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Candidate gene association study of coronary artery calcification in chronic kidney disease: findings from the CRIC study (Chronic Renal Insufficiency Cohort).

ABSTRACT: OBJECTIVES:This study sought to identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD). BACKGROUND:CKD is associated with increased CAC and subsequent coronary heart disease (CHD), but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD. METHODS:We performed a candidate gene study (?2,100 genes; ?50,000 single nucleotide polymorphisms [SNPs]) of CAC within the CRIC (Chronic Renal Insufficiency Cohort) study (N = 1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in the PennCAC (Penn Coronary Artery Calcification) (N = 2,560) and AFCS (Amish Family Calcification Study) (N = 784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the PROMIS (Pakistan Risk of Myocardial Infarction Study) (N = 14,885). RESULTS:Of 268 SNPs reaching p < 5 × 10(-4) for CAC in CRIC, 28 SNPs in 23 loci had nominal support (p < 0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported genome-wide association study association with hypertension (e.g., ATP2B1). In PROMIS, 4 of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1, and ABCA4) had significant associations with MI, consistent with their direction of effect on CAC. CONCLUSIONS:We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.

SUBMITTER: Ferguson JF

PROVIDER: S-EPMC3953823 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Candidate gene association study of coronary artery calcification in chronic kidney disease: findings from the CRIC study (Chronic Renal Insufficiency Cohort).

Ferguson Jane F JF Matthews Gregory J GJ Townsend Raymond R RR Raj Dominic S DS Kanetsky Peter A PA Budoff Matthew M Fischer Michael J MJ Rosas Sylvia E SE Kanthety Radhika R Rahman Mahboob M Master Stephen R SR Qasim Atif A Li Mingyao M Mehta Nehal N NN Shen Haiqing H Mitchell Braxton D BD O'Connell Jeffrey R JR Shuldiner Alan R AR Ho Weang Kee WK Young Robin R Rasheed Asif A Danesh John J He Jiang J Kusek John W JW Ojo Akinlolu O AO Flack John J Go Alan S AS Gadegbeku Crystal A CA Wright Jackson T JT Saleheen Danish D Feldman Harold I HI Rader Daniel J DJ Foulkes Andrea S AS Reilly Muredach P MP

Journal of the American College of Cardiology 20130530 9

<h4>Objectives</h4>This study sought to identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD).<h4>Background</h4>CKD is associated with increased CAC and subsequent coronary heart disease (CHD), but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD.<h4>Methods</h4>We performed a candidate gene study (∼2,100 genes; ∼50,000 single nucleotide polymorphisms [SNPs]) of C ...[more]

PMID: 23727086

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Project description:RATIONALE & OBJECTIVE:Coronary artery calcification (CAC) is prevalent among patients with chronic kidney disease (CKD) and increases risks for cardiovascular disease events and mortality. We hypothesized that a novel serum measure of calcification propensity is associated with CAC among patients with CKD stages 2 to 4. STUDY DESIGN:Prospective cohort study. SETTING & PARTICIPANTS:Participants from the Chronic Renal Insufficiency Cohort (CRIC) Study with baseline (n=1,274) and follow-up (n=780) CAC measurements. PREDICTORS:Calcification propensity, quantified as transformation time (T50) from primary to secondary calciprotein particles, with lower T50 corresponding to higher calcification propensity. Covariates included age, sex, race/ethnicity, clinical site, estimated glomerular filtration rate, proteinuria, diabetes, systolic blood pressure, number of antihypertensive medications, current smoking, history of cardiovascular disease, total cholesterol level, and use of statin medications. OUTCOMES:CAC prevalence, severity, incidence, and progression. ANALYTICAL APPROACH:Multivariable-adjusted generalized linear models. RESULTS:At baseline, 824 (65%) participants had prevalent CAC. After multivariable adjustment, T50 was not associated with CAC prevalence but was significantly associated with greater CAC severity among participants with prevalent CAC: 1-SD lower T50 was associated with 21% (95% CI, 6%-38%) greater CAC severity. Among 780 participants followed up an average of 3 years later, 65 (20%) without baseline CAC developed incident CAC, while 89 (19%) with baseline CAC had progression, defined as annual increase≥100 Agatston units. After multivariable adjustment, T50 was not associated with incident CAC but was significantly associated with CAC progression: 1-SD lower T50 was associated with 28% (95% CI, 7%-53%) higher risk for CAC progression. LIMITATIONS:Potential selection bias in follow-up analyses; inability to distinguish intimal from medial calcification. CONCLUSIONS:Among patients with CKD stages 2 to 4, higher serum calcification propensity is associated with more severe CAC and CAC progression.

Project description:Rationale & objectivesFew studies have investigated racial disparities in survival among dialysis patients in a manner that considers risk factors and mortality during the phase of kidney disease before maintenance dialysis. Our objective was to explore racial variations in survival among dialysis patients and relate them to racial differences in comorbid conditions and rates of death in the setting of kidney disease not yet requiring dialysis therapy.Study designRetrospective cohort study.Settings & participants3,288 black and white participants in the Chronic Renal Insufficiency Cohort (CRIC), none of whom were receiving dialysis at enrollment.ExposureRace.OutcomeMortality.Analytic approachCox proportional hazards regression was used to examine the association between race and mortality starting at: (1) time of dialysis initiation and (2) entry into the CRIC.ResultsDuring 7.1 years of median follow-up, 678 CRIC participants started dialysis. Starting from the time of dialysis initiation, blacks had lower risk for death (unadjusted HR, 0.67; 95% CI, 0.51-0.87) compared with whites. Starting from baseline CRIC enrollment, the strength of the association between some risk factors and dialysis was notably stronger for whites than blacks. For example, the HR for dialysis onset in the presence (vs absence) of heart failure at CRIC enrollment was 1.30 (95% CI, 1.01-1.68) for blacks versus 2.78 (95% CI, 1.90-4.50) for whites, suggesting differential severity of these risk factors by race. When we included deaths occurring both before and after dialysis, risk for death was higher among blacks (vs whites) starting from CRIC enrollment (HR, 1.41; 95% CI, 1.22-1.64), but this finding was attenuated in adjusted models (HR, 1.08; 95% CI, 0.91-1.28).LimitationsResidual confounding.ConclusionsThe apparent survival advantage among blacks over whites treated with dialysis may be attributed to selected transition of a subset of whites with more severe comorbid conditions onto dialysis.

Project description:Rationale & objectiveDysnatremias have been associated with an increased risk of mortality in the chronic kidney disease (CKD) population. Our objective is to identify the prevalence of and risk factors associated with dysnatremias in a CKD population and assess the association of dysnatremias with kidney failure and mortality among patients with CKD enrolled in the Chronic Renal Insufficiency Cohort Study.Study designAnalysis of prospective cohort study.Setting & participantsAdult patients aged 21-74 years with CKD from the Chronic Renal Insufficiency Cohort study.PredictorsBaseline and time-dependent hyponatremia and hypernatremia.OutcomesAll-cause mortality and kidney failure.Analytical approachBaseline characteristics were compared using χ2 tests for categorical variables, analysis of variance for age, and Kruskal-Wallis tests for laboratory variables. Cox proportional hazards models and competing risk models were used to evaluate the association between baseline sodium level and overall mortality.ResultsOf a total of 5,444 patients with CKD, 486 (9%) had hyponatremia and 53 (1%) had hypernatremia. Altogether, 1,508 patients died and 1,206 reached kidney failure. In adjusted Cox models, time-dependent dysnatremias were strongly associated with mortality for both hyponatremia (HR, 1.38; 95% CI, 1.16-1.64) and hypernatremia (HR, 1.54; 95% CI, 1.04-2.29). Factors associated with hyponatremia included female sex, diabetes, and hypertension. Regardless of age, time-dependent hypernatremia was associated with an increased risk of kidney failure (HR, 1.64; 95% CI, 1.06-2.53). Baseline and time-dependent hyponatremia were associated with an increased risk of kidney failure in patients younger than 65 (baseline hyponatremia HR, 1.30; 95% CI, 1.03-1.64 and time-dependent hyponatremia HR, 1.36; 95% CI, 1.09-1.70) but not among patients aged >65 years.LimitationsInability to establish causality and lack of generalizability to hospitalized patients.ConclusionsDysnatremias are prevalent among ambulatory CKD patients and are associated with mortality and kidney failure. Time-dependent dysnatremias were significantly associated with mortality in patients with CKD. Time-dependent hypernatremia was associated with progression to kidney failure. Baseline and time-dependent hyponatremia were associated with an increased risk of progression to kidney failure in those younger than 65 years.

Project description:BackgroundCardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD.Study designCross-sectional and longitudinal observational analysis.Setting & participantsAdults with CKD from 7 US sites participating in the Chronic Renal Insufficiency Cohort (CRIC) Study.PredictorQuartiles of plasma CX3CL1 levels at baseline.OutcomesBaseline estimated glomerular filtration rate from a creatinine and cystatin C-based equation, prevalent and incident CVD, diabetes, metabolic syndrome and its criteria, homeostatic model assessment of insulin resistance, hemoglobin A1c level, myocardial infarction, all-cause mortality, and the composite outcome of myocardial infarction/all-cause mortality.ResultsAmong 3,687 participants, baseline CX3CL1 levels were associated positively with several CVD risk factors and metabolic traits, lower estimated glomerular filtration rate, and higher levels of inflammatory cytokines, as well as prevalent CVD (OR, 1.09; 95% CI, 1.01-1.19; P=0.03). Higher CX3CL1 level also was associated with prevalent diabetes (OR, 1.26; 95% CI, 1.16-1.38; P<0.001) in adjusted models. During a mean follow-up of 6 years, there were 352 deaths, 176 myocardial infarctions, and 484 composite outcomes. In fully adjusted models, 1-SD higher CX3CL1 level increased the hazard for all-cause mortality (1.11; 95% CI, 1.00-1.22; P=0.02) and the composite outcome (1.09; 95% CI, 1.00-1.19; P=0.04).LimitationsStudy design did not allow evaluation of changes over time, correlation with progression of phenotypes, or determination of causality of effect.ConclusionsCirculating CX3CL1 level may contribute to both atherosclerotic CVD and diabetes in a CKD cohort. Further studies are required to establish mechanisms through which CX3CL1 affects the pathogenesis of atherosclerosis and diabetes.

Project description:Rationale & objectiveQuality of life in chronic kidney disease (CKD) is impaired by a large burden of symptoms including some that overlap with the symptoms of heart failure (HF). We studied a group of individuals with CKD to understand the patterns and trajectories of HF-type symptoms in this setting.Study designProspective cohort study.Setting & participants3,044 participants in the Chronic Renal Insufficiency Cohort (CRIC) without prior diagnosis of HF.PredictorsSociodemographics, medical history, medications, vital signs, laboratory values, echocardiographic and electrocardiographic parameters.OutcomeTrajectory over 5.5 years of a HF-type symptom score (modified Kansas City Cardiomyopathy Questionnaire [KCCQ] Overall Summary Score with a range of 0-100 where<75 reflects clinically significant symptoms).Analytical approachLatent class mixed models were used to model trajectories. Multinomial logistic regression was used to model relationships of predictors with trajectory group membership.ResultsFive trajectories of KCCQ score were identified in the cohort of 3,044 adults, 45% of whom were female, and whose median age was 61 years. Group 1 (41.7%) had a stable high score (minimal symptoms, average score of 96); groups 2 (35.6%) and 3 (15.6%) had stable but lower scores (mild symptoms [average of 81] and clinically significant symptoms [average of 52], respectively). Group 4 (4.9%) had a substantial worsening in symptoms over time (mean 31-point decline), and group 5 (2.2%) had a substantial improvement (mean 33-point increase) in KCCQ score. A majority of group 1 was male, without diabetes or obesity, and this group had higher baseline kidney function. A majority of groups 2 and 3 had diabetes and obesity. A majority of group 4 was male and had substantial proteinuria. Group 5 had the highest proportion of baseline cardiovascular disease (CVD).LimitationsNo validation cohort available, CKD management changes in recent years may alter trajectories, and latent class models depend on the missing at random assumption.ConclusionsDistinct HF-type symptom burden trajectories were identified in the setting of CKD, corresponding to different baseline characteristics. These results highlight the diversity of HF-type symptom experiences in individuals with CKD.

Project description:Rationale & objectiveFew studies have examined incident type 2 diabetes mellitus (T2DM) in chronic kidney disease (CKD). Our objective was to examine rates of and risk factors for T2DM in CKD, using several alternative measures of glycemic control.Study designProspective cohort study.Setting & participants1,713 participants with reduced glomerular filtration rates and without diabetes at baseline, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study.PredictorsMeasures of kidney function and damage, fasting blood glucose, hemoglobin A1c (HbA1c), HOMA-IR (homeostatic model assessment of insulin resistance), demographics, family history of diabetes mellitus (DM), smoking status, medication use, systolic blood pressure, triglyceride level, high-density lipoprotein cholesterol level, body mass index, and physical activity.OutcomeIncident T2DM (defined as fasting blood glucose ≥ 126mg/dL or prescription of insulin or oral hypoglycemic agents).Analytical approachConcordance between fasting blood glucose and HbA1c levels was assessed using κ. Cause-specific hazards modeling, treating death and end-stage kidney disease as competing events, was used to predict incident T2DM.ResultsOverall T2DM incidence rate was 17.81 cases/1,000 person-years. Concordance between fasting blood glucose and HbA1c levels was low (κ for categorical versions of fasting blood glucose and HbA1c = 13%). Unadjusted associations of measures of kidney function and damage with incident T2DM were nonsignificant (P ≥ 0.4). In multivariable models, T2DM was significantly associated with fasting blood glucose level (P = 0.002) and family history of DM (P = 0.03). The adjusted association of HOMA-IR with T2DM was comparable to that of fasting blood glucose level; the association of HbA1c level was nonsignificant (P ≥ 0.1). Harrell's C for the models ranged from 0.62 to 0.68.LimitationsLimited number of outcome events; predictors limited to measures taken at baseline.ConclusionsThe T2DM incidence rate among individuals with CKD is markedly higher than in the general population, supporting the need for greater vigilance in this population. Measures of glycemic control and family history of DM were independently associated with incident T2DM.

Dataset Information

Candidate gene association study of coronary artery calcification in chronic kidney disease: findings from the CRIC study (Chronic Renal Insufficiency Cohort).

Publications

Candidate gene association study of coronary artery calcification in chronic kidney disease: findings from the CRIC study (Chronic Renal Insufficiency Cohort).

Similar Datasets

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