Genome-wide association study identifies 18 novel loci associated with left atrial volume and function.

AIMS: Left atrial (LA) volume and function impose significant impact on cardiovascular pathogenesis if compromised. We aimed at investigating the genetic architecture of LA volume and function using cardiac magnetic resonance imaging data. METHODS AND RESULTS: We used the UK Biobank, which is a large prospective population study with available phenotypic and genetic data. On a subset of 35 658 European individuals, we performed genome-wide association studies on five volumetric and functional LA variables, generated using a machine learning algorithm. In total, we identified 18 novel genetic loci, mapped to genes with known roles in cardiomyopathy (e.g. MYO18B, TTN, DSP, ANKRD1) and arrhythmia (e.g. TTN, CASQ2, MYO18B, C9orf3). We observed high genetic correlation between LA volume and function and stroke, which was most pronounced for LA passive emptying fraction (rg = 0.40, P = 4 × 10-6). To investigate whether the genetic risk of atrial fibrillation (AF) is associated with LA traits that precede overt AF, we produced a polygenetic risk score for AF. We found that polygenetic risk for AF is associated with increased LA volume and decreased LA function in participants without AF [LAmax 0.25 (mL/m2)/standard deviation (SD), 95% confidence interval (CI) (0.15; 0.36), P = 5.13 × 10-6; LAmin 0.21 (mL/m2)/SD, 95% CI (0.15; 0.28), P = 1.86 × 10-10; LA active emptying fraction -0.35%/SD, 95% CI (-0.43; -0.26), P = 3.14 × 10-14]. CONCLUSION: We report on 18 genetic loci associated with LA volume and function and show evidence for several plausible candidate genes important for LA structure.

Genetic variants on chromosomes 7p31 and 12p12 are associated with abnormal atrial electrical activation in patients with early-onset lone atrial fibrillation.

BACKGROUND: Abnormal P-wave morphology (PWM) has been associated with a history of atrial fibrillation (AF) in earlier studies. Although lone AF is believed to have substantial genetic basis, studies on associations between single nucleotide polymorphisms (SNP) linked to lone AF and PWM have not been reported. We aimed to assess whether SNPs previously associated with lone AF (rs2200733, rs13376333, rs3807989, and rs11047543) are also linked to P-wave abnormalities. METHODS: Four SNPs were studied in 176 unrelated individuals with early-onset lone AF (age at onset <50 years), median age 38 years (19-63 years), 149 men. Using sinus rhythm ECG, orthogonal PWM was classified as Type 1-positive in leads X and Y and negative in lead Z, Type 2-positive in leads X and Y and biphasic (-/+) in lead Z, Type 3-positive in lead X and biphasic in lead Y (+/-), and the remaining as atypical. RESULTS: Two SNPs were found to be significantly associated with altered P-wave morphology distribution: rs3807989 near the gene CAV1/CAV2 and rs11047543 near the gene SOX5. Both SNPs were associated with a higher risk of non-Type 1 P-wave morphology (rs3807989: OR = 4.8, 95% CI = 2.3-10.2, p < 0.001; rs11047543: OR = 4.7, 95% CI = 1.1-20.5, p = 0.04). No association was observed for rs2200733 and rs13376333. CONCLUSION: In this study, the two variants rs3807989 and rs11047543, previously associated with PR interval and lone AF, were associated with altered P-wave morphology distribution in patients with early-onset lone AF. These findings suggest that common genetic variants may modify atrial conduction properties.

Numerous Brugada syndrome-associated genetic variants have no effect on J-point elevation, syncope susceptibility, malignant cardiac arrhythmia, and all-cause mortality.

PURPOSE: We investigated whether Brugada syndrome (BrS)-associated variants identified in the general population have an effect on J-point elevation as well as whether carriers of BrS variants were more prone to experience syncope and malignant ventricular arrhythmia and had increased mortality compared with noncarriers. METHODS: All BrS-associated variants were identified using the Human Gene Mutation Database (HGMD). Individuals were randomly selected from a general population study using whole-exome sequencing data (n = 870) and genotype array data (n = 6,161) and screened for BrS-associated variants. Electrocardiograms (ECG) were analyzed electronically, and data on syncope, ventricular arrhythmias, and mortality were obtained from administrative health-care registries. RESULTS: In HGMD, 382 BrS-associated genetic variants were identified. Of these, 28 variants were identified in the study cohort. None of the carriers presented with type 1 BrS ECG pattern. Mean J-point elevation in V1 and V2 were within normal guideline limits for carriers and noncarriers. There was no difference in syncope susceptibility (carriers 8/624; noncarriers 98/5,562; P = 0.51), ventricular arrhythmia (carriers 4/620; noncarriers 9/5,524; P = 0.24), or overall mortality (hazard ratio 0.93, 95% CI 0.63-1.4). CONCLUSIONS: Our data indicate that a significant number of BrS-associated variants are not the monogenic cause of BrS.Genet Med advance online publication 06 October 2016.

Association of common genetic variants related to atrial fibrillation and the risk of ventricular fibrillation in the setting of first ST-elevation myocardial infarction.

BACKGROUND: Cohort studies have revealed an increased risk for ventricular fibrillation (VF) and sudden cardiac death (SCD) in patients with atrial fibrillation (AF). In this study, we hypothesized that single nucleotide polymorphisms (SNP) previously associated with AF may be associated with the risk of VF caused by first ST-segment elevation myocardial infarction (STEMI). METHODS: We investigated association of 24 AF-associated SNPs with VF in the prospectively assembled case-control study among first STEMI-patients of Danish ancestry. RESULTS: We included 257 cases (STEMI with VF) and 537 controls (STEMI without VF). The median age at index infarction was 60 years for the cases and 61 years for the controls (p = 0.100). Compared to the control group, the case group was more likely to be male (86% vs. 75%, p = 0.001), have a history of AF (7% vs. 2%, p = 0.006) or hypercholesterolemia (39% vs. 31%, p = 0.023), and a family history of sudden death (40% vs. 25%, p < 0.001). All 24 selected SNPs have previously been associated with AF. None of the 24 SNPs were associated with the risk of VF after adjustment for age and sex under additive genetic model of inheritance in the logistic regression model. CONCLUSION: In this study, we found that the 24 AF-associated SNPs may not be involved in increasing the risk of VF. Larger VF cohorts and use of new next generation sequencing and epigenetic may in future identify additional AF and VF risk loci and improve our understanding of genetic pathways behind the two arrhythmias.

Gender differences in sudden cardiac death in the young-a nationwide study.

BACKGROUND: Hitherto, sudden cardiac death (SCD) in the young has been described with no distinction between genders. SCD occurs more often in men (SCDm) than women (SCDw), but this disparity is not understood and has not been investigated systematically in a nationwide setting. Our objective was to report gender differences in SCD in the young in a nationwide (Denmark) setting. METHODS: All deaths in persons aged 1-35 years nationwide in Denmark between 2000 and 2009 were included. Death certificates and autopsy reports were obtained. The extensive health care registries in Denmark were used to investigate any known disease prior to death. SCDw were compared to SCDm. RESULTS: During the 10-year study period there were a total of 8756 deaths in 23.7 million person-years. In total, 635 deaths were SCD. SCDw constituted 205 deaths (32%). Women had a higher proportion of witnessed deaths (51 vs. 41%, p = 0.02) and died less often in a public place (16 vs. 26%, p = 0.01). Age at death, ratios of autopsies and sudden unexplained deaths, and comorbidities, did not differ. Causes of SCD were largely comparable between genders. The incidence rate of SCDw was half of that of SCDm (1.8 vs. 3.6 per 100,000 person-years, incidence rate ratio 2.0 (95% CI 1.7-2.4), p < 0.01). CONCLUSIONS: Incidence rate ratio of SCDm vs SCDw is 2. Young SCDw and SCDm are equally investigated, have comparable comorbidity, and causes of SCD. SCD due to potentially inherited cardiac diseases is less often in young women and could reflect a protection of female gender.

Cardiac symptoms before sudden cardiac death caused by hypertrophic cardiomyopathy: a nationwide study among the young in Denmark.

AIMS: Hypertrophic cardiomyopathy (HCM) is a frequent cause of sudden cardiac death (SCD) among the young (SCDY). The aim of this study was to characterize symptoms before SCDY due to HCM. METHODS AND RESULTS: Through review of all death certificates, we identified all SCDs in Danes aged 1-35 years in 2000-2009. Nationwide we included all deaths (n = 8756) and identified 431 autopsied SCDYs. All available records from hospitals and general practitioners were retrieved. To compare symptoms, we included a control groups consisting of traffic accident victims (n = 74). In the 10-year study period, 431 autopsied SCDY cases were reviewed and 38 cases (9%) were included, of which 22 (58%) had morphologic findings diagnostic of HCM and 16 (42%) had findings suggestive, but not diagnostic, of HCM ('possible HCM'). Cardiac symptoms >1 h prior to death were reported in 21 (55%) of cases, and 16 (42%) sought medical attention. One (1%) control had cardiac symptoms before death. Consequently, a significantly higher proportion of cases had cardiac symptoms before death and cases more often sought medical attention than controls (P < 0.001). CONCLUSION: In conclusion, this nationwide study demonstrates a high frequency of cardiac symptoms prior to death in SCDY cases who died of HCM, as 55% had cardiac symptoms and nearly half of the cases sought medical attention.

Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval.

AIMS: We studied whether variants previously associated with congenital long QT syndrome (cLQTS) have an effect on the QTc interval in a Danish population sample. Furthermore, we assessed whether carriers of variants in cLQTS-associated genes are more prone to experience syncope compared with non-carriers and whether carriers have an increased mortality compared with non-carriers. METHODS AND RESULTS: All genetic variants previously associated with cLQTS were surveyed using the Human Gene Mutation Database. We screened a Danish population-based sample with available whole-exome sequencing data (n = 870) and genotype array data (n = 6161) for putative cLQTS genetic variants. In total, 33 of 1358 variants previously reported to associate with cLQTS were identified. Of these, 10 variants were found in 8 or more individuals. Electrocardiogram results showed normal mean QTc intervals in carriers compared with non-carriers. Syncope data analysis between variant and non-variant carriers showed that 4 of 227 (1.8%) and 95 of 5861 (1.6%) individuals, respectively, had experienced syncope during follow-up (P = 0.80). There was no significant difference in overall mortality rates between carriers [7/217 (3.2%)] and non-carriers [301/6453 (4.7%)] (P = 0.24). CONCLUSION: We present QTc data and register data, indicating that 26 cLQTS-associated variants neither had any effect on the QTc intervals nor on syncope propensity or overall mortality. Based on the frequency of individual gene variants, we suggest that the 10 variants frequently identified, assumed to relate to cLQTS, are less likely to associate with a dominant monogenic form of the disease.

IKs Gain- and Loss-of-Function in Early-Onset Lone Atrial Fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is the most frequent cardiac arrhythmia. The potassium current IKs is essential for cardiac repolarization. Gain-of-function mutation in KCNQ1, the gene encoding the pore-forming α-subunit of the IKs channel (KV 7.1), was the first ion channel dysfunction to be associated with familial AF. We hypothesized that early-onset lone AF is associated with a high prevalence of mutations in KCNQ1. METHODS AND RESULTS: We bidirectionally sequenced the entire coding sequence of KCNQ1 in 209 unrelated patients with early-onset lone AF (<40 years) and investigated the identified mutations functionally in a heterologous expression system. We found 4 nonsynonymous KCNQ1 mutations (A46T, R195W, A302V, and R670K) in 4 unrelated patients (38, 31, 39, and 36 years, respectively). None of the mutations were present in the control group (n = 416 alleles). No other mutations were found in genes previously associated with AF. The mutations A46T, R195W, and A302V have previously been associated with long-QT syndrome. In line with previous reports, we found A302V to display a pronounced loss-of-function of the IKs current, while the other mutants exhibited a gain-of-function phenotype. CONCLUSIONS: Mutations in the IKs channel leading to gain-of-function have previously been described in familial AF, yet this is the first time a loss-of-function mutation in KCNQ1 is associated with early-onset lone AF. These findings suggest that both gain-of-function and loss-of-function of cardiac potassium currents enhance the susceptibility to AF.

Symptoms Before Sudden Arrhythmic Death Syndrome: A Nationwide Study Among the Young in Denmark.

INTRODUCTION: No studies in an unselected and nationwide setting have characterized the symptoms and medical history of patients with sudden arrhythmic death syndrome (SADS). The aim of this study was to identify and describe the symptoms and medical history of patients before the presentation of SADS. METHODS AND RESULTS: We have previously identified all of the autopsied sudden cardiac deaths (SCD; n = 314) in Danes aged 1-35 years between 2000 and 2006. After comprehensive pathological and toxicological investigation did not reveal a cause of SCD, 136 of the patients were identified as SADS. The National Patient Registry was utilized to obtain information on all in- and outpatient activity in Danish hospitals. All medical records from hospitals and general practitioners, including death certificates and autopsy reports were reviewed. Before death, 48 (35%) SADS patients had cardiac symptoms; among these, 30 (22%) had contacted the healthcare system. Antecedent symptoms (symptoms >24 hours before death) were present in 34 (25%) patients. Prodromal symptoms (symptoms ≤24 hours before death) were present in 23 (17%) patients. Cardiac symptoms included chest pain (n = 16, 12%), dyspnea (n = 18, 13%), palpitations (n = 2, 1%), presyncope/syncope (n = 23, 17%), and aborted SCD (n = 2, 1%). In addition, seizures (n = 25, 18%) were prevalent. In 61 (45%) SADS cases, no previous medical history were recorded. CONCLUSION: In this unselected, nationwide study of 136 young SADS patients, 35% had experienced cardiac symptoms before death, most commonly presyncope/syncope, but only one out of five had contacted a healthcare provider with cardiac symptoms.

Sudden death in young persons with uncontrolled asthma--a nationwide cohort study in Denmark.

BACKGROUND: Asthma is a common chronic disease among young adults, and several studies have reported increased mortality rates in patients with asthma. However, no study has described sudden unexpected death in a nationwide setting in patients with uncontrolled asthma. We defined uncontrolled asthma as a previous hospital admittance because of asthma (of any severity) or when asthma was considered to have influenced the death according to the death certificate. The purpose of this study is to increase the medical focus on young persons with uncontrolled asthma and thereby hopefully aid in preventing sudden unexpected deaths. We therefore aimed to describe clinical characteristics, symptoms, causes of death, and contact with the healthcare system prior to sudden unexpected death in young persons with uncontrolled asthma. METHODS: Through the review of death certificates, we found 625 sudden unexpected death cases in individuals aged 1-35 years in Denmark from 2000 to 2006. Of those, 49 persons with uncontrolled asthma were identified. Previous contacts with the healthcare system were identified, and available records from general practitioners were retrieved. RESULTS: We identified 49 individuals who suffered from uncontrolled asthma. This corresponds to an incidence rate of 0.32 per 100,000 person-years. The cause of death in 31 cases (63%) was sudden cardiac death, and in 13 cases (27%), it was a fatal asthma attack. Symptoms (chest pain, dyspnea, seizures, general malaise, syncope, and palpitations) prior to death were reported in 41 (84%) of the cases. In 34 (69%) of the cases, antecedent symptoms (symptoms >24 hours before death) were present, and 28 (57%) patients had prodromal symptoms (symptoms <24 hours before death). The most common antecedent symptoms were dyspnea and chest pain, whereas the most common prodromal symptoms were dyspnea, general malaise, and/or fatigue. Twenty-eight patients (57%) sought medical advice from a general practitioner and/or emergency department due to these symptoms. CONCLUSION: The cause of death was predominantly sudden cardiac death followed by fatal asthma attack. We found that 41 (84%) of patients suffered from symptoms prior to death and that 28 (57%) sought medical advice from the emergency department and/or general practitioners.

Sudden cardiac death in children (1-18 years): symptoms and causes of death in a nationwide setting.

AIMS: Hitherto, sudden cardiac death in children (SCDc)-defined as sudden cardiac death (SCD) in the 1-18 years old-has been incompletely described in the general population. Knowledge on incidence rates, causes of death and symptoms prior to death is sparse and has been affected by reporting and referral bias. METHODS AND RESULTS: In a nationwide setting all deaths in children aged 1-18 years in Denmark in 2000-06 were included. To chart causes of death and incidence rates, death certificates and autopsy reports were collected and read. By additional use of the extensive healthcare registries in Denmark, we were also able to investigate prior disease and symptoms. During the 7-year study period there was an average of 1.11 million persons aged 1-18 years. There were a total of 1504 deaths (214 deaths per year) from 7.78 million person-years. A total of 114 (7.5%) were sudden and unexpected. A cardiac disease was known prior to death in 18% of all sudden unexpected death cases. In two-thirds of all sudden unexpected death cases no previous medical history was registered. Causes of death in autopsied cases were cardiac or unknown in 70%. Unexplained deaths, presumed to be a primary cardiac arrhythmia, accounted for 28% of autopsied sudden unexpected death cases. Autopsy rate was 77%. There were a total of 87 cases of SCDc (5.8% of all deaths). Prodromal symptoms were noted in 26% and antecedent symptoms in 45% of SCDc cases. The most frequent antecedent symptoms were seizures, dyspnoea, and syncope. In total, 61% of SCDc were not known with any prior disease; 23% were known with congenital or other heart disease prior to death. In total, 43 (49%) of all sudden unexpected deaths died of a potential inherited cardiac disease. The incidence rate of sudden unexpected death was 1.5 per 100 000 person-years. The highest possible incidence rate of SCDc was 1.1 per 100 000 person-years. CONCLUSION: From a nationwide study of all deaths in a 7-year period more than half of all victims of SCDc experienced antecedent and/or prodromal symptoms prior to death. The incidence rate of sudden death and SCDc was 1.5 and 1.1 per 100 000 person-years, respectively. Cardiac symptoms in young persons should warrant clinical work-up and an autopsy should be performed in all cases of sudden unexpected death in which the deceased was not known with congenital heart disease prior to death. This is pivotal, in the subsequent familial cascade screening, to diagnose and treat potential inherited cardiac diseases in family members.

Risk prediction of cardiovascular death based on the QTc interval: evaluating age and gender differences in a large primary care population.

AIMS: Using a large, contemporary primary care population we aimed to provide absolute long-term risks of cardiovascular death (CVD) based on the QTc interval and to test whether the QTc interval is of value in risk prediction of CVD on an individual level. METHODS AND RESULTS: Digital electrocardiograms from 173 529 primary care patients aged 50-90 years were collected during 2001-11. The Framingham formula was used for heart rate-correction of the QT interval. Data on medication, comorbidity, and outcomes were retrieved from administrative registries. During a median follow-up period of 6.1 years, 6647 persons died from cardiovascular causes. Long-term risks of CVD were estimated for subgroups defined by age, gender, cardiovascular disease, and QTc interval categories. In general, we observed an increased risk of CVD for both very short and long QTc intervals. Prolongation of the QTc interval resulted in the worst prognosis for men whereas in women, a very short QTc interval was equivalent in risk to a borderline prolonged QTc interval. The effect of the QTc interval on the absolute risk of CVD was most pronounced in the elderly and in those with cardiovascular disease whereas the effect was negligible for middle-aged women without cardiovascular disease. The most important improvement in prediction accuracy was noted for women aged 70-90 years. In this subgroup, a total of 9.5% were reclassified (7.2% more accurately vs. 2.3% more inaccurately) within clinically relevant 5-year risk groups when the QTc interval was added to a conventional risk model for CVD. CONCLUSION: Important differences were observed across subgroups when the absolute long-term risk of CVD was estimated based on QTc interval duration. The accuracy of the personalized CVD prognosis can be improved when the QTc interval is introduced to a conventional risk model for CVD.

Genetic variation in the two-pore domain potassium channel, TASK-1, may contribute to an atrial substrate for arrhythmogenesis.

The two-pore domain potassium channel, K2P3.1 (TASK-1) modulates background conductance in isolated human atrial cardiomyocytes and has been proposed as a potential drug target for atrial fibrillation (AF). TASK-1 knockout mice have a predominantly ventricular phenotype however, and effects of TASK-1 inactivation on atrial structure and function have yet to be demonstrated in vivo. The extent to which genetic variation in KCNK3, that encodes TASK-1, might be a determinant of susceptibility to AF is also unknown. To address these questions, we first evaluated the effects of transient knockdown of the zebrafish kcnk3a and kcnk3b genes and cardiac phenotypes were evaluated using videomicroscopy. Combined kcnk3a and kcnk3b knockdown in 72 hour post fertilization embryos resulted in lower heart rate (p<0.001), marked increase in atrial diameter (p<0.001), and mild increase in end-diastolic ventricular diameter (p=0.01) when compared with control-injected embryos. We next performed genetic screening of KCNK3 in two independent AF cohorts (373 subjects) and identified three novel KCNK3 variants. Two of these variants, present in one proband with familial AF, were located at adjacent nucleotides in the Kozak sequence and reduced expression of an engineered reporter. A third missense variant, V123L, in a patient with lone AF, reduced resting membrane potential and altered pH sensitivity in patch-clamp experiments, with structural modeling predicting instability in the vicinity of the TASK-1 pore. These in vitro data suggest that the double Kozak variants and V123L will have loss-of-function effects on ITASK. Cardiac action potential modeling predicted that reduced ITASK prolongs atrial action potential duration, and that this is potentiated by reciprocal changes in activity of other ion channel currents. Our findings demonstrate the functional importance of ITASK in the atrium and suggest that inactivation of TASK-1 may have diverse effects on atrial size and electrophysiological properties that can contribute to an arrhythmogenic substrate.

New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome.

BACKGROUND: Marfan syndrome (MFS) is a rare autosomal dominantly inherited connective tissue disorder with an estimated prevalence of 1:5,000. More than 1000 variants have been previously reported to be associated with MFS. However, the disease-causing effect of these variants may be questionable as many of the original studies used low number of controls. To study whether there are possible false-positive variants associated with MFS, four in silico prediction tools (SIFT, Polyphen-2, Grantham score, and conservation across species) were used to predict the pathogenicity of these variant. RESULTS: Twenty-three out of 891 previously MFS-associated variants were identified in the ESP. These variants were distributed on 100 heterozygote carriers in 6494 screened individuals. This corresponds to a genotype prevalence of 1:65 for MFS. Using a more conservative approach (cutoff value of >2 carriers in the EPS), 10 variants affected a total of 82 individuals. This gives a genotype prevalence of 1:79 (82:6494) in the ESP. A significantly higher frequency of MFS-associated variants not present in the ESP were predicted to be pathogenic with the agreement of ≥3 prediction tools, compared to the variants present in the ESP (p = 3.5 × 10-15). CONCLUSIONS: This study showed a higher genotype prevalence of MFS than expected from the phenotype prevalence in the general population. The high genotype prevalence suggests that these variants are not the monogenic cause of MFS. Therefore, caution should be taken with regard to disease stratification based on these previously reported MFS-associated variants.

Risk of cardiovascular disease in family members of young sudden cardiac death victims.

AIMS: Descriptive and genetic studies suggest that relatives of sudden cardiac death (SCD) victims have an increased risk of several cardiovascular diseases (CVDs). Given the severe consequences of undiagnosed CVD and the availability of effective treatment, the potential for prevention in this group is enormous if they do have an increased CVD risk. This nationwide prospective population-based cohort study described the risk of CVDs in relatives of young SCD victims, compared with the general population. METHODS AND RESULTS: All SCD victims aged 1-35 years in Denmark, 2000-2006, were identified (n = 470), along with their first- and second-degree relatives (n = 3073). We compared the incidence of CVD in those relatives with that in the background population using standardized incidence ratios (SIRs). The observed number of CVDs over 11 years of follow-up was 292, compared with 219 expected based on national rates [SIR 1.33, 95% confidence interval (CI) 1.19-1.50]. Risks varied significantly with age; the SIR for those <35 years was 3.53 (95% CI 2.65-4.69), compared with SIRs of 1.59 (95% CI 1.35-1.89) and 0.91 (95% CI 0.75-1.10) for those aged 35-60 years or >60 years, respectively (P(homogeneity) < 0.0001). For first-degree relatives <35 years, SIRs for ischaemic heart disease, cardiomyopathy, and ventricular arrhythmia were 5.99 (95% CI 1.95-0.13.98), 17.91 (95% CI 4.88-45.87), and 19.15 (95% CI 7.70-39.45), respectively. CONCLUSION: CVDs co-aggregated significantly with SCD in families, with young first-degree relatives at greatest risk. Results clearly indicate that family members of young SCD victims should be offered comprehensive and systematic screening, with focus on the youngest relatives.

Genetic variation in KCNA5: impact on the atrial-specific potassium current IKur in patients with lone atrial fibrillation.

AIMS: Genetic factors may be important in the development of atrial fibrillation (AF) in the young. KCNA5 encodes the potassium channel α-subunit KV1.5, which underlies the voltage-gated atrial-specific potassium current IKur. KCNAB2 encodes KVß2, a ß-subunit of KV1.5, which increases IKur. Three studies have identified loss-of-function mutations in KCNA5 in patients with idiopathic AF. We hypothesized that early-onset lone AF is associated with high prevalence of genetic variants in KCNA5 and KCNAB2. METHODS AND RESULTS: The coding sequences of KCNA5 and KCNAB2 were sequenced in 307 patients with mean age of 33 years at the onset of lone AF, and in 216 healthy controls. We identified six novel non-synonymous mutations [E48G, Y155C, A305T (twice), D322H, D469E, and P488S] in KCNA5 in seven patients. None were present in controls. We identified a significantly higher frequency of rare deleterious variants in KCNA5 in the patients than in controls. The mutations were analysed with confocal microscopy and whole-cell patch-clamp techniques. The mutant proteins Y155C, D469E, and P488S displayed decreased surface expression and loss-of-function in patch-clamp studies, whereas E48G, A305T, and D322H showed preserved surface expression and gain-of-function for KV1.5. CONCLUSION: This study is the first to present gain-of-function mutations in KCNA5 in patients with early-onset lone AF. We identified three gain-of-function and three loss-of-function mutations. We report a high prevalence of variants in KCNA5 in these patients. This supports the hypothesis that both increased and decreased potassium currents enhance AF susceptibility.

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Epilepsy and risk of death and sudden unexpected death in the young: a nationwide study.

PURPOSE: Patients with epilepsy are at increased risk of premature death from all causes and likely also from sudden unexplained death (SUD). Many patients with epilepsy have significant comorbidity, and it is unclear how much of the increased risk can be explained by epilepsy itself. We aimed to chart the incidence of sudden unexpected death in epilepsy (SUDEP) and estimate the risk of death from all causes and SUD conferred by epilepsy independently. METHODS: We conducted a historical cohort study using data from Danish registries and a complete manual review of all death certificates. The population studied consisted of all Danish residents in the age group 1-35 years, in the period 2000-2006 (inclusive), and the main outcome measures were risk of death and SUD. KEY FINDINGS: We identified 33,022 subjects with epilepsy (median follow-up 3.7 years) and 3,001,952 subjects without (median follow-up 7.0 years). Among 685 deaths in the population with epilepsy, we identified 50 cases of definite and probable SUDEP corresponding to an incidence rate of 41.1 (95% confidence interval [CI] 31.6-54.9) per 100,000 person-years. Incidence rates increased with age from 17.6 (95% CI 9.5-32.8) in the age group 1-18 years to 73.8 (95% CI 52.5-103.8) for the age group 24-35 years. Having epilepsy increased the crude risk of death with a hazard ratio (HR) of 11.9 (95% CI 11.0-12.9). When adjusting for sex and comorbidities often encountered in patients with epilepsy (neurologic disease including cerebral palsy, psychiatric disease including mental retardation, and congenital disorders), as well as the Charlson comorbidity score, the HR fell to 5.4 (95% CI 4.9-6.0). The crude HR for SUD was 27.5 (95% CI 18.1-41.8) and fell to 16.3 (95% CI 9.8-26.9) when adjusted for the same covariates as above. SIGNIFICANCE: Epilepsy in and of itself carries a significant risk of premature death and SUD. These findings highlight the potential gains of risk factor modification for the prevention of premature death and SUDEP in patients with epilepsy.

Prior myocardial infarction in the young: predisposes to a high relative risk but low absolute risk of a sudden cardiac death.

AIMS: The study reports the relative and absolute risk of sudden cardiac death (SCD) in patients <36 years with prior myocardial infarction (MI). METHODS AND RESULTS: Through review of death certificates, we identified all SCDs in Danes aged 18-35 years between 1 January 2000 until 31st December 2006. We then used the unique Danish civil registration number, which enabled us to follow all Danes in national registries, in the same period. Through the National Patient Registry we identified those with a prior myocardial infarction [implantable cardioverter defibrillator (ICD)-8: 410, ICD-10: I21 and I22] and incidence rates for SCD were estimated for survivors of MI and for individuals who had not yet suffered an MI, respectively. We estimated the relative risk of SCD and all-cause mortality by using extended Cox regression models. The 1,862,431 Danes aged between 18 and 35 years were followed in 9,388,453 person-years between 2000 and 2006. There were 7434 deaths of which 387 (5.2%) were SCDs. Myocardial infarction was diagnosed in 1234 patients, of those 10 died of SCD. Prior MI increased the incidence rate of SCD from 4.1 to 305.0 per 100,000 person-years [95% confidence interval (CI): 164.1-567.0]. Myocardial infarction was correlated with SCD and all-cause mortality, with a hazard ratio (HR) of 55.5 (95% CI: 29.5-104.4), P< 0.0001 and HR 8.3 (95% CI: 6.0-11.3), P< 0.0001, respectively. CONCLUSION: We report that prior MI at a young age significantly increases SCD incidence from 4.1 to 305.0 per 100,000 person-years. Myocardial infarction is furthermore correlated with SCD and all-cause mortality with HR of 55.5 and 8.3, respectively.