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1.  Visceral and Subcutaneous Fat Quality is Associated with Cardiometabolic Risk 
JACC. Cardiovascular imaging  2013;6(7):762-771.
The aim of this study was to evaluate whether computed tomography (CT) attenuation, as a measure of fat quality, is associated with cardiometabolic risk factors above and beyond fat quantity.
Visceral (VAT) and subcutaneous adipose tissue (SAT) are pathogenic fat depots associated with cardiometabolic risk. Adipose tissue attenuation in CT images is variable, similar to adipose tissue volume. However, whether the quality of abdominal fat attenuation is associated to cardiometabolic risk independent of the quantity is uncertain.
Participants were drawn from the Framingham Heart Study CT sub-study. VAT and SAT volumes were acquired by semi-quantitative assessment. Fat quality was measured by CT attenuation and recorded as mean Hounsfield Units (HU) within each fat depot. Sex-specific linear and logistic multivariable regression models were used to assess the association between standard deviation (SD) decrease in HU and each risk factor.
Lower CT attenuation of VAT and SAT was correlated with higher BMI levels in both sexes. Risk factors were generally more adverse with decreasing HU values. For example, in women, per 1-SD decrease in VAT HU, the odds ratio (OR) was increased for hypertension (OR 1.80), impaired fasting glucose (OR 2.10), metabolic syndrome (OR 3.65) and insulin resistance (OR 3.36) (all p<0.0001). In models that further adjusted for VAT volume, impaired fasting glucose, metabolic syndrome and insulin resistance remained significant. Trends were similar but less pronounced in SAT and in men. There was evidence of an interaction between HU and fat volume among both women and men.
Lower CT attenuation of VAT and SAT is associated with adverse cardiometabolic risk above and beyond total adipose tissue volume. Qualitative indices of abdominal fat depots may provide insight regarding cardiometabolic risk independent of fat quantity.
PMCID: PMC3745280  PMID: 23664720
Obesity; Epidemiology; CT Imaging; Risk Factors
2.  Overlap Between Common Genetic Polymorphisms Underpinning Kidney Traits and Cardiovascular Disease Phenotypes: The CKDGen Consortium 
Chronic kidney disease is associated with cardiovascular disease. We tested for evidence of a shared genetic basis to these traits.
Study Design
We conducted two targeted analyses. First, we examined whether known single nucleotide polymorphisms (SNPs) underpinning kidney traits were associated with a series of vascular phenotypes. Additionally, we tested whether vascular SNPs were associated with markers of kidney damage. Significance was set to 1.5 × 10-4 (0.05/325 tests).
Setting & Participants
Vascular outcomes were analyzed in participants from the AortaGen (20,634), CARDIoGRAM (86,995), CHARGE Eye (15,358), CHARGE IMT (31,181), ICBP (69,395) and NeuroCHARGE (12,385) consortia. Tests for kidney outcomes were conducted in up to 67,093 participants from the CKDGen consortium.
We used 19 kidney SNPs and 64 vascular SNPs.
Outcomes & Measurements
Vascular outcomes tested were blood pressure, coronary artery disease, carotid intima-media thickness, pulse wave velocity, retinal venular caliber and brain white matter lesions. Kidney outcomes were estimated glomerular filtration rate and albuminuria.
In general, we found that kidney disease variants were not associated with vascular phenotypes (127 of 133 tests were non-significant). The one exception was rs653178 near SH2B3 (SH2B adaptor protein 3), which showed direction-consistent association with systolic (p=9.3E-10) and diastolic (p=1.6E-14) blood pressure and coronary artery disease (p=2.2E-6), all previously reported. Similarly, the 64 SNPs associated with vascular phenotypes were not associated with kidney phenotypes (187 of 192 tests were non-significant), with the exception of 2 high-correlated SNPs at the SH2B3 locus (p=1.06E-07 and p=7.05E-08).
Combined effect size of the SNPs for kidney and vascular outcomes may be too low to detect shared genetic associations.
Overall, although we confirmed one locus (SH2B3) as associated with both kidney and cardiovascular disease, our primary findings suggest that there is little overlap between kidney and cardiovascular disease risk variants in the overall population. The reciprocal risks of kidney and cardiovascular disease may not be genetically mediated, but rather a function of the disease milieu itself.
PMCID: PMC3660426  PMID: 23474010
3.  Early-Adulthood Cardiovascular Disease Risk Factor Profiles Among Individuals With and Without Diabetes in the Framingham Heart Study 
Diabetes Care  2013;36(6):1590-1596.
Many studies of diabetes have examined risk factors at the time of diabetes diagnosis instead of considering the lifetime burden of adverse risk factor levels. We examined the 30-year cardiovascular disease (CVD) risk factor burden that participants have up to the time of diabetes diagnosis.
Among participants free of CVD, incident diabetes cases (fasting plasma glucose ≥126 mg/dL or treatment) occurring at examinations 2 through 8 (1979–2008) of the Framingham Heart Study Offspring cohort were age- and sex-matched 1:2 to controls. CVD risk factors (hypertension, high LDL cholesterol, low HDL cholesterol, high triglycerides, obesity) were measured at the time of diabetes diagnosis and at time points 10, 20, and 30 years prior. Conditional logistic regression was used to compare risk factor levels at each time point between diabetes cases and controls.
We identified 525 participants with new-onset diabetes who were matched to 1,049 controls (mean age, 60 years; 40% women). Compared with those without diabetes, individuals who eventually developed diabetes had higher levels of hypertension (odds ratio [OR], 2.2; P = 0.003), high LDL (OR, 1.5; P = 0.04), low HDL (OR, 2.1; P = 0.0001), high triglycerides (OR, 1.7; P = 0.04), and obesity (OR, 3.3; P < 0.0001) at time points 30 years before diabetes diagnosis. After further adjustment for BMI, the ORs for hypertension (OR, 1.9; P = 0.02) and low HDL (OR, 1.7; P = 0.01) remained statistically significant.
CVD risk factors are increased up to 30 years before diagnosis of diabetes. These findings highlight the importance of a life course approach to CVD risk factor identification among individuals at risk for diabetes.
PMCID: PMC3661800  PMID: 23340887
4.  Genetic variation associated with circulating monocyte count in the eMERGE Network 
Human Molecular Genetics  2013;22(10):2119-2127.
With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genome-wide association analyses to identify variants specifically associated with monocyte count in 11 014 subjects in the electronic Medical Records and Genomics Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (P-value = 2.78×10(−16), β = −0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value = 1.88×10(−7), β = 0.30) and a region of replication found in ribophorin I (RPN1) (P-value = 2.63×10(−16), β = −0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA binding protein2 gene that has been previously shown to be associated with coronary heart disease. On chromosome 9, we found a novel association in the prostaglandin reductase 1 gene (P-value = 2.29×10(−7), β = 0.16), which is downstream from lysophosphatidic acid receptor 1. This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (P-value = 5.68×10(−17), β = −0.23) at the integrin, alpha 4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count.
PMCID: PMC3633369  PMID: 23314186
5.  Distribution, Determinants,and Normal Reference Values of Thoracic and Abdominal Aortic Diameters by Computed Tomography (From the Framingham Heart Study) 
The American journal of cardiology  2013;111(10):1510-1516.
Current screening and detection of asymptomatic aortic aneurysms is largely based on uniform cut-point diameters. Our objective was to define normal aortic diameters in asymptomatic men and women in a community-based cohort and to determine the association between aortic diameters and traditional risk factors for cardiovascular disease (CVD).Measurements of the diameter of the ascending aorta(AA), descending thoracic aorta (DTA), infrarenal abdominal (IRA) and lower abdominal aorta (LAA) were acquired from 3,431 Framingham Heart Study participants. Mean diameters were stratified by sex, age, and body surface area (BSA). Univariate associations with risk factor levels were examined and multivariable linear regression analysis was used to assess the significance of covariate-adjusted relations with aortic diameters. For men, the average diameter was 34.1 mm for AA, 25.8 mm for DTA, 19.3 mm for IRA and 18.7 mm for LAA.For women, the average diameter was 31.9 mm for AA, 23.1 mm for DTA, 16.7 mm for IRA, and 16.0 mm for LAA. The mean aorticdiameters were strongly correlated (p<0.0001) with age and BSA in age-adjusted analyses, and these relations remained significant in multivariable regression analyses. Positive associations of diastolic BP with AA and DTA in both sexes and pack years of cigarette smoking with DTA in women and with IRA in men and women were observed. In conclusion, average diameters of the thoracic and abdominal aorta by CT are larger in men compared with women, vary significantly with age and BSA, and are associated with modifiable CVD risk factors including diastolic blood pressure and cigarette smoking.
PMCID: PMC3644324  PMID: 23497775
Aortic diameter; computed tomography; sex; age; body surface area
6.  Risk of type 2 diabetes and cumulative excess weight exposure in the framingham offspring study☆ 
Mid-life obesity is associated with T2D risk. However, less is known about the cumulative effect of obesity during adulthood.
Framingham Offspring Study participants who had an examination at 35±2 years and were initially free of T2D were included in this study (N=1026). A cumulative excess weight (CEW) score (year*kg/m2) was calculated until T2D diagnostic or the end of follow-up.
Eighty-four individuals (8.2%) developed T2D over 20±6 years. Mean CEW scores were 118.0± 114.6 year*kg/m2 in individuals who developed T2D and 30.2±91.4 year*kg/m2 in those who did not develop T2D (P<0.01). T2D risk was doubled for each standard deviation increase in the CEW score (OR= 1.99 [1.64–2.40]; P<0.001). However, CEW score was only significantly associated with T2D incidence for participants with a baseline BMI <25 kg/m2 (OR =2.13 [1.36–3.36]; P <0.001).
Accumulating weight between the mid-thirties to the mid-fifties increases the risk of developing T2D. However, BMI in mid-thirties remains a stronger predictor of T2D risk.
PMCID: PMC3670768  PMID: 23312789
Adults; Aging; BMI; Diagnosis; Epidemiology
7.  Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture 
Berndt, Sonja I. | Gustafsson, Stefan | Mägi, Reedik | Ganna, Andrea | Wheeler, Eleanor | Feitosa, Mary F. | Justice, Anne E. | Monda, Keri L. | Croteau-Chonka, Damien C. | Day, Felix R. | Esko, Tõnu | Fall, Tove | Ferreira, Teresa | Gentilini, Davide | Jackson, Anne U. | Luan, Jian’an | Randall, Joshua C. | Vedantam, Sailaja | Willer, Cristen J. | Winkler, Thomas W. | Wood, Andrew R. | Workalemahu, Tsegaselassie | Hu, Yi-Juan | Lee, Sang Hong | Liang, Liming | Lin, Dan-Yu | Min, Josine L. | Neale, Benjamin M. | Thorleifsson, Gudmar | Yang, Jian | Albrecht, Eva | Amin, Najaf | Bragg-Gresham, Jennifer L. | Cadby, Gemma | den Heijer, Martin | Eklund, Niina | Fischer, Krista | Goel, Anuj | Hottenga, Jouke-Jan | Huffman, Jennifer E. | Jarick, Ivonne | Johansson, Åsa | Johnson, Toby | Kanoni, Stavroula | Kleber, Marcus E. | König, Inke R. | Kristiansson, Kati | Kutalik, Zoltán | Lamina, Claudia | Lecoeur, Cecile | Li, Guo | Mangino, Massimo | McArdle, Wendy L. | Medina-Gomez, Carolina | Müller-Nurasyid, Martina | Ngwa, Julius S. | Nolte, Ilja M. | Paternoster, Lavinia | Pechlivanis, Sonali | Perola, Markus | Peters, Marjolein J. | Preuss, Michael | Rose, Lynda M. | Shi, Jianxin | Shungin, Dmitry | Smith, Albert Vernon | Strawbridge, Rona J. | Surakka, Ida | Teumer, Alexander | Trip, Mieke D. | Tyrer, Jonathan | Van Vliet-Ostaptchouk, Jana V. | Vandenput, Liesbeth | Waite, Lindsay L. | Zhao, Jing Hua | Absher, Devin | Asselbergs, Folkert W. | Atalay, Mustafa | Attwood, Antony P. | Balmforth, Anthony J. | Basart, Hanneke | Beilby, John | Bonnycastle, Lori L. | Brambilla, Paolo | Bruinenberg, Marcel | Campbell, Harry | Chasman, Daniel I. | Chines, Peter S. | Collins, Francis S. | Connell, John M. | Cookson, William | de Faire, Ulf | de Vegt, Femmie | Dei, Mariano | Dimitriou, Maria | Edkins, Sarah | Estrada, Karol | Evans, David M. | Farrall, Martin | Ferrario, Marco M. | Ferrières, Jean | Franke, Lude | Frau, Francesca | Gejman, Pablo V. | Grallert, Harald | Grönberg, Henrik | Gudnason, Vilmundur | Hall, Alistair S. | Hall, Per | Hartikainen, Anna-Liisa | Hayward, Caroline | Heard-Costa, Nancy L. | Heath, Andrew C. | Hebebrand, Johannes | Homuth, Georg | Hu, Frank B. | Hunt, Sarah E. | Hyppönen, Elina | Iribarren, Carlos | Jacobs, Kevin B. | Jansson, John-Olov | Jula, Antti | Kähönen, Mika | Kathiresan, Sekar | Kee, Frank | Khaw, Kay-Tee | Kivimaki, Mika | Koenig, Wolfgang | Kraja, Aldi T. | Kumari, Meena | Kuulasmaa, Kari | Kuusisto, Johanna | Laitinen, Jaana H. | Lakka, Timo A. | Langenberg, Claudia | Launer, Lenore J. | Lind, Lars | Lindström, Jaana | Liu, Jianjun | Liuzzi, Antonio | Lokki, Marja-Liisa | Lorentzon, Mattias | Madden, Pamela A. | Magnusson, Patrik K. | Manunta, Paolo | Marek, Diana | März, Winfried | Mateo Leach, Irene | McKnight, Barbara | Medland, Sarah E. | Mihailov, Evelin | Milani, Lili | Montgomery, Grant W. | Mooser, Vincent | Mühleisen, Thomas W. | Munroe, Patricia B. | Musk, Arthur W. | Narisu, Narisu | Navis, Gerjan | Nicholson, George | Nohr, Ellen A. | Ong, Ken K. | Oostra, Ben A. | Palmer, Colin N.A. | Palotie, Aarno | Peden, John F. | Pedersen, Nancy | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P. | Prokopenko, Inga | Pütter, Carolin | Radhakrishnan, Aparna | Raitakari, Olli | Rendon, Augusto | Rivadeneira, Fernando | Rudan, Igor | Saaristo, Timo E. | Sambrook, Jennifer G. | Sanders, Alan R. | Sanna, Serena | Saramies, Jouko | Schipf, Sabine | Schreiber, Stefan | Schunkert, Heribert | Shin, So-Youn | Signorini, Stefano | Sinisalo, Juha | Skrobek, Boris | Soranzo, Nicole | Stančáková, Alena | Stark, Klaus | Stephens, Jonathan C. | Stirrups, Kathleen | Stolk, Ronald P. | Stumvoll, Michael | Swift, Amy J. | Theodoraki, Eirini V. | Thorand, Barbara | Tregouet, David-Alexandre | Tremoli, Elena | Van der Klauw, Melanie M. | van Meurs, Joyce B.J. | Vermeulen, Sita H. | Viikari, Jorma | Virtamo, Jarmo | Vitart, Veronique | Waeber, Gérard | Wang, Zhaoming | Widén, Elisabeth | Wild, Sarah H. | Willemsen, Gonneke | Winkelmann, Bernhard R. | Witteman, Jacqueline C.M. | Wolffenbuttel, Bruce H.R. | Wong, Andrew | Wright, Alan F. | Zillikens, M. Carola | Amouyel, Philippe | Boehm, Bernhard O. | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Chanock, Stephen J. | Cupples, L. Adrienne | Cusi, Daniele | Dedoussis, George V. | Erdmann, Jeanette | Eriksson, Johan G. | Franks, Paul W. | Froguel, Philippe | Gieger, Christian | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hengstenberg, Christian | Hicks, Andrew A. | Hingorani, Aroon | Hinney, Anke | Hofman, Albert | Hovingh, Kees G. | Hveem, Kristian | Illig, Thomas | Jarvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Keinanen-Kiukaanniemi, Sirkka M. | Kiemeney, Lambertus A. | Kuh, Diana | Laakso, Markku | Lehtimäki, Terho | Levinson, Douglas F. | Martin, Nicholas G. | Metspalu, Andres | Morris, Andrew D. | Nieminen, Markku S. | Njølstad, Inger | Ohlsson, Claes | Oldehinkel, Albertine J. | Ouwehand, Willem H. | Palmer, Lyle J. | Penninx, Brenda | Power, Chris | Province, Michael A. | Psaty, Bruce M. | Qi, Lu | Rauramaa, Rainer | Ridker, Paul M. | Ripatti, Samuli | Salomaa, Veikko | Samani, Nilesh J. | Snieder, Harold | Sørensen, Thorkild I.A. | Spector, Timothy D. | Stefansson, Kari | Tönjes, Anke | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | van der Harst, Pim | Vollenweider, Peter | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Wichmann, H.-Erich | Wilson, James F. | Abecasis, Goncalo R. | Assimes, Themistocles L. | Barroso, Inês | Boehnke, Michael | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Frayling, Timothy | Groop, Leif C. | Haritunian, Talin | Heid, Iris M. | Hunter, David | Kaplan, Robert C. | Karpe, Fredrik | Moffatt, Miriam | Mohlke, Karen L. | O’Connell, Jeffrey R. | Pawitan, Yudi | Schadt, Eric E. | Schlessinger, David | Steinthorsdottir, Valgerdur | Strachan, David P. | Thorsteinsdottir, Unnur | van Duijn, Cornelia M. | Visscher, Peter M. | Di Blasio, Anna Maria | Hirschhorn, Joel N. | Lindgren, Cecilia M. | Morris, Andrew P. | Meyre, David | Scherag, André | McCarthy, Mark I. | Speliotes, Elizabeth K. | North, Kari E. | Loos, Ruth J.F. | Ingelsson, Erik
Nature genetics  2013;45(5):501-512.
Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups.
PMCID: PMC3973018  PMID: 23563607
8.  Intramuscular Fat and Associations with Metabolic Risk Factors in the Framingham Heart Study 
Intramuscular fat accumulates between muscle fibers or within muscle cells. We investigated the association of intramuscular fat with other ectopic fat deposits and metabolic risk factors.
Approach and Results
Participants (n = 2945; 50.2% women; mean age 50.8 years) from the Framingham Heart Study underwent multidetector computed tomography scanning of the abdomen. Regions of interest were placed on the left and right paraspinous muscle and the muscle attenuation (MA) in Hounsfield units were averaged. We examined the association between MA and metabolic risk factors in multivariable models and additionally adjusted for BMI and visceral fat (VAT) in separate models. MA was associated with dysglycemia, dyslipidemia, and hypertension in both sexes. In women, per standard deviation decrease in MA, there was a 1.34 (95% CI 1.10–1.64) increase in the odds of diabetes, a 1.40 (95% CI 1.22 – 1.61) increase in the odds of high triglycerides, and a 1.29 (95% CI 1.12 – 1.48) increase in the odds of hypertension. However, none of these associations persisted after adjustment for BMI or VAT. In men, we observed similar patterns for most risk factors. The exception was metabolic syndrome, which retained association in women even after adjustment for BMI and VAT, and low HDL and high triglycerides in men, whose associations also persisted after adjustment for BMI and VAT.
MA was associated with metabolic risk factors, but most of these associations were lost after adjustment for BMI or VAT. However, a unique association remained for metabolic syndrome in women and lipids in men.
PMCID: PMC3696991  PMID: 23349188
Metabolism; obesity; intramuscular fat; epidemiology
9.  Biomarkers Of Cardiovascular Stress And Incident Chronic Kidney Disease 
Clinical chemistry  2013;59(11):1613-1620.
Growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) are emerging predictors of adverse clinical outcomes. We sought to examine whether circulating concentrations are related to the development of kidney disease in the community.
Plasma GDF-15, sST2, and hsTnI concentrations were measured in 2,614 Framingham Offspring cohort participants (mean age 57 years, 54% women) at the sixth examination cycle (1995–1998). Associations of biomarkers with incident chronic kidney disease (CKD, eGFR<60 ml/min/1.73m2, n=276), microalbuminuria (urinary albumin to creatinine ratio ≥ 25 mg/g in women and 17 mg/g in men, n=191), and rapid decline in renal function (decline in eGFR ≥ 3 ml/min/1.73m2 per year, n=237), were evaluated using multivariable logistic regression; P<0.006 was considered statistically significant in primary analyses.
Participants were followed over a mean of 9.5 years. Higher plasma GDF-15 was associated with incident CKD (multivariable-adjusted OR 1.9 per 1-unit increase in log-GDF-15, 95% CI 1.6–2.3, P<0.0001) and rapid decline in renal function (OR 1.6, 95% CI 1.3–1.8, P<0.0001). GDF-15, sST2, and hsTnI had suggestive associations with incident microalbuminuria but did not meet the pre-specified P-value threshold after multivariable adjustment. Adding plasma GDF-15 to clinical covariates improved risk prediction of incident CKD: the c-statistic increased from 0.826 to 0.845 (P=0.0007), and categorical net reclassification was 6.3% (95% CI 2.7–9.9%).
Higher circulating GDF-15 is associated with incident renal outcomes, and improves risk prediction of incident CKD. These findings may provide insights into mechanisms of renal injury.
PMCID: PMC3972213  PMID: 23873716
Kidney; Risk Factors; Epidemiology
10.  Importance of different types of prior knowledge in selecting genome-wide findings for follow-up 
Genetic epidemiology  2013;37(2):10.1002/gepi.21705.
Biological plausibility and other prior information could help select genome-wide association (GWA) findings for further follow-up, but there is no consensus on which types of knowledge should be considered or how to weight them. We used experts’ opinions and empirical evidence to estimate the relative importance of 15 types of information at the single nucleotide polymorphism (SNP) and gene levels. Opinions were elicited from ten experts using a two-round Delphi survey. Empirical evidence was obtained by comparing the frequency of each type of characteristic in SNPs established as being associated with seven disease traits through GWA meta-analysis and independent replication, with the corresponding frequency in a randomly selected set of SNPs. SNP and gene characteristics were retrieved using a specially developed bioinformatics tool. Both the expert and the empirical evidence rated previous association in a meta-analysis or more than one study as conferring the highest relative probability of true association, while previous association in a single study ranked much lower. High relative probabilities were also observed for location in a functional protein domain, while location in a region evolutionarily conserved in vertebrates was ranked high by the data but not by the experts. Our empirical evidence did not support the importance attributed by the experts to whether the gene encodes a protein in a pathway or shows interactions relevant to the trait. Our findings provide insight into the selection and weighting of different types of knowledge in SNP or gene prioritization, and point to areas requiring further research.
PMCID: PMC3725558  PMID: 23307621
Gene prioritization; Genome-wide association studies; Bioinformatics databases
11.  SNP prioritization using a Bayesian probability of association 
Genetic epidemiology  2012;37(2):10.1002/gepi.21704.
Prioritization is the process whereby a set of possible candidate genes or SNPs is ranked so that the most promising can be taken forward into further studies. In a genome-wide association study, prioritization is usually based on the p-values alone, but researchers sometimes take account of external annotation information about the SNPs such as whether the SNP lies close to a good candidate gene. Using external information in this way is inherently subjective and is often not formalized, making the analysis difficult to reproduce. Building on previous work that has identified fourteen important types of external information, we present an approximate Bayesian analysis that produces an estimate of the probability of association. The calculation combines four sources of information: the genome-wide data, SNP information derived from bioinformatics databases, empirical SNP weights, and the researchers’ subjective prior opinions. The calculation is fast enough that it can be applied to millions of SNPS and although it does rely on subjective judgments, those judgments are made explicit so that the final SNP selection can be reproduced. We show that the resulting probability of association is intuitively more appealing than the p-value because it is easier to interpret and it makes allowance for the power of the study. We illustrate the use of the probability of association for SNP prioritization by applying it to a meta-analysis of kidney function genome-wide association studies and demonstrate that SNP selection performs better using the probability of association compared with p-values alone.
PMCID: PMC3725584  PMID: 23280596
replication; prior knowledge; genome-wide studies
12.  Low Ankle Brachial Index and the Development of Rapid Estimated GFR Decline and CKD 
Low ankle brachial index (ABI) is associated with increases in serum creatinine. Whether low ABI is associated with the development of rapid estimated glomerular filtration rate (eGFR) decline, stage 3 chronic kidney disease (CKD), or microalbuminuria is uncertain.
Study Design
Prospective cohort study.
Setting & Participants
Framingham Offspring cohort participants who attended the sixth (1995-98) and eighth (2005-08) exams.
ABI, categorized as normal (>1.1 to <1.4), low-normal (>0.9 to 1.1), and low (≤0.9).
Rapid eGFR decline (eGFR decline ≥3mL/min/1.73m2 per year), incident stage 3 CKD (eGFR<60mL/min/1.73m2), incident microalbuminuria.
GFR was estimated using the serum creatinine-based CKD-EPI (CKD Epidemiology Collaboration) equation. Urinary albumin-creatinine ratio (UACR) was determined based on spot urine samples.
Over 9.5 years, 9.0% (232 of 2592) experienced rapid eGFR decline and 11.1% (270 of 2426) developed stage 3 CKD. Compared to a normal ABI, low ABI was associated with a 5.73-fold increased odds of rapid eGFR decline (95% CI, 2.77-11.85; p<0.001) after age, sex, and baseline eGFR adjustment; this persisted after multivariable adjustment for standard CKD risk factors (OR, 3.60; 95% CI, 1.65-7.87; p=0.001). After adjustment for age, sex, and baseline eGFR, low ABI was associated with a 2.51-fold increased odds of stage 3 CKD (OR, 2.51; 95% CI, 1.16-5.44; p=0.02), although this was attenuated after multivariable adjustment (OR, 1.68; 95% CI, 0.75-3.76; p=0.2). Among 1902 free of baseline microalbuminuria, low ABI was associated with an increased odds of microalbuminuria after adjustment for age, sex, and baseline UACR (OR, 2.81; 95% CI, 1.07-7.37; p=0.04), with attenuation upon further adjustment (OR, 1.88; p=0.1).
Limited number of events with a low ABI. Outcomes based on single serum creatinine and UACR measurements at each exam.
Low ABI is associated with an increased risk of rapid eGFR decline, suggesting that systemic atherosclerosis predicts decline in kidney function.
PMCID: PMC3517695  PMID: 22901770
13.  Depressive symptoms are associated with visceral adiposity in a community-based sample of middle-aged women and men 
Obesity (Silver Spring, Md.)  2013;21(8):1713-1719.
To examine the relation between measures of adiposity and depressive symptoms in a large well characterized community-based sample, we examined the relations of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) to depressive symptoms in 1581 women (mean age 52.2 years) and 1718 men (mean age 49.8 years) in the Framingham Heart Study. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression (CES-D) scale. Regression models were created to examine the association between each fat depot (exposure) and depressive symptoms (outcome). Sex specific models were adjusted for age, body mass index, smoking, alcohol consumption, diabetes, hypertension, total and HDL cholesterol, lipid lowering treatment, CVD, menopause, C-reactive protein, and physical activity. Mean CES-D scores were 6.8 and 5.6 in women and men. High levels of depressive symptoms were present in 22.5% of women and 12.3% of men. In women, one standard deviation increase in VAT was associated with a 1.3 point higher CES-D score after adjusting for age and BMI (p<0.01) and remained significant in the fully adjusted model (p=0.03). The odds ratio of depressive symptoms per 1 standard deviation increase in VAT in women was 1.33 (p=0.015); results were attenuated in fully adjusted models (OR 1.29, p=0.055). In men, the association between VAT and CES-D score and depressive symptoms was not significant. SAT was not associated with CES-D score or depressive symptoms. This study supports an association between VAT and depressive symptoms in women. Further work is needed to uncover the complex biologic mechanisms mediating the association.
PMCID: PMC3748158  PMID: 23666906
14.  Relation of Circulating Liver Transaminase Concentrations to Risk of New-onset Atrial Fibrillation 
The American journal of cardiology  2012;111(2):219-224.
Heart failure, a strong risk factor for atrial fibrillation (AF), often is accompanied by elevated liver transaminases. We hypothesized that elevated transaminases are associated with the risk of incident AF in the community. We studied 3,744 participants (mean age 65 ± 10 years, 56.8% women) of the Framingham Heart Study Original and Offspring cohorts, free of clinical heart failure. We examined Cox proportional hazards models adjusted for standard AF risk factors (age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, anti-hypertensive treatment, smoking, diabetes, valvular heart disease, alcohol consumption) to investigate associations between baseline serum transaminase levels [alanine transaminase (ALT), aspartate transaminase (AST)] and incidence of AF in up to 10 years (29,099 person years) follow-up. During follow-up, 383 individuals developed AF. Both transaminases were significantly associated with greater risk of incident AF (hazard ratio expressed per standard deviation of natural logarithmically transformed biomarker: ALT hazard ratio 1.19, 95% confidence interval 1.07 to1.32, p = 0.002; AST hazard ratio 1.12, 95% confidence interval 1.01 to1.24, p = 0.03). The associations between transaminases and AF remained consistent after exclusion of participants with moderate-to-severe alcohol consumption. However, when added to known risk factors for AF, ALT and AST only subtly improved the prediction of AF. In conclusion, elevated transaminase concentrations are associated with increased AF incidence. The mechanisms by which higher mean transaminase concentrations are associated with incident AF remain to be determined.
PMCID: PMC3538882  PMID: 23127690
atrial fibrillation; biomarker; risk factors; liver function tests
16.  Aminotransferase Levels are Associated with Cardiometabolic Risk above and beyond Visceral Fat and Insulin Resistance: The Framingham Heart Study 
We sought to characterize associations between aminotransferase levels and cardiometabolic risk after accounting for visceral adipose tissue (VAT) and insulin resistance.
Methods and Results
Participants (n=2621) from the Framingham Heart Study (mean age 51, 49.8% women) were included. Sex-specific linear and logistic regressions were used to evaluate associations between aminotransferase levels and cardiometabolic risk factors. In multivariable models, increased ALT levels were associated with elevated blood pressure, fasting plasma glucose, and triglycerides and lower HDL levels (all p ≤ 0.007). Further, each 1 standard deviation (SD) increase in ALT corresponded to an increased odds of hypertension, diabetes, the metabolic syndrome, impaired fasting glucose, and insulin resistance estimated by HOMA-IR (OR 1.29–1.85, all p ≤ 0.002). Associations with ALT persisted after additional adjustment for VAT, insulin resistance, and BMI with the exception of HDL cholesterol in both sexes and blood pressure in women. Results were materially unchanged when moderate drinkers were excluded, when the sample was restricted to those with ALT<40 U/L, and when the sample was restricted to those without diabetes. Similar trends were observed for AST levels, but associations were more modest.
Aminotransferase levels are correlated with multiple cardiometabolic risk factors above and beyond VAT and insulin resistance.
PMCID: PMC3593729  PMID: 23162012
liver function tests; obesity; visceral fat; insulin resistance; cardiometabolic risk factors
17.  Yogurt consumption is associated with better diet quality and metabolic profile in American men and women 
The evidence-based Dietary Guidelines for Americans recommends increasing the intake of fat-free or low-fat milk and milk products. However, yogurt, a nutrient-dense milk product, has been understudied. This cross-sectional study examined whether yogurt consumption was associated with better diet quality and metabolic profile among adults (n = 6526) participating in the Framingham Heart Study Offspring (1998-2001) and Third Generation (2002-2005) cohorts. A validated food frequency questionnaire was used to assess dietary intake, and the Dietary Guidelines Adherence Index (DGAI) was used to measure overall diet quality. Standardized clinical examinations and laboratory tests were conducted. Generalized estimating equations examined the associations of yogurt consumption with diet quality and levels of metabolic factors. Approximately 64% of women (vs 41% of men) were yogurt consumers (ie, consumed >0 servings/week). Yogurt consumers had a higher DGAI score (ie, better diet quality) than nonconsumers. Adjusted for demographic and lifestyle factors and DGAI, yogurt consumers, compared with nonconsumers, had higher potassium intakes (difference, 0.12 g/d) and were 47%, 55%, 48%, 38%, and 34% less likely to have inadequate intakes (based on Dietary Reference Intake) of vitamins B2 and B12, calcium, magnesium, and zinc, respectively (all P ≤ .001). In addition, yogurt consumption was associated with lower levels of circulating triglycerides, glucose, and lower systolic blood pressure and insulin resistance (all P < .05). Yogurt is a good source of several micronutrients and may help to improve diet quality and maintain metabolic well-being as part of a healthy, energy-balanced dietary pattern.
PMCID: PMC3606818  PMID: 23351406
Yogurt; Milk; Diet; Nutrition status; Metabolic profile; Human
18.  Thoracic Periaortic and Visceral Adipose Tissue and Their Cross-sectional Associations with Measures of Vascular Function 
Obesity (Silver Spring, Md.)  2013;21(7):1496-1503.
Perivascular fat may have a local adverse effect on the vasculature. We evaluated whether thoracic periaortic adipose tissue (TAT), a type of perivascular fat, and visceral adipose tissue (VAT) are associated with vascular function.
Design and Methods
TAT and VAT were quantified in Framingham Heart Study participants using multidetector computed tomography; vascular function was assessed using brachial artery vasodilator function, peripheral arterial tone and arterial tonometry (n= 2735, 48% women, mean age 50 years, mean BMI 27.7 kg/m2). Using multiple linear regression, we examined relations between TAT, VAT, and vascular measures while adjusting for cardiovascular risk factors.
Mean TAT and VAT volumes were 13.2 and 1763 cm3. TAT and VAT were associated with multiple vascular function measures after multivariable adjustment. After BMI adjustment, TAT and VAT remained negatively associated with peripheral arterial tone and inverse carotid femoral pulse wave velocity (p<0.02); TAT was negatively associated with hyperemic mean flow velocity (p=0.03). Associations of TAT with vascular function were attenuated after VAT adjustment (all p>0.06).
Thoracic periaortic and visceral fat are associated with microvascular function and large artery stiffness after BMI adjustment. These findings support the growing recognition of associations between ectopic fat and vascular function.
PMCID: PMC3742564  PMID: 23754461
obesity; vascular function; arterial stiffness; perivascular adipose tissue; visceral adipose tissue
19.  Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function 
Chasman, Daniel I. | Fuchsberger, Christian | Pattaro, Cristian | Teumer, Alexander | Böger, Carsten A. | Endlich, Karlhans | Olden, Matthias | Chen, Ming-Huei | Tin, Adrienne | Taliun, Daniel | Li, Man | Gao, Xiaoyi | Gorski, Mathias | Yang, Qiong | Hundertmark, Claudia | Foster, Meredith C. | O'Seaghdha, Conall M. | Glazer, Nicole | Isaacs, Aaron | Liu, Ching-Ti | Smith, Albert V. | O'Connell, Jeffrey R. | Struchalin, Maksim | Tanaka, Toshiko | Li, Guo | Johnson, Andrew D. | Gierman, Hinco J. | Feitosa, Mary F. | Hwang, Shih-Jen | Atkinson, Elizabeth J. | Lohman, Kurt | Cornelis, Marilyn C. | Johansson, Åsa | Tönjes, Anke | Dehghan, Abbas | Lambert, Jean-Charles | Holliday, Elizabeth G. | Sorice, Rossella | Kutalik, Zoltan | Lehtimäki, Terho | Esko, Tõnu | Deshmukh, Harshal | Ulivi, Sheila | Chu, Audrey Y. | Murgia, Federico | Trompet, Stella | Imboden, Medea | Coassin, Stefan | Pistis, Giorgio | Harris, Tamara B. | Launer, Lenore J. | Aspelund, Thor | Eiriksdottir, Gudny | Mitchell, Braxton D. | Boerwinkle, Eric | Schmidt, Helena | Cavalieri, Margherita | Rao, Madhumathi | Hu, Frank | Demirkan, Ayse | Oostra, Ben A. | de Andrade, Mariza | Turner, Stephen T. | Ding, Jingzhong | Andrews, Jeanette S. | Freedman, Barry I. | Giulianini, Franco | Koenig, Wolfgang | Illig, Thomas | Meisinger, Christa | Gieger, Christian | Zgaga, Lina | Zemunik, Tatijana | Boban, Mladen | Minelli, Cosetta | Wheeler, Heather E. | Igl, Wilmar | Zaboli, Ghazal | Wild, Sarah H. | Wright, Alan F. | Campbell, Harry | Ellinghaus, David | Nöthlings, Ute | Jacobs, Gunnar | Biffar, Reiner | Ernst, Florian | Homuth, Georg | Kroemer, Heyo K. | Nauck, Matthias | Stracke, Sylvia | Völker, Uwe | Völzke, Henry | Kovacs, Peter | Stumvoll, Michael | Mägi, Reedik | Hofman, Albert | Uitterlinden, Andre G. | Rivadeneira, Fernando | Aulchenko, Yurii S. | Polasek, Ozren | Hastie, Nick | Vitart, Veronique | Helmer, Catherine | Wang, Jie Jin | Stengel, Bénédicte | Ruggiero, Daniela | Bergmann, Sven | Kähönen, Mika | Viikari, Jorma | Nikopensius, Tiit | Province, Michael | Ketkar, Shamika | Colhoun, Helen | Doney, Alex | Robino, Antonietta | Krämer, Bernhard K. | Portas, Laura | Ford, Ian | Buckley, Brendan M. | Adam, Martin | Thun, Gian-Andri | Paulweber, Bernhard | Haun, Margot | Sala, Cinzia | Mitchell, Paul | Ciullo, Marina | Kim, Stuart K. | Vollenweider, Peter | Raitakari, Olli | Metspalu, Andres | Palmer, Colin | Gasparini, Paolo | Pirastu, Mario | Jukema, J. Wouter | Probst-Hensch, Nicole M. | Kronenberg, Florian | Toniolo, Daniela | Gudnason, Vilmundur | Shuldiner, Alan R. | Coresh, Josef | Schmidt, Reinhold | Ferrucci, Luigi | Siscovick, David S. | van Duijn, Cornelia M. | Borecki, Ingrid B. | Kardia, Sharon L.R. | Liu, Yongmei | Curhan, Gary C. | Rudan, Igor | Gyllensten, Ulf | Wilson, James F. | Franke, Andre | Pramstaller, Peter P. | Rettig, Rainer | Prokopenko, Inga | Witteman, Jacqueline | Hayward, Caroline | Ridker, Paul M | Parsa, Afshin | Bochud, Murielle | Heid, Iris M. | Kao, W.H. Linda | Fox, Caroline S. | Köttgen, Anna
Human Molecular Genetics  2012;21(24):5329-5343.
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.
PMCID: PMC3607468  PMID: 22962313
20.  Relations of Long-Term and Contemporary Lipid Levels and Lipid Genetic Risk Scores with Coronary Artery Calcium in the Framingham Heart Study 
This study evaluated the association of timing of lipid levels and lipid genetic risk score (GRS) with subclinical atherosclerosis.
Atherosclerosis is a slowly progressive disorder influenced by suboptimal lipid levels. Long-term versus contemporary lipid levels may more strongly impact the development of coronary artery calcium (CAC).
Framingham Heart Study (FHS) Offspring Cohort participants (n=1156, 44%M, 63±9 years) underwent serial fasting lipids [low-density lipoprotein (LDL-C), high-density lipoprotein, and triglycerides], Exam 1 (1971–1975) – Exam 7 (1998–2001). FHS Third Generation Cohort participants (n=1954, 55%M, 45±6 years) had fasting lipid profiles assessed, 2002–2005. Computed tomography (2002–2005) measured CAC. Lipid GRSs were computed from significantly associated single nucleotide polymorphisms. The association between early, long-term average, and contemporary lipids, and lipid GRS, with elevated CAC was assessed using logistic regression.
In FHS Offspring, Exam 1 and long-term average versus Exam 7 lipid measurements, including untreated lipid levels, were strongly associated with elevated CAC. In the FHS Third Generation, contemporary lipids were associated with CAC. The LDL-C GRS was associated with CAC (age/sex-adjusted OR 1.14, 95%CI 1.00–1.29, p=0.04). However, addition of the GRS to the lipid models did not result in a significant increase in the OR or C-statistic for any lipid measure.
Early and long-term average lipid levels, as compared with contemporary measures, are more strongly associated with elevated CAC. Lipid GRS was associated with lipid levels but did not predict elevated CAC. Adult early and long-term average lipid levels provide important information when assessing subclinical atherosclerosis and cardiovascular risk.
PMCID: PMC3702262  PMID: 23141485
Lipids; Genetic risk score; Coronary artery calcium
21.  A Meta-Analysis Identifies New Loci Associated with Body Mass index in Individuals of African Ancestry 
Monda, Keri L. | Chen, Gary K. | Taylor, Kira C. | Palmer, Cameron | Edwards, Todd L. | Lange, Leslie A. | Ng, Maggie C.Y. | Adeyemo, Adebowale A. | Allison, Matthew A. | Bielak, Lawrence F. | Chen, Guanji | Graff, Mariaelisa | Irvin, Marguerite R. | Rhie, Suhn K. | Li, Guo | Liu, Yongmei | Liu, Youfang | Lu, Yingchang | Nalls, Michael A. | Sun, Yan V. | Wojczynski, Mary K. | Yanek, Lisa R. | Aldrich, Melinda C. | Ademola, Adeyinka | Amos, Christopher I. | Bandera, Elisa V. | Bock, Cathryn H. | Britton, Angela | Broeckel, Ulrich | Cai, Quiyin | Caporaso, Neil E. | Carlson, Chris | Carpten, John | Casey, Graham | Chen, Wei-Min | Chen, Fang | Chen, Yii-Der I. | Chiang, Charleston W.K. | Coetzee, Gerhard A. | Demerath, Ellen | Deming-Halverson, Sandra L. | Driver, Ryan W. | Dubbert, Patricia | Feitosa, Mary F. | Freedman, Barry I. | Gillanders, Elizabeth M. | Gottesman, Omri | Guo, Xiuqing | Haritunians, Talin | Harris, Tamara | Harris, Curtis C. | Hennis, Anselm JM | Hernandez, Dena G. | McNeill, Lorna H. | Howard, Timothy D. | Howard, Barbara V. | Howard, Virginia J. | Johnson, Karen C. | Kang, Sun J. | Keating, Brendan J. | Kolb, Suzanne | Kuller, Lewis H. | Kutlar, Abdullah | Langefeld, Carl D. | Lettre, Guillaume | Lohman, Kurt | Lotay, Vaneet | Lyon, Helen | Manson, JoAnn E. | Maixner, William | Meng, Yan A. | Monroe, Kristine R. | Morhason-Bello, Imran | Murphy, Adam B. | Mychaleckyj, Josyf C. | Nadukuru, Rajiv | Nathanson, Katherine L. | Nayak, Uma | N’Diaye, Amidou | Nemesure, Barbara | Wu, Suh-Yuh | Leske, M. Cristina | Neslund-Dudas, Christine | Neuhouser, Marian | Nyante, Sarah | Ochs-Balcom, Heather | Ogunniyi, Adesola | Ogundiran, Temidayo O. | Ojengbede, Oladosu | Olopade, Olufunmilayo I. | Palmer, Julie R. | Ruiz-Narvaez, Edward A. | Palmer, Nicholette D. | Press, Michael F. | Rampersaud, Evandine | Rasmussen-Torvik, Laura J. | Rodriguez-Gil, Jorge L. | Salako, Babatunde | Schadt, Eric E. | Schwartz, Ann G. | Shriner, Daniel A. | Siscovick, David | Smith, Shad B. | Wassertheil-Smoller, Sylvia | Speliotes, Elizabeth K. | Spitz, Margaret R. | Sucheston, Lara | Taylor, Herman | Tayo, Bamidele O. | Tucker, Margaret A. | Van Den Berg, David J. | Velez Edwards, Digna R. | Wang, Zhaoming | Wiencke, John K. | Winkler, Thomas W. | Witte, John S. | Wrensch, Margaret | Wu, Xifeng | Yang, James J. | Levin, Albert M. | Young, Taylor R. | Zakai, Neil A. | Cushman, Mary | Zanetti, Krista A. | Zhao, Jing Hua | Zhao, Wei | Zheng, Yonglan | Zhou, Jie | Ziegler, Regina G. | Zmuda, Joseph M. | Fernandes, Jyotika K. | Gilkeson, Gary S. | Kamen, Diane L. | Hunt, Kelly J. | Spruill, Ida J. | Ambrosone, Christine B. | Ambs, Stefan | Arnett, Donna K. | Atwood, Larry | Becker, Diane M. | Berndt, Sonja I. | Bernstein, Leslie | Blot, William J. | Borecki, Ingrid B. | Bottinger, Erwin P. | Bowden, Donald W. | Burke, Gregory | Chanock, Stephen J. | Cooper, Richard S. | Ding, Jingzhong | Duggan, David | Evans, Michele K. | Fox, Caroline | Garvey, W. Timothy | Bradfield, Jonathan P. | Hakonarson, Hakon | Grant, Struan F.A. | Hsing, Ann | Chu, Lisa | Hu, Jennifer J. | Huo, Dezheng | Ingles, Sue A. | John, Esther M. | Jordan, Joanne M. | Kabagambe, Edmond K. | Kardia, Sharon L.R. | Kittles, Rick A. | Goodman, Phyllis J. | Klein, Eric A. | Kolonel, Laurence N. | Le Marchand, Loic | Liu, Simin | McKnight, Barbara | Millikan, Robert C. | Mosley, Thomas H. | Padhukasahasram, Badri | Williams, L. Keoki | Patel, Sanjay R. | Peters, Ulrike | Pettaway, Curtis A. | Peyser, Patricia A. | Psaty, Bruce M. | Redline, Susan | Rotimi, Charles N. | Rybicki, Benjamin A. | Sale, Michèle M. | Schreiner, Pamela J. | Signorello, Lisa B. | Singleton, Andrew B. | Stanford, Janet L. | Strom, Sara S. | Thun, Michael J. | Vitolins, Mara | Zheng, Wei | Moore, Jason H. | Williams, Scott M. | Zhu, Xiaofeng | Zonderman, Alan B. | Kooperberg, Charles | Papanicolaou, George | Henderson, Brian E. | Reiner, Alex P. | Hirschhorn, Joel N. | Loos, Ruth JF | North, Kari E. | Haiman, Christopher A.
Nature genetics  2013;45(6):690-696.
Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.
PMCID: PMC3694490  PMID: 23583978
22.  Dietary Patterns, Abdominal Visceral Adipose Tissue and Cardiometabolic Risk Factors in African Americans: the Jackson Heart Study 
Obesity (Silver Spring, Md.)  2013;21(3):10.1002/oby.20265.
Dietary behavior is an important lifestyle factor to impact an individual’s risk of developing cardiovascular disease (CVD). However, the influence of specific dietary factors on CVD risk for African Americans remains unclear. We conducted a cross-sectional study of 1775 participants from Jackson Heart Study (JHS) Exam 2 (between 2006 and 2009) who were free of hypertension, diabetes and CVD at the baseline (between 2001 and 2004). Dietary intakes were documented using a validated food-frequency questionnaire (FFQ) and dietary patterns were generated by factor analysis. Three major dietary patterns were identified: a “southern”, a “fast food” and a “prudent” pattern. After adjustment for age, sex, smoking and alcohol status, education level and physical activity, high “southern” pattern score was associated with an increased odds ratio (OR) for high abdominal visceral adipose tissue (VAT) (OR:1.80, 95%CI:1.1–3.0, p=0.02), hypertension (OR:1.42, 95%CI:1.1–1.9, p=0.02), diabetes (OR:2.03, 95%CI:1.1–3.9, p=0.03) and metabolic syndrome (OR:2.16, 95%CI:1.3–3.6, p=0.004). Similar associations were also observed in the “fast food” pattern (p ranges 0.03–0.0001). The “prudent” pattern was significantly associated, in a protective direction, with hypertension (OR 0.69, 95%CI 0.5–0.9, p=0.02). In conclusion, dietary patterns, especially the “southern” pattern, identified from a regional specific FFQ in this Deep South African Americans, are correlated with abdominal VAT and cardiometabolic risk factors.
PMCID: PMC3478414  PMID: 23592674
Jackson Heart Study; dietary patterns; cardiometabolic risk factors
24.  Association of smoking cessation and weight change with cardiovascular disease among people with and without diabetes 
Smoking cessation reduces the risks of cardiovascular disease (CVD), but weight gain that follows quitting smoking may weaken the CVD benefit of quitting.
To test the hypothesis that weight gain following smoking cessation does not attenuate the benefits of smoking cessation among people with and without diabetes.
Design, Setting, and Participants
Prospective community-based cohort study using data from the Framingham Offspring Study collected from 1984 to 2011. At each 4-year exam, self-reported smoking status was assessed and categorized as smoker, recent quitter (≤ 4 years), long-term quitter (> 4 years), and non-smoker. Pooled Cox proportional hazards models were used to estimate the association between quitting smoking and 6-year CVD events and to test whether 4-year change in weight following smoking cessation modified the association between smoking cessation and CVD events.
Main outcome measure
Incidence over 6 years of total CVD events, comprising coronary heart disease, cerebrovascular events, peripheral artery disease, and congestive heart failure.
After a mean follow-up of 25 years (SD, 9.6), 631 CVD events occurred among 3251 participants. Median 4-year weight gain was greater for recent quitters without diabetes (2.7 kg, Interquartile range [IQR] −0.5-6.4) and with diabetes (3.6 kg, IQR −1.4-8.2) than for long term quitters (0.9 kg, IQR −1.4-3.2 and 0.0 kg, IQR −3.2-3.2, respectively, p<0.001). Among people without diabetes, age and sex-adjusted incidence rate of CVD was 5.9/ 100 person-exams (95% confidence interval [CI] 4.9-7.1) in smokers, 3.2/ 100 person-exams (95% CI 2.1-4.5) in recent quitters, 3.1 /100 person-exams (95% CI 2.6-3.7) in long-term quitters, and 2.4 /100 person-exams (95% CI 2.0-3.0) in non-smokers. After adjustment for CVD risk factors, compared with smokers, recent quitters had a hazard ratio (HR) for CVD of 0.47 (95% CI, 0.23-0.94) and long-term quitters had an HR of 0.46 (95% CI, 0.34-0.63); these associations had only a minimal change after further adjustment for weight change. Among people with diabetes, there were similar point estimates that did not reach statistical significance.
Conclusions and Relevance
In this community based cohort, smoking cessation was associated with a lower risk of CVD events among participants without diabetes, and weight gain that occurred following smoking cessation did not modify this association. This supports a net cardiovascular benefit of smoking cessation despite subsequent weight gain.
PMCID: PMC3791107  PMID: 23483176
25.  Fine-scale spatiotemporal influences of salmon on growth and nitrogen signatures of Sitka spruce tree rings 
BMC Ecology  2013;13:38.
The marine-terrestrial transfer of salmon (Oncorhynchus spp.) provides a substantial pulse of nutrients to receiving ecosystems along the Pacific coast of North America and has been shown to enhance productivity and isotopic signatures of conifers and other riparian vegetation. An explicitly spatial, within-watershed investigation of the influence of salmon on conifers has never been previously investigated. In a small salmon-bearing watershed in Haida Gwaii, Canada, the transfer and distributional pattern of salmon carcasses into the riparian zone by black bears provided a spatial basis for investigating the influence of salmon on Sitka spruce tree ring growth and nitrogen isotopic signatures (δ15N) across a gradient of salmon carcass densities in relation to salmon escapement.
Annual growth was found to be highest in the high salmon carcass zone and δ15N signatures closely tracked the known distribution of salmon carcasses at distances into the forest and upstream. Tree diameter demonstrated a positive relationship with δ15N signatures for trees with and without salmon carcass influence. Using an information theoretics approach with general linear mixed models (GLMMs), we show that salmon abundance, mean annual temperature and the interaction terms salmon abundance*temperature and salmon abundance*distance into the forest best predict tree growth. In addition, spatial variables (distance into forest and upstream) and their interaction are the strongest predictors of δ15N signatures. However patterns observed in individual trees, particularly those at increased distance into the forest, suggest positive relationships with historical salmon abundance.
Using a replicated spatial sampling design across a sharp gradient in salmon nutrient loading, our study provides clear evidence that the temporal pattern in an allochthonous nutrient source and an interaction with temperature and spatial location influences conifer growth. Although salmon abundance has been previously linked to annual conifer growth and δ15N levels, our approach demonstrates the need to incorporate additional predictors including tree size and opens up the prospect of their dual use as historical proxies for salmon abundance.
PMCID: PMC3850941  PMID: 24093666
Spatial subsidy; Salmon; Nitrogen; Sitka spruce; Conifer; Riparian; Stable isotope

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