lower probability (0.66, [0.46, 0.97]) of maintaining cognitive function, respectively. In these models neither WMHv nor GMv from total brain were significantly associated with probability of maintaining cognitive function.
Preserving the volume of the medial temporal area and the microstructure of the cingulate cortex may contribute to maintaining cognitive function late in life.
NeuroImage 04/2012; 62(1):307-13. · 5.89 Impact Factor
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Cristian Pattaro,
Anna Köttgen,
Alexander Teumer,
Maija Garnaas,
Carsten A Böger,
Christian Fuchsberger,
Matthias Olden,
Ming-Huei Chen,
Adrienne Tin,
Daniel Taliun, [......],
Jacqueline C M Witteman,
Caroline Hayward,
Paul Ridker,
Afshin Parsa,
Murielle Bochud,
Iris M Heid,
Wolfram Goessling,
Daniel I Chasman,
W H Linda Kao,
Caroline S Fox
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ABSTRACT: Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
PLoS Genetics 03/2012; 8(3):e1002584. · 8.69 Impact Factor
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Nancy S Jenny,
Benjamin French,
Alice M Arnold,
Elsa S Strotmeyer,
Mary Cushman,
Paulo H M Chaves, Jingzhong Ding,
Linda P Fried,
Stephen B Kritchevsky,
Dena E Rifkin,
Mark J Sarnak,
Anne B Newman
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ABSTRACT: Associations of inflammation with age-related pathologies are documented; however, it is not understood how changes in inflammation over time impact healthy aging.
We examined associations of long-term change in C-reactive protein (CRP) and interleukin-6 (IL-6) with concurrent onset of physical and cognitive impairment, subsequent cardiovascular disease (CVD), and mortality in 1,051 participants in the Cardiovascular Health Study All Stars Study. Biomarkers were measured in 1996-1997 and 2005-2006.
In 2005-2006, median age was 84.9 years, 63% were women and 17% non-white; 21% had at least a doubling in CRP over time and 23% had at least a doubling in IL-6. Adjusting for demographics, CVD risk factors, and 1996-1997 CRP level, each doubling in CRP change over 9 years was associated with higher risk of physical or cognitive impairment (odds ratio 1.29; 95% confidence interval 1.15, 1.45). Results were similar for IL-6 (1.45; 1.20, 1.76). A doubling in IL-6 change over time, but not CRP, was associated with incident CVD events; hazard ratio (95% confidence interval) 1.34 (1.03, 1.75). Doubling in change in each biomarker was individually associated with mortality (CRP: 1.12 [1.03, 1.22]; IL-6 1.39 [1.16, 1.65]). In models containing both change and 2005-2006 level, only level was associated with CVD events and mortality.
Although increases in inflammation markers over 9 years were associated with higher concurrent risk of functional impairment and subsequent CVD events and mortality, final levels of each biomarker appeared to be more important in determining risk of subsequent events than change over time.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 02/2012; 67(9):970-6. · 4.60 Impact Factor
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Joanne M Murabito,
Charles C White,
Maryam Kavousi,
Yan V Sun,
Mary F Feitosa,
Vijay Nambi,
Claudia Lamina,
Arne Schillert,
Stefan Coassin,
Joshua C Bis, [......],
H-Erich Wichmann,
James F Wilson,
Jacqueline C M Witteman,
Yongmei Liu,
Caroline Hayward,
Ingrid B Borecki,
Andreas Ziegler,
Kari E North,
L Adrienne Cupples,
Florian Kronenberg
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ABSTRACT: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).
Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.
Circulation Cardiovascular Genetics 12/2011; 5(1):100-12. · 6.11 Impact Factor
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Gary F Mitchell,
Germaine C Verwoert,
Kirill V Tarasov,
Aaron Isaacs,
Albert V Smith,
Yasmin,
Ernst R Rietzschel,
Toshiko Tanaka,
Yongmei Liu,
Afshin Parsa, [......],
John R Cockcroft,
Vilmundur Gudnason,
Guy G De Backer,
Luigi Ferrucci,
Tamara B Harris,
Alan R Shuldiner,
Cornelia M van Duijn,
Daniel Levy,
Edward G Lakatta,
Jacqueline C M Witteman
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ABSTRACT: Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events.
We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3'-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, β=-0.075±0.012 SD/allele, P=2.8×10(-10); replication β=-0.086±0.020 SD/allele, P=1.4×10(-6)). Combined results for rs7152623 from 11 cohorts gave β=-0.076±0.010 SD/allele, P=3.1×10(-15). The association persisted when adjusted for mean arterial pressure (β=-0.060±0.009 SD/allele, P=1.0×10(-11)). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, β=-0.081±0.014 SD/allele, P=2.3×10(-9)) and older (9 cohorts, n=12 026, β=-0.061±0.014 SD/allele, P=9.4×10(-6)) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02-1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03-1.16, P=0.004).
Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.
Circulation Cardiovascular Genetics 11/2011; 5(1):81-90. · 6.11 Impact Factor
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Amidou N'diaye,
Gary K Chen,
Cameron D Palmer,
Bing Ge,
Bamidele Tayo,
Rasika A Mathias, Jingzhong Ding,
Michael A Nalls,
Adebowale Adeyemo,
Véronique Adoue, [......],
Alan B Zonderman,
Michele K Evans,
Yongmei Liu,
Diane M Becker,
Richard S Cooper,
Tomi Pastinen,
Brian E Henderson,
Joel N Hirschhorn,
Guillaume Lettre,
Christopher A Haiman
PLoS Genetics 11/2011; 7(11). · 8.69 Impact Factor
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Amidou N'Diaye,
Gary K Chen,
Cameron D Palmer,
Bing Ge,
Bamidele Tayo,
Rasika A Mathias, Jingzhong Ding,
Michael A Nalls,
Adebowale Adeyemo,
Véronique Adoue, [......],
Alan B Zonderman,
Michele K Evans,
Yongmei Liu,
Diane M Becker,
Richard S Cooper,
Tomi Pastinen,
Brian E Henderson,
Joel N Hirschhorn,
Guillaume Lettre,
Christopher A Haiman
[show abstract]
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ABSTRACT: Adult height is a classic polygenic trait of high heritability (h(2) approximately 0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain approximately10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10(-12) and 2p14-rs4315565, P = 1.2×10(-8)). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10(-4) for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits.
PLoS Genetics 10/2011; 7(10):e1002298. · 8.69 Impact Factor
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Lenore J Launer,
Michael E Miller,
Jeff D Williamson,
Ron M Lazar,
Hertzel C Gerstein,
Anne M Murray,
Mark Sullivan,
Karen R Horowitz, Jingzhong Ding,
Santica Marcovina, [......],
Karen L Margolis,
Patrick O'Connor,
Edward W Lipkin,
Joy Hirsch,
Laura Coker,
Joseph Maldjian,
Jeffrey L Sunshine,
Charles Truwit,
Christos Davatzikos,
R Nick Bryan
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ABSTRACT: People with type 2 diabetes are at risk of cognitive impairment and brain atrophy. We aimed to compare the effects on cognitive function and brain volume of intensive versus standard glycaemic control.
The Memory in Diabetes (MIND) study was done in 52 clinical sites in North America as part of Action to Control Cardiovascular Risk in Diabetes (ACCORD), a double two-by-two factorial parallel group randomised trial. Participants (aged 55-80 years) with type 2 diabetes, high glycated haemoglobin A(1c) (HbA(1c)) concentrations (>7·5%; >58 mmol/mol), and a high risk of cardiovascular events were randomly assigned to receive intensive glycaemic control targeting HbA(1c) to less than 6·0% (42 mmol/mol) or a standard strategy targeting HbA(1c) to 7·0-7·9% (53-63 mmol/mol). Randomisation was via a centralised web-based system and treatment allocation was not masked from clinic staff or participants. We assessed our cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, at baseline and at 20 and 40 months. We assessed total brain volume (TBV), our primary brain structure outcome, with MRI at baseline and 40 months in a subset of participants. We included all participants with follow-up data in our primary analyses. In February, 2008, raised mortality risk led to the end of the intensive treatment and transition of those participants to standard treatment. We tested our cognitive function hypotheses with a mixed-effects model that incorporated information from both the 20 and 40 month outcome measures. We tested our MRI hypotheses with an ANCOVA model that included intracranial volume and factors used to stratify randomisation. This study is registered with ClinicalTrials.gov, number NCT00182910.
We consecutively enrolled 2977 patients (mean age 62·5 years; SD 5·8) who had been randomly assigned to treatment groups in the ACCORD study. Our primary cognitive analysis was of patients with a 20-month or 40-month DSST score: 1378 assigned to receive intensive treatment and 1416 assigned to receive standard treatment. Of the 614 patients with a baseline MRI, we included 230 assigned to receive intensive treatment and 273 assigned to receive standard treatment in our primary MRI analysis at 40 months. There was no significant treatment difference in mean 40-month DSST score (difference in mean 0·32, 95% CI -0·28 to 0·91; p=0·2997). The intensive-treatment group had a greater mean TBV than the standard-treatment group (4·62, 2·0 to 7·3; p=0·0007).
Although significant differences in TBV favoured the intensive treatment, cognitive outcomes were not different. Combined with the non-significant effects on other ACCORD outcomes, and increased mortality in participants in the intensive treatment group, our findings do not support the use of intensive therapy to reduce the adverse effects of diabetes on the brain in patients with similar characteristics to those of our participants.
US National Institute on Aging and US National Heart, Lung, and Blood Institute.
The Lancet Neurology 09/2011; 10(11):969-77. · 23.46 Impact Factor
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Ching-Ti Liu,
Maija K Garnaas,
Adrienne Tin,
Anna Kottgen,
Nora Franceschini,
Carmen A Peralta,
Ian H de Boer,
Xiaoning Lu,
Elizabeth Atkinson, Jingzhong Ding, [......],
Sharon L R Kardia,
Michele K Evans,
Michael G Shlipak,
Holly Kramer,
Michael F Flessner,
Albert W Dreisbach,
Wolfram Goessling,
L Adrienne Cupples,
W Linda Kao,
Caroline S Fox
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ABSTRACT: Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10(-7)) and FNDC1 (p-value = 3.0×10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6×10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.
PLoS Genetics 09/2011; 7(9):e1002264. · 8.69 Impact Factor
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Cuilian Miao,
Shaoguang Chen, Jingzhong Ding,
Kiang Liu,
Debiao Li,
Robson Macedo,
Shenghan Lai,
Jens Vogel-Claussen,
Elizabeth R Brown,
João A C Lima,
David A Bluemke
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ABSTRACT: To determine the relationship of pericardial fat, which secretes proinflammatory markers that have been implicated in coronary atherosclerosis, with atherosclerotic plaque in an asymptomatic population-based cohort.
In this institutional review board-approved study, all participants supplied written informed consent. One hundred eighty-three participants (89 women, 94 men; mean age, 61 years ± 9 [standard deviation]) from the community-based Multi-Ethnic Study of Atherosclerosis (MESA) were included. The coronary artery eccentricity (ratio of maximal to minimal coronary artery wall thickness) was determined by using magnetic resonance (MR) imaging and served as an index of plaque burden. The pericardial fat volume was determined by using computed tomography. Linear regression coefficient analysis was used to correlate pericardial fat volume with coronary artery wall thickness and plaque eccentricity.
Pericardial fat volume correlated significantly with degree of plaque eccentricity (P < .05) in both men and women. After adjustments for body mass index (BMI) and waist circumference, traditional risk factors, C-reactive protein level, and coronary artery calcium content, the relationship between pericardial fat and plaque eccentricity remained significant in men (P < .01) but not in women. BMI and waist circumference correlated with degree of plaque eccentricity in the univariate model (P < .05) but not after adjustment for pericardial fat volume or traditional risk factors.
Pericardial fat volume, rather than BMI and waist circumference, was more strongly related to plaque eccentricity as a measure of coronary atherosclerotic plaque burden. The results support the proposed role of pericardial fat in association with atherosclerosis.
Radiology 08/2011; 261(1):109-15. · 5.73 Impact Factor
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ABSTRACT: Increased intraperitoneal (IP) fat is associated with increased cardiovascular (CV) risk, but mechanisms for this increase in risk are not completely established. We performed this study to assess whether IP fat is associated with ascending aortic wall thickness (AOWT), a risk factor for CV events. Four hundred and forty-one consecutive participants, aged 55-85 years, with risk factors for CV events underwent magnetic resonance measures of AOWT and abdominal fat (subcutaneous (SC) fat + IP fat). For the ascending aorta, mean wall thickness of the 4th quartile of the IP fat was higher relative to the 1st quartile (P ≤ 0.001). This difference persisted after accounting for SC fat (P ≤ 0.001), as well as age, gender, height, weight, smoking, diabetes, hypertension, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and C-reactive protein (CRP) (P < 0.03). Elevated IP fat volume is associated with an increase in ascending AOWT, a condition that promotes CV events in middle aged and elderly adults.
Obesity 06/2011; 19(9):1784-90. · 4.28 Impact Factor
