David O. Arnar

Variants conferring risk of atrial fibrillation on chromosome 4q25.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left–right asymmetry of the heart.

Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 × 10−14, 5.4 × 10−10, 8.6 × 10−17, 1.2 × 10−10 and 6.5 × 10−19, respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 × 10−12) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 × 10−6, 2.2 × 10−5 and 2.4 × 10−4, respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 × 10−8) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke

We expanded our genome-wide association study on atrial fibrillation (AF) in Iceland, which previously identified risk variants on 4q25, and tested the most significant associations in samples from Iceland, Norway and the United States. A variant in the ZFHX3 gene on chromosome 16q22, rs7193343-T, associated significantly with AF (odds ratio OR = 1.21, P = 1.4 × 10−10). This variant also associated with ischemic stroke (OR = 1.11, P = 0.00054) and cardioembolic stroke (OR = 1.22, P = 0.00021) in a combined analysis of five stroke samples.

Several common variants modulate heart rate, PR interval and QRS duration

Electrocardiographic measures are indicative of the function of the cardiac conduction system. To search for sequence variants that modulate heart rate, PR interval and QRS duration in individuals of European descent, we performed a genome-wide association study in ∼10,000 individuals and followed up the top signals in an additional ∼10,000 individuals. We identified several genome-wide significant associations (with P < 1.6 × 10−7). We identified one locus for heart rate (MYH6), four for PR interval (TBX5, SCN10A, CAV1 and ARHGAP24) and four for QRS duration (TBX5, SCN10A, 6p21 and 10q21). We tested for association between these loci and subjects with selected arrhythmias in Icelandic and Norwegian case-control sample sets. We observed correlations between TBX5 and CAV1 and atrial fibrillation (P = 4.0 × 10−5 and P = 0.00032, respectively), between TBX5 and advanced atrioventricular block (P = 0.0067), and between SCN10A and pacemaker implantation (P = 0.0029). We also replicated previously described associations with the QT interval.

Large-scale whole-genome sequencing of the Icelandic population

Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.

EHRA Expert Consensus Statement on the management of cardiovascular implantable electronic devices in patients nearing end of life or requesting withdrawal of therapy

The purpose of this Consensus Statement is to focus on implantable cardioverter-defibrillator (ICD) deactivation in patients with irreversible or terminal illness. This statement summarizes the opinions of the Task Force members, convened by the European Heart Rhythm Association (EHRA) and the Heart Rhythm Society (HRS), based on ethical and legal principles, as well as their own clinical, scientific, and technical experience. It is directed to all healthcare professionals who treat patients with implanted ICDs, nearing end of life, in order to improve the patient dying process. This statement is not intended to recommend or promote device deactivation. Rather, the ultimate judgement regarding this procedure must be made by the patient (or in special conditions by his/her legal representative) after careful communication about the deactivations consequences, respecting his/her autonomy and clarifying that he/she has a legal and ethical right to refuse it. Obviously, the physician asked to deactivate the ICD and the industry representative asked to assist can conscientiously object to and refuse to perform device deactivation.

Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke

To find sequence variants that associate with the risk for ischemic stroke (IS), we performed a genome‐wide association study.

A rare variant in MYH6 is associated with high risk of sick sinus syndrome

Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10−29. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.

Trends in the incidence and prevalence of atrial fibrillation in Iceland and future projections

AIMSnData are scarce on the epidemiology of atrial fibrillation (AF) in Europe. The aim of this study was to examine recent trends in the incidence and prevalence of AF and project the prevalence to the year 2050.nnnMETHODS AND RESULTSnFrom 1991 to 2008 a total of 4905 residents of Reykjavik, Iceland were diagnosed with AF at the citys main health care centre. The age-standardized incidence of AF increased in women (0.9% per year, 95% CI 0.1-1.8) but not in men (0.1% per year, 95% CI -0.6 to 0.9). The age-standardized prevalence increased per year by 1.8% (95% CI 1.3-2.3) in men and 2.3% (95% CI 1.7-2.9) in women from 1998 to 2008. The number of adults with AF in Iceland is projected to increase from 4495 (prevalence 2.0%) in 2008 to 11 088 (prevalence 3.5%) in 2050, if the incidence of AF and mortality remain constant beyond 2008. However, if the incidence continues to increase as it has and mortality decreases according to projections for the general population, the projected number will rise to 13 583 (prevalence 4.3%).nnnCONCLUSIONnIn this study in a northern European population, the incidence of AF increased in women but not men from 1991 to 2008. The prevalence of AF is currently high and the number of patients with AF is expected to triple in the next four decades. AF is already a serious public health problem and the burden of this disease could reach epidemic proportions in the coming years.

Does treatment with n-3 polyunsaturated fatty acids prevent atrial fibrillation after open heart surgery?

AIMSnTo examine the effect of n-3 polyunsaturated fatty acid (PUFA) treatment on the incidence of post-operative atrial fibrillation (POAF).nnnMETHODS AND RESULTSnA prospective, randomized, double-blinded, placebo-controlled trial was conducted in patients admitted for coronary artery bypass grafting and/or valvular repair surgery. The patients received either n-3 PUFA capsules, containing a daily dose of 1240 mg eicosapentaenoic acid and 1000 mg docosahexaenoic acid, or olive oil capsules for 5-7 days prior to surgery and post-operatively until hospital discharge. The endpoint was POAF, defined as an episode detected by continuous electrocardiographic monitoring, lasting >5 min. A total of 170 patients were enrolled in the study, and 168 patients underwent surgery. Their median age was 67 (range 43-82) years, and 79.2% were males. There was no difference in baseline characteristics between the n-3 PUFA group (n = 83) and the placebo group (n = 85), and the incidence of POAF was 54.2 and 54.1% (P = 0.99), respectively. Factors associated with POAF included advanced age, peak post-operative C-reactive protein level, valvular surgery, lower body mass index, and non-smoking, but n-3 PUFA concentration in plasma lipids was not associated with POAF.nnnCONCLUSIONnThere is no evidence for a beneficial effect of treatment with n-3 PUFA on the occurrence of POAF in patients undergoing open heart surgery.