Familial aggregation of atrial fibrillation in Iceland

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldAIMS: To examine the heritability of atrial fibrillation (AF) in Icelanders, utilizing a nationwide genealogy database and population-based data on AF. AF is a disorder with a high prevalence, which has been known to cluster in families, but the heritability of the common form has not been well defined. METHODS AND RESULTS: The study population included 5269 patients diagnosed since 1987 and age-sex-matched controls randomly selected from the genealogy database. Kinship coefficients (KC), expressed as genealogical index of familiality (GIF = average KC x 100,000), were calculated before and after exclusion of relatives separated by one to five meiotic events. Risk ratios (RR) were calculated for first- to fifth-degree relatives. The average pairwise GIF among patients with AF was 15.9 (mean GIF for controls 13.9, 95%CI = 13.3, 14.4); this declined to 15.4 (mean GIF for controls 13.6, 95%CI = 13.1, 14.2) after exclusion of relatives separated by one meiosis and to 13.7 (mean GIF for controls 12.6, 95%CI = 12.1, 13.2), 12.7 (mean GIF for controls 11.9, 95%CI = 11.4, 12.4), and 11.3 (mean GIF for controls 10.6, 95%CI = 10.1, 11.1) after exclusion of relatives within two, three, and four meioses, respectively (all P<0.00001). RRs among relative pairs also declined incrementally, from 1.77 in first-degree relatives to 1.36, 1.18, 1.10, and 1.05 in second- through fifth-degree relatives (all P<0.001), consistent with the declining proportion of alleles shared identically by descent. When the analysis was limited to subjects diagnosed with AF before the age of 60, first-degree relatives of the AF cases were nearly five times more likely to have AF than the general population. CONCLUSION: AF shows strong evidence of heritability among unselected patients in Iceland, suggesting that there may be undiscovered genetic variants underlying the risk of the common form of AF

The association between glucose abnormalities and heart failure in the population-based Reykjavik study

To access publisher full text version of this article. Please click on the hyperlink in Additional Link fieldOBJECTIVE: Diabetes is an independent risk factor for heart failure, whereas the relation between heart failure and abnormal glucose regulation (AGR) needs further evaluation. We studied this combination in the Reykjavik Study. RESEARCH DESIGN AND METHODS: The Reykjavik Study, a population-based cohort study during 1967-1997, recruited 19,381 participants aged 33-84 years who were followed until 2002. Oral glucose tolerance tests and chest X-rays were obtained from all participants. Cases were defined in accordance with World Health Organization criteria for type 2 diabetes or AGR (impaired glucose tolerance or impaired fasting glucose) and European Society of Cardiology guidelines for heart failure. RESULTS: The overall prevalence of type 2 diabetes and heart failure was 0.5% in men and 0.4% in women, while AGR and heart failure were found in 0.7% of men and 0.6% of women. Among participants with normal glucose regulation, heart failure was diagnosed in 3.2% compared with 6.0 and 11.8% among those with AGR and type 2 diabetes, respectively. The prevalence of type 2 diabetes in the age-group 45-65 years increased in both sexes during the period (P for trend = 0.007). The odds ratio was 2.8 (95% CI 2.2-3.6) for the association between type 2 diabetes and heart failure and 1.7 (1.4-2.1) between AGR and heart failure. CONCLUSIONS: There is a strong association between any form of glucometabolic perturbation and heart failure. Future studies in this field should focus on all types of glucose abnormalities rather than previously diagnosed diabetes only

Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesAIMS: Scavenger receptor Class B Type 1 (SR-BI) is a major receptor for high-density lipoprotein (HDL) that promotes hepatic uptake of cholesterol from HDL. A rare mutation p.P376L, in the gene encoding SR-BI, SCARB1, was recently reported to associate with elevated HDL cholesterol (HDL-C) and increased risk of coronary artery disease (CAD), suggesting that increased HDL-C caused by SR-BI impairment might be an independent marker of cardiovascular risk. We tested the hypothesis that alleles in or close to SCARB1 that associate with elevated levels of HDL-C also associate with increased risk of CAD in the relatively homogeneous population of Iceland. METHODS AND RESULTS: Using a large resource of whole-genome sequenced Icelanders, we identified thirteen SCARB1 coding mutations that we examined for association with HDL-C (n = 136 672). Three rare SCARB1 mutations, encoding p.G319V, p.V111M, and p.V32M (combined allelic frequency = 0.2%) associate with elevated levels of HDL-C (p.G319V: β = 11.1 mg/dL, P = 8.0 × 10-7; p.V111M: β = 8.3 mg/dL, P = 1.1 × 10-6; p.V32M: β = 10.2 mg/dL, P = 8.1 × 10-4). These mutations do not associate with CAD (36 886 cases/306 268 controls) (odds ratio = 0.90, 95% confidence interval 0.67-1.22, P = 0.49), despite effects on HDL-C comparable to that reported for p.P376L, both in terms of direction and magnitude. Furthermore, HDL-C raising alleles of three common SCARB1 non-coding variants, including one previously unreported (rs61941676-C: β = 1.25 mg/dL, P = 1.7 × 10-18), and of one low frequency coding variant (p.V135I) that independently associate with higher HDL-C, do not confer increased risk of CAD. CONCLUSION: Elevated HDL-C due to genetically compromised SR-BI function is not a marker of CAD risk.deCODE genetics/Amge

Migraine with aura and risk of cardiovascular and all cause mortality in men and women: prospective cohort study

Objective To estimate whether migraine in mid-life is associated with mortality from cardiovascular disease, other causes, and all causes

Sequence variant at 4q25 near PITX2 associates with appendicitis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesAppendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 × 10(-11)). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk

A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldPreviously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.info:eu-repo/grantAgreement/EC/FP7/21807

RANTES/CCL5 and risk for coronary events: Results from the MONICA/KORA Augsburg case-cohort, Athero-express and CARDIoGRAM studies

Background: The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. Methods and Findings: We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±

Time course analysis of gene expression identifies multiple genes with differential expression in patients with in-stent restenosis

Abstract Background The vascular disease in-stent restenosis (ISR) is characterized by formation of neointima and adverse inward remodeling of the artery after injury by coronary stent implantation. We hypothesized that the analysis of gene expression in peripheral blood mononuclear cells (PBMCs) would demonstrate differences in transcript expression between individuals who develop ISR and those who do not. Methods and Results We determined and investigated PBMC gene expression of 358 patients undergoing an index procedure to treat in de novo coronary artery lesions with bare metallic stents, using a novel time-varying intercept model to optimally assess the time course of gene expression across a time course of blood samples. Validation analyses were conducted in an independent sample of 97 patients with similar time-course blood sampling and gene expression data. We identified 47 probesets with differential expression, of which 36 were validated upon independent replication testing. The genes identified have varied functions, including some related to cellular growth and metabolism, such as the NAB2 and LAMP genes. Conclusions In a study of patients undergoing bare metallic stent implantation, we have identified and replicated differential gene expression in peripheral blood mononuclear cells, studied across a time series of blood samples. The genes identified suggest alterations in cellular growth and metabolism pathways, and these results provide the basis for further specific functional hypothesis generation and testing of the mechanisms of ISR.http://deepblue.lib.umich.edu/bitstream/2027.42/112500/1/12920_2010_Article_214.pd

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms