%0 Journal Article %J Nat Commun %D 2018 %T GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. %A Franceschini, Nora %A Giambartolomei, Claudia %A de Vries, Paul S %A Finan, Chris %A Bis, Joshua C %A Huntley, Rachael P %A Lovering, Ruth C %A Tajuddin, Salman M %A Winkler, Thomas W %A Graff, Misa %A Kavousi, Maryam %A Dale, Caroline %A Smith, Albert V %A Hofer, Edith %A van Leeuwen, Elisabeth M %A Nolte, Ilja M %A Lu, Lingyi %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Pitkänen, Niina %A Franzén, Oscar %A Joshi, Peter K %A Noordam, Raymond %A Marioni, Riccardo E %A Hwang, Shih-Jen %A Musani, Solomon K %A Schminke, Ulf %A Palmas, Walter %A Isaacs, Aaron %A Correa, Adolfo %A Zonderman, Alan B %A Hofman, Albert %A Teumer, Alexander %A Cox, Amanda J %A Uitterlinden, André G %A Wong, Andrew %A Smit, Andries J %A Newman, Anne B %A Britton, Annie %A Ruusalepp, Arno %A Sennblad, Bengt %A Hedblad, Bo %A Pasaniuc, Bogdan %A Penninx, Brenda W %A Langefeld, Carl D %A Wassel, Christina L %A Tzourio, Christophe %A Fava, Cristiano %A Baldassarre, Damiano %A O'Leary, Daniel H %A Teupser, Daniel %A Kuh, Diana %A Tremoli, Elena %A Mannarino, Elmo %A Grossi, Enzo %A Eric Boerwinkle %A Schadt, Eric E %A Ingelsson, Erik %A Veglia, Fabrizio %A Rivadeneira, Fernando %A Beutner, Frank %A Chauhan, Ganesh %A Heiss, Gerardo %A Snieder, Harold %A Campbell, Harry %A Völzke, Henry %A Markus, Hugh S %A Deary, Ian J %A Jukema, J Wouter %A de Graaf, Jacqueline %A Price, Jacqueline %A Pott, Janne %A Hopewell, Jemma C %A Liang, Jingjing %A Thiery, Joachim %A Engmann, Jorgen %A Gertow, Karl %A Rice, Kenneth %A Taylor, Kent D %A Dhana, Klodian %A Kiemeney, Lambertus A L M %A Lind, Lars %A Raffield, Laura M %A Launer, Lenore J %A Holdt, Lesca M %A Dörr, Marcus %A Dichgans, Martin %A Traylor, Matthew %A Sitzer, Matthias %A Kumari, Meena %A Kivimaki, Mika %A Nalls, Mike A %A Melander, Olle %A Raitakari, Olli %A Franco, Oscar H %A Rueda-Ochoa, Oscar L %A Roussos, Panos %A Whincup, Peter H %A Amouyel, Philippe %A Giral, Philippe %A Anugu, Pramod %A Wong, Quenna %A Malik, Rainer %A Rauramaa, Rainer %A Burkhardt, Ralph %A Hardy, Rebecca %A Schmidt, Reinhold %A de Mutsert, Renée %A Morris, Richard W %A Strawbridge, Rona J %A Wannamethee, S Goya %A Hägg, Sara %A Shah, Sonia %A McLachlan, Stela %A Trompet, Stella %A Seshadri, Sudha %A Kurl, Sudhir %A Heckbert, Susan R %A Ring, Susan %A Harris, Tamara B %A Lehtimäki, Terho %A Galesloot, Tessel E %A Shah, Tina %A de Faire, Ulf %A Plagnol, Vincent %A Rosamond, Wayne D %A Post, Wendy %A Zhu, Xiaofeng %A Zhang, Xiaoling %A Guo, Xiuqing %A Saba, Yasaman %A Dehghan, Abbas %A Seldenrijk, Adrie %A Morrison, Alanna C %A Hamsten, Anders %A Psaty, Bruce M %A van Duijn, Cornelia M %A Lawlor, Deborah A %A Mook-Kanamori, Dennis O %A Bowden, Donald W %A Schmidt, Helena %A Wilson, James F %A Wilson, James G %A Rotter, Jerome I %A Wardlaw, Joanna M %A Deanfield, John %A Halcox, Julian %A Lyytikäinen, Leo-Pekka %A Loeffler, Markus %A Evans, Michele K %A Debette, Stephanie %A Humphries, Steve E %A Völker, Uwe %A Gudnason, Vilmundur %A Hingorani, Aroon D %A Björkegren, Johan L M %A Casas, Juan P %A O'Donnell, Christopher J %K ADAMTS9 Protein %K Amino Acid Oxidoreductases %K Carotid Intima-Media Thickness %K Coronary Disease %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Lod Score %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Protein-Lysine 6-Oxidase %K Quantitative Trait Loci %K Risk Factors %X

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

%B Nat Commun %V 9 %P 5141 %8 2018 Dec 03 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/30510157?dopt=Abstract %R 10.1038/s41467-018-07340-5 %0 Journal Article %J J Card Fail %D 2017 %T Incident Heart Failure and Cognitive Decline: The Atherosclerosis Risk in Communities Study. %A Bressler, Jan %A Knopman, David S %A Sharrett, A Richey %A Gottesman, Rebecca F %A Penman, Alan %A Chang, Patricia P %A Rosamond, Wayne D %A Eric Boerwinkle %A Mosley, Thomas H %K Adult %K Aged %K Atherosclerosis %K Cognition %K Cognitive Dysfunction %K Female %K Follow-Up Studies %K Heart Failure %K Humans %K Incidence %K Male %K Middle Aged %K Neuropsychological Tests %K Prospective Studies %K Residence Characteristics %K Risk Assessment %K Risk Factors %K Time Factors %K United States %X

BACKGROUND: Cognitive impairment is found in a significant proportion of patients with heart failure (HF). Although cognitive impairment may be a consequence of HF, early signs of cognitive impairment may also indicate subclinical vascular disease, and thus a risk factor for future cardiovascular events.

METHODS AND RESULTS: The Atherosclerosis Risk in Communities Study is a prospective cohort study of the development of atherosclerosis. Cox proportional hazards regression was used to examine the association between mean 6-year change in cognitive function and incident HF in 7962 white and 1933 African-American men and women aged 46 to 70 years and free of clinical stroke. Scores were obtained for the Delayed Word Recall Test, the Digit Symbol Substitution Test (DSST), and the Word Fluency Test. There was a significantly increased risk of developing HF during the mean 12.6-year follow-up period after adjustment for age, gender, race, and education for those in the quartile with the greatest decline in DSST scores (hazard ratio [HR] = 1.17, P = .009), and in the quartile with the lowest baseline DSST scores (HR = 1.43, P < .001).

CONCLUSIONS: The results suggest that relatively low performance on a test of information processing speed may serve as an indicator of HF risk in middle age.

%B J Card Fail %V 23 %P 47-55 %8 2017 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/27864030?dopt=Abstract %R 10.1016/j.cardfail.2016.11.002 %0 Journal Article %J Circ Cardiovasc Genet %D 2010 %T Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium. %A Morrison, Alanna C %A Felix, Janine F %A Cupples, L Adrienne %A Glazer, Nicole L %A Loehr, Laura R %A Dehghan, Abbas %A Demissie, Serkalem %A Bis, Joshua C %A Rosamond, Wayne D %A Aulchenko, Yurii S %A Wang, Ying A %A Haritunians, Talin %A Folsom, Aaron R %A Rivadeneira, Fernando %A Benjamin, Emelia J %A Lumley, Thomas %A Couper, David %A Stricker, Bruno H %A O'Donnell, Christopher J %A Rice, Kenneth M %A Chang, Patricia P %A Hofman, Albert %A Levy, Daniel %A Rotter, Jerome I %A Fox, Ervin R %A Uitterlinden, André G %A Wang, Thomas J %A Psaty, Bruce M %A Willerson, James T %A van Duijn, Cornelia M %A Boerwinkle, Eric %A Witteman, Jacqueline C M %A Vasan, Ramachandran S %A Smith, Nicholas L %K Aged %K Aged, 80 and over %K Black or African American %K Chemokines %K Cohort Studies %K Female %K Genome-Wide Association Study %K Genotype %K Heart Failure %K Humans %K Introns %K Male %K MARVEL Domain-Containing Proteins %K Membrane Proteins %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %K White People %X

BACKGROUND: Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

METHODS AND RESULTS: Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance.

CONCLUSIONS: This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.

%B Circ Cardiovasc Genet %V 3 %P 248-55 %8 2010 Jun %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/20400778?dopt=Abstract %R 10.1161/CIRCGENETICS.109.895995