@article {982, title = {IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study.}, journal = {Hum Genet}, volume = {122}, year = {2007}, month = {2007 Dec}, pages = {485-94}, abstract = {

Interleukin-6 (IL-6) and C-reactive protein (CRP) levels increase with age and likely play a role in adverse health outcomes in older adults. The relationship between IL-6 gene tag single nucleotide polymorphisms (SNPs) and circulating IL-6 and CRP levels, cardiovascular disease (CVD) outcomes, and mortality in Caucasian (CA) and African American (AA) participants of the Cardiovascular Health Study (CHS) was evaluated using ANCOVA and Cox proportional hazards models. The minor allele of the promoter SNP 1510 and intronic SNP 3572 associates with significantly higher serum IL-6 and CRP levels in CA but not AA. The CRP association persisted after CA and AA populations were combined and after accounting for multiple comparisons. These associations did not carry through to cardiovascular disease outcomes. Decreased risk of stroke was identified in CA, with the minor allele of SNP 1111 (HRR 0.71, 95\% CI 0.52, 0.95), P = 0.02, and increased risk of CVD and all-cause mortality (HRR 1.31, 95\% CI 1.05-1.64) in AAs heterozygote for SNP 2989. While genetic variation in the IL-6 gene was associated with circulating IL-6 and especially with CRP concentrations in this study, there is little evidence for association between common IL-6 gene variation and adverse health outcomes in this population of older adults.

}, keywords = {African Americans, Aged, Alleles, C-Reactive Protein, Cardiovascular Diseases, Cohort Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Humans, Interleukin-6, Introns, Longitudinal Studies, Male, Polymorphism, Single Nucleotide, Promoter Regions, Genetic}, issn = {1432-1203}, doi = {10.1007/s00439-007-0428-x}, author = {Walston, Jeremy D and Fallin, M Daniele and Cushman, Mary and Lange, Leslie and Psaty, Bruce and Jenny, Nancy and Browner, Warren and Tracy, Russell and Durda, Peter and Reiner, Alex} } @article {6108, title = {Ischemic stroke is associated with the ABO locus: the EuroCLOT study.}, journal = {Ann Neurol}, volume = {73}, year = {2013}, month = {2013 Jan}, pages = {16-31}, abstract = {

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.

METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).

RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 {\texttimes} 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 {\texttimes} 10(-186)), rs10665 with FVII (p = 2.4 {\texttimes} 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 {\texttimes} 10(-57)) and factor VIII (p = 1.2 {\texttimes} 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95\% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).

INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

}, keywords = {ABO Blood-Group System, Adolescent, Adult, Aged, Aged, 80 and over, Blood Coagulation, Brain Ischemia, Cohort Studies, Europe, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Stroke, Young Adult}, issn = {1531-8249}, doi = {10.1002/ana.23838}, author = {Williams, Frances M K and Carter, Angela M and Hysi, Pirro G and Surdulescu, Gabriela and Hodgkiss, Dylan and Soranzo, Nicole and Traylor, Matthew and Bevan, Steve and Dichgans, Martin and Rothwell, Peter M W and Sudlow, Cathie and Farrall, Martin and Silander, Kaisa and Kaunisto, Mari and Wagner, Peter and Saarela, Olli and Kuulasmaa, Kari and Virtamo, Jarmo and Salomaa, Veikko and Amouyel, Philippe and Arveiler, Dominique and Ferrieres, Jean and Wiklund, Per-Gunnar and Ikram, M Arfan and Hofman, Albert and Boncoraglio, Giorgio B and Parati, Eugenio A and Helgadottir, Anna and Gretarsdottir, Solveig and Thorsteinsdottir, Unnur and Thorleifsson, Gudmar and Stefansson, Kari and Seshadri, Sudha and DeStefano, Anita and Gschwendtner, Andreas and Psaty, Bruce and Longstreth, Will and Mitchell, Braxton D and Cheng, Yu-Ching and Clarke, Robert and Ferrario, Marco and Bis, Joshua C and Levi, Christopher and Attia, John and Holliday, Elizabeth G and Scott, Rodney J and Fornage, Myriam and Sharma, Pankaj and Furie, Karen L and Rosand, Jonathan and Nalls, Mike and Meschia, James and Mosely, Thomas H and Evans, Alun and Palotie, Aarno and Markus, Hugh S and Grant, Peter J and Spector, Tim D} } @article {9260, title = {The Impact of Time Horizon on Classification Accuracy: Application of Machine Learning to Prediction of Incident Coronary Heart Disease.}, journal = {JMIR Cardio}, volume = {6}, year = {2022}, month = {2022 Nov 02}, pages = {e38040}, abstract = {

BACKGROUND: Many machine learning approaches are limited to classification of outcomes rather than longitudinal prediction. One strategy to use machine learning in clinical risk prediction is to classify outcomes over a given time horizon. However, it is not well-known how to identify the optimal time horizon for risk prediction.

OBJECTIVE: In this study, we aim to identify an optimal time horizon for classification of incident myocardial infarction (MI) using machine learning approaches looped over outcomes with increasing time horizons. Additionally, we sought to compare the performance of these models with the traditional Framingham Heart Study (FHS) coronary heart disease gender-specific Cox proportional hazards regression model.

METHODS: We analyzed data from a single clinic visit of 5201 participants of a cardiovascular health study. We examined 61 variables collected from this baseline exam, including demographic and biologic data, medical history, medications, serum biomarkers, electrocardiographic, and echocardiographic data. We compared several machine learning methods (eg, random forest, L1 regression, gradient boosted decision tree, support vector machine, and k-nearest neighbor) trained to predict incident MI that occurred within time horizons ranging from 500-10,000 days of follow-up. Models were compared on a 20\% held-out testing set using area under the receiver operating characteristic curve (AUROC). Variable importance was performed for random forest and L1 regression models across time points. We compared results with the FHS coronary heart disease gender-specific Cox proportional hazards regression functions.

RESULTS: There were 4190 participants included in the analysis, with 2522 (60.2\%) female participants and an average age of 72.6 years. Over 10,000 days of follow-up, there were 813 incident MI events. The machine learning models were most predictive over moderate follow-up time horizons (ie, 1500-2500 days). Overall, the L1 (Lasso) logistic regression demonstrated the strongest classification accuracy across all time horizons. This model was most predictive at 1500 days follow-up, with an AUROC of 0.71. The most influential variables differed by follow-up time and model, with gender being the most important feature for the L1 regression and weight for the random forest model across all time frames. Compared with the Framingham Cox function, the L1 and random forest models performed better across all time frames beyond 1500 days.

CONCLUSIONS: In a population free of coronary heart disease, machine learning techniques can be used to predict incident MI at varying time horizons with reasonable accuracy, with the strongest prediction accuracy in moderate follow-up periods. Validation across additional populations is needed to confirm the validity of this approach in risk prediction.

}, issn = {2561-1011}, doi = {10.2196/38040}, author = {Simon, Steven and Mandair, Divneet and Albakri, Abdel and Fohner, Alison and Simon, Noah and Lange, Leslie and Biggs, Mary and Mukamal, Kenneth and Psaty, Bruce and Rosenberg, Michael} } @article {9025, title = {Intake and Sources of Dietary Fiber, Inflammation, and Cardiovascular Disease in Older US Adults.}, journal = {JAMA Netw Open}, volume = {5}, year = {2022}, month = {2022 Mar 01}, pages = {e225012}, abstract = {

Importance: Higher intake of dietary fiber has been associated with lower inflammation, but whether there are differences in this association by source of dietary fiber (ie, cereal, vegetable, or fruit) has not been studied to date.

Objectives: To evaluate the associations of total fiber intake and source (ie, cereal, vegetable, and fruit fiber intake) with inflammation and to evaluate whether inflammation mediates the inverse association between dietary fiber intake and cardiovascular disease (CVD).

Design, Setting, and Participants: At the baseline visit (1989-1990) of 4125 adults aged 65 years or older in an ongoing US cohort study, dietary intake was assessed by a food frequency questionnaire among study participants without prevalent CVD (stroke and myocardial infarction) at enrollment. Inflammation was assessed from blood samples collected at baseline with immunoassays for markers of inflammation. Multivariable linear regression models tested the association of dietary fiber intake with inflammation. Also assessed was whether each inflammatory marker and its composite derived from principal component analysis mediated the association of baseline cereal fiber intake with development of CVD (stroke, myocardial infarction, and atherosclerotic cardiovascular death) through June 2015. Data from June 1, 1989, through June 30, 2015, were analyzed.

Exposures: Total fiber intake and sources of fiber (cereal, vegetable, and fruit).

Main Outcomes and Measures: Systemic markers of inflammation. Cardiovascular disease was the outcome in the mediation analysis.

Results: Of 4125 individuals, 0.1\% (n = 3) were Asian or Pacific Islander, 4.4\% (n = 183) were Black, 0.3\% (n = 12) were Native American, 95.0\% (n = 3918) were White, and 0.2\% (n = 9) were classified as other. Among these 4125 individuals (2473 women [60\%]; mean [SD] age, 72.6 [5.5] years; 183 Black individuals [4.4\%]; and 3942 individuals of other races and ethnicitites [95.6\%] [ie, race and ethnicity other than Black, self-classified by participant]), an increase in total fiber intake of 5 g/d was associated with significantly lower concentrations of C-reactive protein (adjusted mean difference, -0.05 SD; 95\% CI, -0.08 to -0.01 SD; P = .007) and interleukin 1 receptor antagonist (adjusted mean difference, -0.04 SD; 95\% CI, -0.07 to -0.01 SD; P < .02) but with higher concentrations of soluble CD163 (adjusted mean difference, 0.05 SD; 95\% CI, 0.02-0.09 SD; P = .005). Among fiber sources, only cereal fiber was consistently associated with lower inflammation. Similarly, cereal fiber intake was associated with lower CVD incidence (adjusted hazard ratio, 0.90; 95\% CI, 0.81-1.00; 1941 incident cases). The proportion of the observed association of cereal fiber with CVD mediated by inflammatory markers ranged from 1.5\% for interleukin 18 to 14.2\% for C-reactive protein, and 16.1\% for their primary principal component.

Conclusions and Relevance: Results of this study suggest that cereal fiber intake was associated with lower levels of various inflammatory markers and lower risk of CVD and that inflammation mediated approximately one-sixth of the association between cereal fiber intake and CVD.

}, keywords = {Adult, Aged, Cardiovascular Diseases, Cohort Studies, Dietary Fiber, Female, Humans, Inflammation, Middle Aged, Risk Factors}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2022.5012}, author = {Shivakoti, Rupak and Biggs, Mary L and Djouss{\'e}, Luc and Durda, Peter Jon and Kizer, Jorge R and Psaty, Bruce and Reiner, Alex P and Tracy, Russell P and Siscovick, David and Mukamal, Kenneth J} }