@article {1108, title = {Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.}, journal = {JAMA}, volume = {302}, year = {2009}, month = {2009 Jul 08}, pages = {168-78}, abstract = {

CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.

OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.

DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55\% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.

MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.

RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1\% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1\%-3\% of trait variance).

CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

}, keywords = {Adult, Aged, Aged, 80 and over, Aorta, Cardiovascular Diseases, Echocardiography, European Continental Ancestry Group, Female, Genome-Wide Association Study, Genotype, Heart Atria, Heart Ventricles, Humans, Male, Middle Aged, Organ Size, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Ventricular Dysfunction, Left, Ventricular Function, Left}, issn = {1538-3598}, doi = {10.1001/jama.2009.978-a}, author = {Vasan, Ramachandran S and Glazer, Nicole L and Felix, Janine F and Lieb, Wolfgang and Wild, Philipp S and Felix, Stephan B and Watzinger, Norbert and Larson, Martin G and Smith, Nicholas L and Dehghan, Abbas and Grosshennig, Anika and Schillert, Arne and Teumer, Alexander and Schmidt, Reinhold and Kathiresan, Sekar and Lumley, Thomas and Aulchenko, Yurii S and K{\"o}nig, Inke R and Zeller, Tanja and Homuth, Georg and Struchalin, Maksim and Aragam, Jayashri and Bis, Joshua C and Rivadeneira, Fernando and Erdmann, Jeanette and Schnabel, Renate B and D{\"o}rr, Marcus and Zweiker, Robert and Lind, Lars and Rodeheffer, Richard J and Greiser, Karin Halina and Levy, Daniel and Haritunians, Talin and Deckers, Jaap W and Stritzke, Jan and Lackner, Karl J and V{\"o}lker, Uwe and Ingelsson, Erik and Kullo, Iftikhar and Haerting, Johannes and O{\textquoteright}Donnell, Christopher J and Heckbert, Susan R and Stricker, Bruno H and Ziegler, Andreas and Reffelmann, Thorsten and Redfield, Margaret M and Werdan, Karl and Mitchell, Gary F and Rice, Kenneth and Arnett, Donna K and Hofman, Albert and Gottdiener, John S and Uitterlinden, Andr{\'e} G and Meitinger, Thomas and Blettner, Maria and Friedrich, Nele and Wang, Thomas J and Psaty, Bruce M and van Duijn, Cornelia M and Wichmann, H-Erich and Munzel, Thomas F and Kroemer, Heyo K and Benjamin, Emelia J and Rotter, Jerome I and Witteman, Jacqueline C and Schunkert, Heribert and Schmidt, Helena and V{\"o}lzke, Henry and Blankenberg, Stefan} } @article {1261, title = {A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3.}, journal = {Hum Mol Genet}, volume = {20}, year = {2011}, month = {2011 Mar 15}, pages = {1241-51}, abstract = {

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 {\texttimes} 10(-8) (P = 3.3 {\texttimes} 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 {\texttimes} 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 {\texttimes} 10(-21)) and higher IGF-I (P = 4.9 {\texttimes} 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 {\texttimes} 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 {\texttimes} 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5\% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 {\texttimes} 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

}, keywords = {Aged, Chromosomes, Human, Pair 7, Cohort Studies, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Polymorphism, Single Nucleotide}, issn = {1460-2083}, doi = {10.1093/hmg/ddq560}, author = {Kaplan, Robert C and Petersen, Ann-Kristin and Chen, Ming-Huei and Teumer, Alexander and Glazer, Nicole L and D{\"o}ring, Angela and Lam, Carolyn S P and Friedrich, Nele and Newman, Anne and M{\"u}ller, Martina and Yang, Qiong and Homuth, Georg and Cappola, Anne and Klopp, Norman and Smith, Holly and Ernst, Florian and Psaty, Bruce M and Wichmann, H-Erich and Sawyer, Douglas B and Biffar, Reiner and Rotter, Jerome I and Gieger, Christian and Sullivan, Lisa S and V{\"o}lzke, Henry and Rice, Kenneth and Spyroglou, Ariadni and Kroemer, Heyo K and Ida Chen, Y-D and Manolopoulou, Jenny and Nauck, Matthias and Strickler, Howard D and Goodarzi, Mark O and Reincke, Martin and Pollak, Michael N and Bidlingmaier, Martin and Vasan, Ramachandran S and Wallaschofski, Henri} } @article {1376, title = {The association between waist circumference and risk of mortality considering body mass index in 65- to 74-year-olds: a meta-analysis of 29 cohorts involving more than 58 000 elderly persons.}, journal = {Int J Epidemiol}, volume = {41}, year = {2012}, month = {2012 Jun}, pages = {805-17}, abstract = {

BACKGROUND: For the elderly, the association between waist circumference (WC) and mortality considering body mass index (BMI) remains unclear, and thereby also the evidence base for using these anthropometric measures in clinical practice. This meta-analysis examined the association between WC categories and (cause-specific) mortality within BMI categories. Furthermore, the association of continuous WC with lowest and increased mortality risks was examined.

METHODS: Age- and smoking-adjusted relative risks (RRs) of mortality associated with WC-BMI categories and continuous WC (including WC and WC(2)) were calculated by the investigators and pooled by means of random-effects models.

RESULTS: During a 5-year-follow-up of 32 678 men and 25 931 women, we ascertained 3318 and 1480 deaths, respectively. A large WC (men: >=102 cm, women: >=88 cm) was associated with increased all-cause mortality RRs for those in the {\textquoteright}healthy{\textquoteright} weight {1.7 [95\% confidence interval (CI): 1.2-2.2], 1.7 (95\% CI: 1.3-2.3)}, overweight [1.1(95\% CI: 1.0-1.3), 1.4 (95\%: 1.1-1.7)] and obese [1.1 (95\% CI: 1.0-1.3), 1.6 (95\% CI: 1.3-1.9)] BMI category compared with the {\textquoteright}healthy{\textquoteright} weight (20-24.9 kg/m(2)) and a small WC (<94 cm, men; <80 cm, women) category. Underweight was associated with highest all-cause mortality RRs in men [2.2 (95\% CI: 1.8-2.8)] and women [2.3 (95\% CI: 1.8-3.1]. We found a J-shaped association for continuous WC with all-cause, cardiovascular (CVD) and cancer, and a U-shaped association with respiratory disease mortality (P < 0.05). An all-cause (CVD) mortality RR of 2.0 was associated with a WC of 132 cm (123 cm) in men and 116 cm (105 cm) in women.

CONCLUSIONS: Our results showed increased mortality risks for elderly people with an increased WC-even across BMI categories- and for those who were classified as {\textquoteright}underweight{\textquoteright} using BMI. The results provide a solid basis for re-evaluation of WC cut-points in ageing populations.

}, keywords = {Aged, Body Mass Index, Body Weight, Cardiovascular Diseases, Female, Humans, Male, Mortality, Neoplasms, Overweight, Respiratory Tract Diseases, Risk Assessment, Waist Circumference}, issn = {1464-3685}, doi = {10.1093/ije/dys008}, author = {de Hollander, Ellen L and Bemelmans, Wanda Je and Boshuizen, Hendriek C and Friedrich, Nele and Wallaschofski, Henri and Guallar-Castill{\'o}n, Pilar and Walter, Stefan and Zillikens, M Carola and Rosengren, Annika and Lissner, Lauren and Bassett, Julie K and Giles, Graham G and Orsini, Nicola and Heim, Noor and Visser, Marjolein and de Groot, Lisette Cpgm} } @article {9918, title = {Clinical and Imaging Markers of Cardiac Function and Brain Health: A Meta-Analysis of Community-Based Studies.}, journal = {Neurology}, volume = {104}, year = {2025}, month = {2025 Apr 22}, pages = {e213421}, abstract = {

BACKGROUND AND OBJECTIVES: Cardiac dysfunction and heart failure are linked to cognitive impairment, but the underlying brain pathology remains undetermined. We investigated associations between cardiac function (measured by echocardiography or cardiac MRI), clinical heart failure, and structural markers on brain MRI, including volumes of gray and white matter (WM), the hippocampus, and white matter hyperintensities (WMHs).

METHODS: We leverage data from 7 prospective, community-based cohorts across Europe and the United States, all part of the Cross-Cohort Collaboration. The included cohorts were the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in Communities study, Austrian Stroke Prevention Study, Cardiovascular Health Study, Framingham Heart Study, Rotterdam Study, and Study of Health in Pomerania (SHIP-START and SHIP-TREND). Each cohort performed cross-sectional multivariable linear regression analyses, after which estimates were pooled through random-effects meta-analysis. Heterogeneity was assessed by the index (\%).

RESULTS: Among 10,889 participants (mean age: 66.8 years, range 52.0-76.0; 56.7\% women), markers of systolic dysfunction were consistently associated with smaller total brain volume (TBV) (e.g., adjusted standardized mean difference for moderate to severe dysfunction -0.19, 95\% CI -0.31 to -0.07, = 20\%). Impaired relaxation and restrictive diastolic dysfunction were also associated with smaller TBV (e.g., for impaired relaxation -0.08, 95\% CI -0.15 to -0.01, = 32\%) and hippocampal volume (-0.18, 95\% CI -0.33 to -0.03, = 0\%), with similar results for the E/A-ratio. Systolic and diastolic dysfunction was not consistently associated with volume of WMHs. Among 5 cohorts with available data, 302 (3.4\%) participants had clinical heart failure, which was associated with smaller brain volumes, particularly in the hippocampus (-0.13, 95\% CI -0.23 to -0.02, = 1\%).

DISCUSSION: In this large study among community-dwelling adults, subclinical cardiac dysfunction was associated with brain imaging markers of neurodegeneration. These findings encourage longitudinal investigations on the effect of maintaining cardiac function on brain health.

}, keywords = {Aged, Brain, Cohort Studies, Echocardiography, Female, Heart Failure, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Prospective Studies, White Matter}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000213421}, author = {Yaqub, Amber and Bis, Joshua C and Frenzel, Stefan and Koini, Marisa and Mbangdadji, Djass and Peloso, Gina M and Talluri, Rajesh and Alonso, Alvaro and Bahls, Martin and B{\"u}low, Robin and D{\"o}rr, Marcus and Felix, Stephan and Fohner, Alison and Friedrich, Nele and Hofer, Edith and Kavousi, Maryam and Launer, Lenore J and Le, Tran and Longstreth, Will and Mosley, Thomas H and Vernooij, Meike W and V{\"o}lzke, Henry and Wittfeld, Katharina and Beiser, Alexa S and Grabe, Hans J and Gudnason, Vilmundur and Ikram, Mohammad Arfan and Psaty, Bruce M and Schmidt, Reinhold and Simino, Jeannette and Seshadri, Sudha and Wolters, Frank J} }