Line Dufresne

CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure.

The caspase recruitment domain gene (CARD15) was recently identified as the underlying gene associated with the IBD1 locus that confers susceptibility to Crohn disease (CD). CARD15 is related to the NOD1/Apaf-1 family of apoptosis regulators, and three sequence variants (Arg702Trp, Gly908Arg, and Leu1007fsinsC) in the gene were demonstrated to be associated with CD. We collected a cohort of 231 patients with CD and 71 healthy control individuals from the Canadian province of Quebec, to determine the prevalence of these sequence variants in an independent population. Clinical records of all patients were systematically reviewed, and detailed phenotypic information was obtained. All patient DNA samples were genotyped for the three variants, thus enabling an analysis of genotype-phenotype correlations. In this cohort, 45.0% of patients with CD carried at least one variant in the CARD15 gene, compared with 9.0% of control individuals (P<10-7). Allele frequencies of Arg702Trp, Gly908Arg, and Leu1007fsinsC were 12.9%, 5.2%, and 10.3% in patients with CD, compared with 4.2%, 0.7%, and 0.7% in control individuals, respectively. Importantly, CARD15 mutants were seen with equal frequency in patients with familial and sporadic CD. Analysis of the relationship between genotype and phenotype convincingly demonstrates that CARD15 variants are significantly associated with ileal disease involvement, as opposed to strictly colonic disease (P<.001). Moreover, we were able to determine the haplotype structure surrounding this disease gene by genotyping 45 single-nucleotide polymorphisms (SNPs) in a 177-kb region that contained the CARD15 gene. This structure helps clarify the history of these causal mutations. Finally, this analysis shows that CARD15 involvement with CD is detectable by use of publicly available SNPs alone.

Predicting relapse in Crohn’s disease: a biopsychosocial model

Background: Crohn’s disease (CD) is a chronic relapsing inflammatory bowel disorder. Both biological and psychosocial factors may modulate the illness experience. Aim: The aim of this study was to identify clinical, biological and psychosocial parameters as predictors of clinical relapse in quiescent CD. Methods: Patients in medically induced remission were followed prospectively for 1 year, or less if they relapsed. Disease characteristics were determined at baseline. Serum cytokines, anti-Saccharomyces cerevisiae antibodies, C-reactive protein (CRP), erythrocyte sedimentation rate and intestinal permeability were measured every 3 months. Psychological distress, perceived stress, minor life stressors and coping strategies were measured monthly. A time-dependent multivariate Cox regression model determined predictors of time to relapse. Results: 101 patients (60 females, 41 males) were recruited. Fourteen withdrew and 37 relapsed. CRP (HR = 1.5 per 10 mg/l, 95% CI 1.1 to 1.9, p = 0.007), fistulising disease (HR = 3.2, 95% CI, 1.1 to 9.4, p = 0.04), colitis (HR = 3.5 95% CI 1.2 to 9.9, p = 0.02) and the interaction between perceived stress and avoidance coping (HR = 7.0 per 5 unit increase for both scales, 95% CI 2.3 to 21.8, p = 0.003) were predictors of earlier relapse. Conclusions: In quiescent CD, a higher CRP, fistulising disease behaviour and disease confined to the colon were independent predictors of relapse. Moreover, patients under conditions of low stress and who scored low on avoidance coping (ie, did not engage in social diversion or distraction) were least likely to relapse. This study supports a biopsychosocial model of CD exacerbation.

Association of Low-Density Lipoprotein Cholesterol–Related Genetic Variants With Aortic Valve Calcium and Incident Aortic Stenosis

IMPORTANCE Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. OBJECTIVE To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease. DESIGN, SETTING, AND PARTICIPANTS Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n = 6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2527), Age Gene/Environment Study-Reykjavik (2000-2012; n = 3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n = 28,461). MAIN OUTCOMES AND MEASURES Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS. RESULTS The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n = 2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n = 473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n = 205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P = .02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P = .007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P = .02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P = .03) and aortic stenosis (P = .009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P = .02). CONCLUSIONS AND RELEVANCE Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.

Tumor necrosis factor receptor gene polymorphisms in Crohn's disease: association with clinical phenotypes.

OBJECTIVES:Crohns disease (CD) is a chronic multifactorial disorder with diverse clinical features that are influenced by a heterogeneous set of genetic factors. TNF-α/TNF receptor interactions play a pivotal role in the pathogenesis of the inflammatory response. Our purpose was to determine whether single nucleotide polymorphisms (SNPs) in the TNF receptors confer susceptibility to Crohns disease and whether they are associated with clinical phenotype.METHODS:A cohort of 205 consecutively identified and unrelated patients with CD and 106 controls were recruited. Subjects were genotyped for polymorphisms in TNFRSF1A (position +36, −609), TNFRSF1B (+196, +1466), along with the three common CARD15 variants and phenotyped for disease behavior. Genotypic and allelic frequencies were compared between CD and controls and a logistic regression model was constructed to determine independent associations with specific clinical phenotypes.RESULTS:Only the TNFRSF1A +36 and TNFRSF1B +196 SNPs were associated with CD (p = 0.0019 and 0.034, respectively). The TNFRSF1A +36 mutation was negatively associated with stricturing disease phenotype (OR = 0.384; CI = 0.166–0.887). In contrast, the TNFRSF1B +196 was negatively associated with colitis (OR = 0.410; CI = 0.191–0.880). These associations were independent of CARD15 mutation status. Finally, TNFRSF1B +196 was negatively associated with surgery in CARD15 negative patients.CONCLUSIONS:These data constitute the first report of an association of TNFRSF1A and TNFRSF1B polymorphisms with CD in a Caucasian population and address the role of TNFR mutations in determining clinical heterogeneity in CD.

Lipoprotein(a) Interactions With Low‐Density Lipoprotein Cholesterol and Other Cardiovascular Risk Factors in Premature Acute Coronary Syndrome (ACS)

Background Current recommendations for lipoprotein(a) (Lp[a]) focus on the control of other risk factors, including lowering low‐density lipoprotein cholesterol (LDL‐C), with little evidence to support this approach. Identifying interactions between Lp(a) and other risk factors could identify individuals at increased risk for Lp(a)‐mediated disease. Methods and Results We used a case‐only study design and included 939 participants (median age=49 years, interquartile range 46–53, women=33.1%) from the GENdEr and Sex determInantS of cardiovascular disease: from bench to beyond‐Premature Acute Coronary Syndrome (GENESIS‐PRAXY) study, a multicenter prospective cohort study of premature acute coronary syndrome. There was a higher prevalence of elevated Lp(a) levels (>50 mg/dL; 80th percentile) in PRAXY participants as compared to the general population (31% versus 20%; P<0.001). Lp(a) was strongly associated with LDL‐C (adjusted β 0.17; P<0.001). Individuals with high Lp(a) were more likely to have LDL‐C >2.5 mmol/L, indicating a synergistic interaction (adjusted odds ratio 1.51; 95% CI 1.08–2.09; P=0.015). The interaction with high Lp(a) was stronger at increasing LDL‐C levels (LDL‐C >3.5, adjusted odds ratio 1.87; LDL‐C >4.5, adjusted odds ratio 2.72). In a polytomous logistic model comparing mutually exclusive LDL‐C categories, the interaction with high Lp(a) became attenuated at LDL‐C ≤3.5 mmol/L (odds ratio 1.16; 95% CI 0.80–1.68, P=0.447). Other risk factors were not associated with high Lp(a). Conclusions In young acute coronary syndrome patients, high Lp(a) is more prevalent than in the general population and is strongly associated with high LDL‐C, suggesting that Lp(a) confers greater risk for acute coronary syndrome when LDL‐C is elevated. Individuals with high Lp(a) and LDL‐C >3.5 mmol/L may warrant aggressive LDL‐C lowering.

Association Between Family History, a Genetic Risk Score, and Severity of Coronary Artery Disease in Patients With Premature Acute Coronary Syndromes

Objective— A genetic risk score (GRS) for coronary artery disease has recently been shown to be independent of family history (FHx) in predicting future cardiovascular events. We sought to determine whether the presence of these risk factors, either individually or together, was associated with a higher burden of angiographic coronary artery disease. Approach and Results— We included 763 patients with premature acute coronary syndrome (median age, 50 [46–53] years; 30.8% women) with at least 1 major epicardial vessel stenosis enrolled in the Gender and Sex Determinants of Cardiovascular Disease From Bench to Beyond in Premature Acute Coronary Syndrome (GENESIS-PRAXY) study, a multicentre prospective cohort study of premature patients with acute coronary syndrome (aged ⩽55 years). The prevalence of multivessel disease (ie, ≥2 vessels with >50% stenosis) in individuals with FHx was 49.7% as compared with 37.9% in those without FHx (P<0.01 for comparison). In adjusted models for age, sex, traditional risk factors, and GRS, FHx was associated with a higher prevalence of 3-vessel disease (odds ratio [OR], 1.42; 95% confidence interval, 0.91–2.21; P=0.12 for 2-vessel disease and OR, 2.26; 95% confidence interval, 1.29–3.95; P=0.005 for 3-vessel disease). Individuals with a high GRS were also more likely to have multivessel disease (OR, 1.41; 95% confidence interval, 1.01–1.99; P=0.047) after adjustment for traditional risk factors, including FHx. Individuals with both a FHx and a high GRS as compared with those with neither had the highest ORs for multivessel disease (adjusted OR, 2.14; 95% confidence interval, 1.24–3.69; P=0.0064). Conclusions— In patients with premature acute coronary syndrome, the presence of either a high GRS or FHx is associated with greater severity of coronary artery disease at angiography. Whether preventive strategies targeted to genetically predisposed individuals will reduce the burden of early acute coronary syndrome warrants further study.

Genetic loci associated with ideal cardiovascular health: A meta-analysis of genome-wide association studies

BACKGROUND Multiple genetic loci are associated with clinical cardiovascular (CV) disease and individual CV risk factors. Individuals with ideal levels of all major CV risk factors have very low risk for CV disease morbidity or mortality. Ideal levels of risk factors can be attained by lifestyle modifications; however, little is known about gene variants associated with ideal CV health. Our objective was to carry out a genome-wide association study on the trait. METHODS AND RESULTS We examined 2 dichotomous phenotypes of ideal CV health-clinical (untreated cholesterol <200 mg/dL, untreated blood pressure <120/<80, not diabetic) and clinical+behavioral (clinical plus: not a current smoker, body mass index <25 kg/m(2))-among white participants aged 50±5 years. We performed a meta-analysis of 4 genome-wide association studies (total n=11,708) from the MESA, CARDIA, ARIC, and Framingham Heart Study cohorts. We identified a single-nucleotide polymorphism (rs445925) in the APOC1/APOE region that was associated with clinical ideal CV health at genome-wide level of significance (P<2.0 × 10(-9)). The significance of this region was validated using exome chip genotyping. The association with ideal CV health was attenuated after adjusting for low-density lipoprotein cholesterol. CONCLUSION A common single-nucleotide polymorphism in the APOC1/APOE region, previously found to be associated with protective levels of cholesterol and lower CV risk, may be associated with ideal health. In future replication studies, larger sample sizes may be needed to detect loci with more modest effects on ideal CV health. In addition to the important impact of lifestyle modifications, we have identified evidence for gene variation that plays a role in ideal CV health.

Association of LPA Variants With Aortic Stenosis: A Large-Scale Study Using Diagnostic and Procedural Codes From Electronic Health Records

Importance Elevated lipoprotein(a) levels are a risk factor for aortic stenosis (AS). However, a large-scale replication of associations between LPA variants and AS, their interactions with risk factors, and the effect of multiple risk alleles is not well established. Objective To replicate the association between LPA variants with AS and identify subgroups who are at higher risk of developing AS. Design, Setting, and Participants This case-control study of AS included 44 703 individuals (3469 cases) 55 years or older who were enrolled in the Genetic Epidemiology Research on Aging cohort and who were members of the Kaiser Permanente Northern California health care delivery system. The study leveraged the linkage of administrative health data, electronic medical records, genotypes, and self-reported questionnaire data. The 3469 AS cases were diagnosed between January 1996 and December 2015. Individuals with valvular congenital heart disease were excluded. Exposures Two single-nucleotide polymorphisms in the LPA locus, rs10455872 and rs3798220, that are known to associate with circulating plasma lipoprotein(a) levels and an LPA risk score. Main Outcomes and Measures Aortic stenosis or aortic valve replacement. Results The 44 703 participants were of European ancestry,of whom 22 019 (49.3%) were men. The mean (SD) age for the control group was 69.3 (8.3) years and the mean (SD) age for AS cases was 74.6 (8.5) years. Both LPA variants were associated with AS, with a per risk allele odds ratio of 1.34 (95% CI, 1.23-1.47; P = 1.7 × 10−10) for rs10455872 and 1.31 (95% CI, 1.09-1.58; P = 3.6 × 10−3) for rs3798220 after adjusting for age, age2, and sex. The results remained significant after adjusting for risk factors. The estimates were similar for an LPA risk score. Individuals with 2 risk alleles had a 2-fold or greater odds of AS compared with individuals with no risk alleles (for rs10455872, homozygous odds ratio, 2.05; 95% CI, 1.37-3.07; P = 5.3 × 10−4; for rs3798220, homozygous odds ratio, 3.74; 95% CI, 1.03-13.6; P = .05; and for compound heterygotes, odds ratio, 2.00; 95% CI, 1.17-3.44; P = .01). For rs10455872, the odds ratio for AS was greatest in individuals aged 55 to 64 years and declined with age (interaction P = .03). Each rs10455872 risk allele was also associated with AS that was diagnosed 0.71 years earlier (95% CI, −1.42 to 0; P = .05). Conclusions and Relevance We provide a large-scale confirmation of the association between 2 LPA variants and AS, reaching genome-wide significance. In addition, individuals with 2 risk alleles have 2-fold or greater odds of developing AS. Age may modify these associations and identify subgroups who are at greater risk of developing AS.

Pathway analysis for genetic association studies: to do, or not to do? That is the question

In Genetic Analysis Workshop 18 data, we used a 3-stage approach to explore the benefits of pathway analysis in improving a model to predict 2 diastolic blood pressure phenotypes as a function of genetic variation. At stage 1, gene-based tests of association in family data of approximately 800 individuals found over 600 genes associated at p<0.05 for each phenotype. At stage 2, networks and enriched pathways were estimated with Cytoscape for genes from stage 1, separately for the 2 phenotypes, then examining network overlap. This overlap identified 4 enriched pathways, and 3 of these pathways appear to interact, and are likely candidates for playing a role in hypertension. At stage 3, using 157 maximally unrelated individuals, partial least squares regression was used to find associations between diastolic blood pressure and single-nucleotide polymorphisms in genes highlighted by the pathway analyses. However, we saw no improvement in the adjusted cross-validated R2. Although our pathway-motivated regressions did not improve prediction of diastolic blood pressure, merging gene networks did identify several plausible pathways for hypertension.

Observational and Genetic Associations of Resting Heart Rate With Aortic Valve Calcium

It is unknown if lifelong exposure to increased hemodynamic stress from an elevated resting heart rate (HR) may contribute to aortic valve calcium (AVC). We performed multivariate regression analyses using data from 1,266 Framingham Heart Study (FHS) Offspring cohort participants and 6,764 Multi-Ethnic Study of Atherosclerosis (MESA) participants. We constructed a genetic risk score (GRS) for HR using summary-level data in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) AVC Consortium to investigate if there was evidence in favor of a causal relation. AVC was present in 39% of FHS Offspring cohort participants and in 13% of MESA cohort participants. In multivariate adjusted models, participants in the highest resting HR quartiles had significantly greater prevalence of AVC, with a prevalence ratio of 1.19 (95% confidence interval [CI] 0.99 to 1.44) for the FHS Offspring cohort and 1.32 (95% CI 1.12 to 1.63) for the MESA cohort, compared with those in the lowest quartile. There was a similar increase in the prevalence of AVC per standard deviation increase in resting HR in both FHS Offspring (prevalence ratio 1.08, 95% CI 1.01 to 1.15) and MESA (1.10, 95% CI 1.03 to 1.17). In contrast with these observational findings, a HR associated GRS was not significantly associated with AVC. Although our observational analysis indicates that a higher resting HR is associated with AVC, our genetic results do not support a causal relation. Unmeasured environmental and/or lifestyle factors associated with both increased resting HR and AVC that are not fully explained by covariates in our observational models may account for the association between resting HR and AVC.