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The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data. Funding Agencies|SciLifeLab; Swedish Research Council (Vetenskapsradet)Swedish Research Council [D0886501]; US National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [MH077139, MH1095320]; European UnionEuropean Commission [610307, 733161, 825843]; Swedish Cancer SocietySwedish Cancer Society; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2018-02837, 2014-03352, 2009-1039, 2018-03307]; Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation; Karolinska Institutet, Karolinska University HospitalKarolinska Institutet; Radiumhemmets Forskningsfonder; European Research CouncilEuropean Research Council (ERC)European Commission [CoG-2015_681742_NASCENT]; Swedish Heart-Lung FoundationSwedish Heart-Lung Foundation [20160872]; Swedish Foundation for Strategic Research (IRC Center); Novo Nordisk FoundationNovo Nordisk FoundationNovocure Limited; ALF; Strategic Research Area Epidemiology at Karolinska Institutet; Swedish Rheumatism Association; Vth 80-year Foundation; Swedish Society of Medicine; Clinical Research Support (Avtal om Lakarutbildning och Forskning); Swedish government; county councils; ALF-agreement; Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research [15-0067]; IMI2 Joint Undertaking [115974]; European Federation of Pharmaceutical Industries and Associations with JDRF; H2020 Program ERA PerMed JTC 2018 Call (VR) [2018-05619]

Background Aortic stenosis (AS) is the most common valvular heart disease in developed countries, confers high mortality in advanced cases, but can effectively be reversed using endovascular or open-heart surgery. We evaluated the association between AS and neighborhood socioeconomic status (NSES). Methods We used Swedish population-based nationwide registers and an echocardiography screening cohort during the study period 1997–2014. NSES was determined by an established neighborhood deprivation index composed of education, income, unemployment, and receipt of social welfare. Multilevel adjusted logistic regression models determined the association between NSES and incident AS (according to ICD-10 diagnostic codes). Results The study population of men and women (n=6,641,905) was divided into individuals living in high (n = 1,608,815 [24%]), moderate (n = 3,857,367 [58%]) and low (n = 1,175,723 [18%]) SES neighborhoods. There were 63,227 AS cases in total. Low NSES (versus high) was associated with a slightly increased risk of AS (OR 1.06 [95% CI 1.03–1.08]) in the nationwide study population. In the echocardiography screening cohort (n = 1586), the association between low NSES and AS was markedly stronger (OR: 2.73 [1.05–7.12]). There were more previously undiagnosed AS cases in low compared to high SES neighborhoods (3.1% versus 1.0%). Conclusions In this nationwide Swedish register study, low NSES was associated with a slightly increased risk of incident AS. However, the association was markedly stronger in the echocardiography screening cohort, which revealed an almost three-fold increase of AS among individuals living in low SES neighborhoods, possibly indicating an underdiagnosis of AS among these individuals.

The mortality in individuals with a family history of heart failure (HF) has not been determined. This nationwide sib-pair study aimed to determine mortality in individuals with a sibling affected with HF.Sib-pairs were linked using the Swedish Multi-Generation Register, the Hospital Discharge Register and the Cause of Death Register for the period 1987-2012. Families with cardiomyopathy or congenital heart disease were excluded. Mortality hazard ratios (HRs) were calculated for siblings of individuals who had been diagnosed with HF compared with siblings of individuals unaffected by HF as the reference group. Similar analyses were made for spouses. HRs were determined for overall mortality, cardiovascular mortality, and death of unknown cause.Among siblings, the adjusted HR for overall mortality was 1.21 (95% CI 1.18-1.25). This risk remained (HR = 1.19, 95% CI 1.15-1.23) also among subjects without HF themselves. The adjusted HRs for cardiovascular mortality and death of unknown cause were 1.39 (95% CI 1.32-1.45) and 1.58 (95% CI 1.29-1.95), respectively. The mortality risk associations with spousal HF were all minimal, with an overall mortality HR of 1.02 (1.01-1.02). Early sibling age of onset of HF 50 years was associated with higher HRs for overall mortality, cardiovascular mortality, and death of unknown cause, 1.33 (1.27-1.41), 1.54 (1.40-1.68) and 1.84 (1.27-2.67), respectively.Sibling HF, especially early-onset HF, is associated with increased mortality. The low risk in spouses suggests genetic factors might be of importance. Screening for HF, and cardiovascular disease in general, in these individuals may be warranted.

ObjectiveTransthyretin amyloid cardiomyopathy (ATTR-CM) is a rare, progressive and fatal condition caused by deposition of transthyretin amyloid fibrils in the heart. This study aims to identify all patients diagnosed with ATTR-CM in Sweden, estimate the prevalence of ATTR-CM, describe patient characteristics and mortality, assess the importance of early symptoms (red flags) for identification of ATTR-CM, and compare with patients with heart failure (HF).MethodsThis retrospective study combined multiple national health registers covering all specialist visits and prescriptions for the entire population of Sweden. Between January 2008 and December 2018, patients with ATTR-CM were identified retrospectively based on a combination of diagnosis codes and compared with matched, all-cause non-ATTR HF patients.ResultsOverall, a total of 994 patients diagnosed with ATTR-CM were identified, with an average age at diagnosis of 73 years, and 30% of whom were female. The prevalence of diagnosed ATTR-CM cases in 2018 was 5.0 per 100 000. The median survival from diagnosis was 37.6 months (CI 33.8 to 43.8), with a lower median survival in women (27.9 months, CI 23.3 to 33.8) compared with men (43.5 months, CI 37.6 to 49.6). Patients with ATTR-CM demonstrated reduced survival compared with patients with HF (pConclusionsThis study provides the first nationwide estimates of ATTR-CM prevalence and risk factors. The results reinforce the severity of the disease and the importance of earlier diagnosis, especially for female patients, in order to allow effective treatment and prevention of disease progression.

Heart failure (HF) is a major public health problem characterized by inability of the heart to maintain sufficient output of blood. The systematic characterization of circulating proteins across different stages of HF may provide pathophysiological insights and identify therapeutic targets. Here we report application of aptamer-based proteomics to identify proteins associated with prospective HF incidence in a population-based cohort, implicating modulation of immunological, complement, coagulation, natriuretic and matrix remodeling pathways up to two decades prior to overt disease onset. We observe further divergence of these proteins from the general population in advanced HF, and regression after heart transplantation. By leveraging coronary sinus samples and transcriptomic tools, we describe likely cardiac and specific cellular origins for several of the proteins, including Nt-proBNP, thrombospondin-2, interleukin-18 receptor, gelsolin, and activated C5. Our findings provide a broad perspective on both cardiac and systemic factors associated with HF development., Heart failure is a major health issue worldwide. Here, Egerstedt et al. perform proteomic profiling of human plasma at different stages of heart failure, providing a comprehensive analysis of changes in the plasma proteome during disease progression.

Background Aortic valve stenosis (AVS) and coronary artery disease (CAD) have a significant genetic contribution and commonly co-exist. To compare and contrast genetic determinants of the two diseases, we investigated associations of the LPA and 9p21 loci, i.e. the two strongest CAD risk loci, with risk of AVS. Methods We genotyped the CAD-associated variants at the LPA (rs10455872) and 9p21 loci (rs1333049) in the GeneCAST (Genetics of Calcific Aortic STenosis) Consortium and conducted a meta-analysis for their association with AVS. Cases and controls were stratified by CAD status. External validation of findings was undertaken in five cohorts including 7880 cases and 851,152 controls. Results In the meta-analysis including 4651 cases and 8231 controls the CAD-associated allele at the LPA locus was associated with increased risk of AVS (OR 1.37; 95%CI 1.24–1.52, p = 6.9 × 10−10) with a larger effect size in those without CAD (OR 1.53; 95%CI 1.31–1.79) compared to those with CAD (OR 1.27; 95%CI 1.12–1.45). The CAD-associated allele at 9p21 was associated with a trend towards lower risk of AVS (OR 0.93; 95%CI 0.88–0.99, p = 0.014). External validation confirmed the association of the LPA risk allele with risk of AVS (OR 1.37; 95%CI 1.27–1.47), again with a higher effect size in those without CAD. The small protective effect of the 9p21 CAD risk allele could not be replicated (OR 0.98; 95%CI 0.95–1.02). Conclusions Our study confirms the association of the LPA locus with risk of AVS, with a higher effect in those without concomitant CAD. Overall, 9p21 was not associated with AVS.

Pathogenesis of abdominal aortic aneurysm (AAA) is unclear. The aim of this study was to evaluate inflammatory and hemodynamic plasma biomarkers as predictors for AAA in the prospective longitudinal cohort of middle-aged individuals from the cardiovascular cohort of the Malmö Diet and Cancer Study ( n=5551; 1991–94). C-reactive protein, cystatin C, copeptin, N-terminal pro-B-type natriuretic peptide (N-BNP), midregional pro-atrial natriuretic peptide (MR-proANP) and conventional risk factors at baseline were measured in patients with incident AAA during follow-up and compared to individuals without a diagnosis of AAA. Subjects were followed until 31 December 2013. Multivariable analyses were expressed in terms of hazard ratios (HR) per 1 standard deviation increment of each respective log-transformed plasma biomarker in the Cox proportional hazard models. Mean follow-up time was 20.7 years. Cumulative incidence of AAA was 1.5% (men 2.9%, women 0.5%). Mean age of individuals with incident AAA was 59.7 years at study entry and AAA was diagnosed on average 14 years later. Adjusting for age, sex, smoking, body mass index, hypertension and diabetes mellitus, N-BNP (HR 1.29; 95% CI 1.03–1.62), but not MR-proANP (HR 1.20; 95% CI 0.95–1.50), was independently associated with incident AAA. In conclusion, the plasma biomarker N-BNP was associated with future development of AAA, which implies that this marker is a sensitive indicator of early subclinical cardiovascular disease.

Background and aims The pathogenesis of abdominal aortic aneurysm (AAA) shares several common pathways with atherosclerosis. Prospective clinical plasma biomarker studies in AAA have been hampered by the need for very large cohorts and long follow-up time. Methods We analyzed a prospective longitudinal cohort of middle-aged individuals from the cardiovascular cohort of the Malmo Diet and Cancer study (n = 5551; 1991-94). The plasma biomarkers lipoprotein-associated phospholipase A2 (Lp-PLA 2 activity and mass), proneurotensin and C-reactive protein, and conventional risk factors at baseline were measured in patients with incident AAA during follow-up, and compared to individuals without a diagnosis of AAA. Subjects were followed until December 31st, 2013. Multivariable analyses were expressed in terms of hazard ratios (HR) per 1 standard deviation increment of each respective log-transformed plasma biomarker in the Cox proportional hazard models. Results Cumulative incidence of AAA was 1.5% (men 2.9%, women 0.5%) during a median follow-up period of 20.7 years. Overall, 84 individuals had an incident AAA, of whom 22 (26.2%) were operated on and 16 (19.0%) had ruptured. Mean age of individuals with incident AAA was 59.7 years at study entry and AAA was diagnosed on average 14 years later. When adjusting for age, gender, smoking, body mass index, hypertension, and diabetes mellitus, Lp-PLA 2 activity (HR 1.40; 95% CI 1.15–1.72) and Lp-PLA 2 mass (HR 1.23; 95% CI 1.00–1.51) were independently associated with incident AAA. Conclusions The plasma biomarkers Lp-PLA 2 activity and mass were markers of AAA risk and this implies that AAA is an athero-thrombotic related disease.

Background and aims Diet and smoking expose the general population to cadmium (Cd), which is a toxic metal that accumulates in the arterial wall. In experimental studies, Cd causes reductions in proliferation of smooth muscle cells and cellular synthesis of procollagen. The aim of this study was to examine whether blood Cd levels, a valid measure of Cd exposure, are associated with increased risk of abdominal aortic aneurysm (AAA). Methods All middle-aged men and women enrolled in the Malmo Diet and Cancer study (n = 30 447) were followed from the baseline examination in 1991–1996 through 2009. A total of 297 cases with AAA and two randomly selected control subjects for each case, matched for age and sex, were included. Blood Cd was analysed by inductively coupled plasma mass spectrometry. Diagnoses of AAA, thoracic aortic aneurysm and aortic dissection were obtained from registers. Results Increased blood Cd was associated with increased risk of incident AAA after adjustment for smoking and other established risk factors for AAA. The highest tertile of blood Cd concentrations had a rate ratio of 2.5 (95% confidence interval 1.3, 5.0) for incident AAA. Concentration of blood Cd (log transformed) was not associated with AAA in never-smokers (n = 24). Conclusions Blood Cd levels corresponding to the upper tertile of the distribution in the age- and sex-matched control group were associated with a 2.5-fold increase in rate ratio for incident AAA. This relationship was not found in the small group of never-smokers.

Background The increasing prevalence of atrial fibrillation and novel therapeutic tools to prevent cardioembolic stroke has increased the need for risk markers. Objectives This study explored the relationship between the midregional sequence of pro-atrial natriuretic peptide (MR-proANP) levels with the risk of atrial fibrillation and stroke, and whether measurement of MR-proANP improves the prediction of these outcomes. Methods MR-proANP was measured in fasting blood samples of 5130 subjects (69% men, mean age 69.2 ± 6.2 years) without a history of atrial fibrillation or stroke from the general population. The incidence of atrial fibrillation and stroke was monitored over a median follow-up of 5.6 years. C-statistics and net reclassification improvement was used to assess the predictive ability of MR-proANP in addition to conventional risk factors. Results Log-normalized MR-proANP was significantly associated with the incidence of atrial fibrillation ( n = 362; hazard ratio (HR); 95% confidence interval (CI) per 1 standard deviation (SD) 2.05, 1.86-2.27) and stroke from all causes ( n = 195; HR 1.30; 95% CI 1.12-1.50). The HR for stroke events related to atrial fibrillation was 1.79 (95% CI 1.25-2.58) per 1 SD. MR-proANP significantly improved the prediction of atrial fibrillation when added to a risk score of conventional risk factors (C statistic 0.69 vs. 0.75), mainly by down-classifying subjects who did not develop atrial fibrillation. A smaller improvement in predictive ability was observed for stroke (C statistic 0.66 vs. 0.68). Conclusion High plasma levels of MR-proANP are associated with the incidence of atrial fibrillation and stroke in the middle-aged and elderly population. MR-proANP may be useful to identify individuals with an increased risk of atrial fibrillation.

Publisher's version (útgefin grein), Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. Objective: To identify novel genetic loci and pathways associated with AS. Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. Exposures: Genetic variants (615643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples. Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. Results: The mean (SD) age of the 44703 GERA participants was 69.7 (8.4) years, and 22019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P =.03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P =.04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]). Conclusions and Relevance: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target., This study was supported by grant R01 HL128550 from the NHLBI of the NIH (Dr Thanassoulis); the Ellison Medical Foundation, Robert Wood Johnson Foundation, Wayne and Gladys Valley Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Regional Community Benefit Programs (The Kaiser Permanente Research Program on Genes, Environment and Health); a grant from the NIH (The Genetic Epidemiology Research on Adult Health and Aging cohort); a strategic partnership between the MRC and the University of Oxford (University of Oxford MRC Population Health Research Unit); application 24281 from the UK Biobank Resource; contracts NO1-HC-25195 and HHSN268201500001I, R01 HL 089590, and the SHARe project from the NHLBI (Framingham Heart Study); the NHLBI in collaboration with Multi-Ethnic Study of Atherosclerosis (MESA) investigators (MESA and the MESA SHARe project); contracts HHSN268201500003I from the NIH, contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the NHLBI, contracts UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, and UL1-TR-001881 from the National Center for Advancing Translational Sciences, and contract DK063491 from the National Institute of Diabetes and Digestive and Kidney Diseases (MESA); contract N02-HL-64278 from the NHLBI (SHARe genotyping); shared instrumentation grant s10rr025141 from the NIH, awards UL1TR002243 and UL1TR000445 from the National Center for Clinical and Translational Science, and award UL1RR024975 from the National Center for Research Resources (Vanderbilt University Medical Center’s Vanderbilt DNA Biobank projects); and investigator-led projects U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD07471 from the NIH (genomic data).

Importance Heart failure (HF) aggregates in families, but the heritability of HF has not been determined. Discerning the genetic and environmental contributions to HF risk is important to further helping to identify individuals at risk. Adoption studies may establish the genetic contribution to HF. Objective This nationwide adoption study aimed to determine the heritability of HF. Design, Setting, and Participants This case-control study and cohort study design used logistic regression for calculating risks of HF in adoptees. Adoptees who were born in Sweden between 1942 and 1990 were linked to their adoptive parents and biological parents. The Swedish Multi-Generation Register was linked to the Swedish Patient Register for information on hospital inpatient and outpatient admissions and to the Swedish Cause of Death Register for the period 1964 through 2015. Heritability (h2with a standard error) for HF was determined both with Falconer regression and with tetrachoric correlation. Data analysis was completed from July 2017 to April 2018. Exposures Heart failure in biological parents and/or adoptive parents. Main Outcomes and Measures Heritability; risk of HF, expressed as odds ratios. Results A total of 21 643 adoptees were included (of whom 10 626 [49.1%] were female), as well as 35 016 adoptive parents (14 872 [42.5%] female) and 43 286 biological parents (21 643 [50.0%] female). There were 194 cases of HF in adoptees, 3972 cases of HF in adoptive parents, and 3657 cases of HF in biological parents. The cohort study odds ratio (OR) for heart failure was 1.45 in adoptees (95% CI, 1.04-2.03) for biological parents with HF, compared with those without an affected biological parent. If cardiomyopathies were excluded, this OR was 1.58 (95% CI, 1.03-2.42). The corresponding OR associated with an affected adoptive parent were nonsignificant, both with cardiomyopathies included (OR, 0.83 [95% CI, 0.57-1.20]) and with cardiomyopathies excluded (OR, 0.79 [95% CI, 0.49-1.29]). The heritability of HF per Falconer regression (h2) was 26% (SE, 14%). With exclusion of cardiomyopathies the heritability using Falconer regression was 34% (SE, 18%). Conclusions and Relevance Heart failure in a biological parent is an HF risk factor that is worth clinical consideration. The increased heritability of HF suggests that genetic factors are important in HF pathogenesis.

Background— The aging of Western populations is expected to result in increasing occurrence of aortic stenosis (AS), but data are limited. Recent studies have reported declining incidence and mortality for other major heart diseases. We aimed to study temporal trends in the incidence and prognosis for AS in Sweden. Methods and Results— With the use of nationwide registers, all adult patients in the Swedish population with a first diagnosis of AS, heart failure, acute myocardial infarction, and aortic valve replacement for AS between 1989 and 2009 were identified and followed up until the end of 2010 for all-cause and cardiovascular-related mortality. The age-adjusted incidence of AS in Sweden declined from 15.0 to 11.4 in men and 9.8 to 7.1 in women per 100 000 between 1989 to 1991 and 2007 to 2009, and the median age at diagnosis increased by 4 years for both men and women. The age- and sex-adjusted relative risk of 1- and 3-year mortality in 2007 to 2009 was 0.58 (95% confidence interval, 0.53–0.63) and 0.60 (95% confidence interval, 0.56–0.65), respectively, compared with 1989 to 1991. Similar improvements were observed for heart failure and acute myocardial infarction. Findings were broadly consistent across subgroups. Postoperative mortality at 30 days declined despite increased median age at diagnosis. Conclusions— Incidence and mortality rates in AS in Sweden declined between 1989 and 2009 to an extent similar to that observed for heart failure and acute myocardial infarction. These findings could suggest that improved risk factor control and cardiovascular therapy, combined with increased use of aortic valve replacement in the elderly and reduced perioperative mortality in aortic valve replacement, have translated into favorable effects for AS.

Introduction Treatment with warfarin in combination with clopidogrel has been shown to reduce the incidence of major bleeding as compared to triple antithrombotic therapy (TT; warfarin, clopidogrel and aspirin). However, there are uncertainties regarding the risk for thrombosis since poor-responsiveness to clopidogrel is common. Ticagrelor is a more potent platelet inhibitor, but data supporting concurrent use of ticagrelor and warfarin (dual antithrombotic therapy, DT) is limited. This study therefore sought to evaluate the risk of bleeding and thrombosis associated with DT after an acute coronary syndrome (ACS). Materials and methods We identified all ACS patients on DT upon discharge from Helsingborg Hospital and Skane University Hospital in Malmo and Lund, Sweden, during 2013. Patients on DT were compared with historical controls discharged with TT. Major bleeding was defined in accordance with the HAS-BLED derivation study. Patients were retrospectively followed for three months. Results In total, 107 DT patients were identified and compared with 159 controls on TT. Mean HAS-BLED bleeding risk score and duration of treatment were similar between the groups (HAS-BLED 2.2 +/− 0.8 vs 2.2 +/− 1.0 units, p = NS; duration 2.7 +/− 0.8 vs 2.5 +/− 0.9 months, p = NS; DT vs TT). The incidence of spontaneous major bleeding was similar between the groups, as was a composite of all thrombotic events, i.e. peripheral embolism, stroke/TIA and acute coronary syndrome (bleeding 8/106 (7.5%) vs 11/157 (7.0%), p = NS; thrombosis 5/106 (4.7%) vs 5/157 (3.2%), p = NS; DT vs TT). Conclusions Rates of thrombotic and bleeding events were similar in patients with TT and patients with ticagrelor and warfarin.

Background and Purpose— Atrial fibrillation (AF) is prevalent and there is a clinical need for biomarkers to identify individuals at higher risk for AF. Fixed throughout a life course and assayable early in life, genetic biomarkers may meet this need. Here, we investigate whether multiple single nucleotide polymorphisms together as an AF genetic risk score (AF-GRS) can improve prediction of one’s risk for AF. Methods— In 27 471 participants of the Malmö Diet and Cancer Study, a prospective, community-based cohort, we used Cox models that adjusted for established AF risk factors to assess the association of AF-GRS with incident AF and ischemic stroke. Median follow-up was 14.4 years for incident AF and 14.5 years for ischemic stroke. The AF-GRS comprised 12 single nucleotide polymorphisms that had been previously shown to be associated with AF at genome-wide significance. Results— During follow-up, 2160 participants experienced a first AF event and 1495 had a first ischemic stroke event. Participants in the top AF-GRS quintile were at increased risk for incident AF (hazard ratio, 2.00; 95% confidence interval, 1.73–2.31; P =2.7×10 –21 ) and ischemic stroke (hazard ratio, 1.23; 95% confidence interval, 1.04–1.46; P =0.02) when compared with the bottom quintile. Addition of the AF-GRS to established AF risk factors modestly improved both discrimination and reclassification ( P Conclusions— An AF-GRS can identify 20% of individuals who are at ≈2-fold increased risk for incident AF and at 23% increased risk for ischemic stroke. Targeting diagnostic or therapeutic interventions to this subset may prove clinically useful.

BackgroundPast research has identified aortic stenosis (AS) as a major risk factor for adverse outcomes in noncardiac surgery; however, more contemporary studies have questioned the grave prognosis. To further our understanding of this, the risks of a 30-day major adverse cardiovascular event (MACE) and all-cause mortality were investigated in a contemporary Danish cohort. HypothesisAS is not an independent risk factor for adverse outcomes in noncardiac surgery. MethodsAll patients with and without diagnosed AS who underwent noncardiac surgery in 2005 to 2011 were identified through nationwide administrative registers. AS patients (n=2823; mean age, 75.5years, 53% female) were matched with patients without AS (n=2823) on propensity score for AS and surgery type. ResultsIn elective surgery, MACE (ie, nonfatal myocardial infarction, ischemic stroke, or cardiovascular death) occurred in 66/1772 (3.7%) of patients with AS and 52/1772 (2.9%) of controls (P=0.19), whereas mortality occurred in 67/1772 (3.8%) AS patients and 51/1772 (2.9%) controls (P=0.13). In emergency surgery, 163/1051 (15.5%) AS patients and 120/1051 (11.4%) controls had a MACE (P=0.006), whereas 225/1051 (21.4%) vs 179/1051 (17.0%) AS patients and controls died, respectively (P=0.01). Event rates were higher for those with symptoms (defined as use of nitrates, congestive heart failure, or use of loop diuretics), compared with those without symptoms (P

rs7629265 and AF Risk ObjectiveWe examined the association of rs7626962 (S1103Y) or rs7629265, a variant in high linkage disequilibrium with S1103Y (r(2) = 0.87 - 1), with sudden cardiac death (SCD) and atrial fibrillation (AF) among African Americans. BackgroundThe SCN5A missense variant S1103Y has been associated with SCD among African Americans in small case-control studies, but larger population-based studies are needed to validate these findings. The association of this variant with AF has not been fully explored. MethodsUsing genotyping data on over 7,000 African Americans from 5 cohorts (Atherosclerosis Risk in Communities [ARIC], Cleveland Family Study [CFS], Jackson Heart Study [JHS], Multi-Ethnic Study of Atherosclerosis [MESA], Cardiovascular Health Study [CHS]), we examined the association of rs7629265 with electrocardiographic PR, QRS, and QT intervals, and with incident AF and SCD. We examined association of S1103Y (rs7626962) with SCD using a population-based case-control study of SCD Cardiac Arrest Blood Study (CABS). ResultsMeta-analyses across 5 cohorts demonstrated that rs7629265 was significantly associated with PR duration ( = -4.1 milliseconds; P = 2.2x10(-6)), but not significantly associated with QRS or QT intervals. In meta-analyses of prospectively followed ARIC and CHS participants (n = 3,656), rs7629265 was associated with increased AF risk (n = 299 AF cases; HR = 1.74, P = 1.9 x 10(-4)). By contrast, rs7629265 was not significantly associated with SCD risk in ARIC (n = 83 SCD cases; P = 0.30) or CHS (n = 54 SCD cases; P = 0.47). Similarly, S1103Y was not significantly associated with SCD risk in CABS (n = 225 SCD cases; P = 0.29). ConclusionThe common SCN5A variant, rs7629265, is associated with increased AF risk and shorter PR interval among African Americans. In contrast to prior reports, we found no evidence of association of rs7629265 or rs7626962 (S1103Y) with SCD risk in the general population. (Less)

Soluble urokinase plasminogen activator receptor (suPAR) in plasma is a novel inflammatory marker thought to be released from the cell surface of neutrophils, T cells, and macrophages. Other inflammatory markers, mainly acute phase proteins produced in the liver, have been associated with the incidence of heart failure (HF) and atrial fibrillation (AF). We investigated the association between suPAR and incident HF and AF in a population-based cohort.

As part of a Swedish national cardiological research initiative, the development of a quantitative MRM assay is reported for the quantification of eleven putative cardiovascular disease markers. Within the study, patient samples from the LUNDHEARTGENE biobank were processed and nanoLC–MS/MS analysis was performed together with a stable isotope dilution strategy for absolute quantification of the target proteins. Excellent linear regressions were achieved for 9 of the 11 peptides with LOQ ranged in the attomolar range. We have utilized the assay for the screening of plasma samples from patients with chest pain, and performed a comparative analysis of patients with ST-segment elevation myocardial infarction and chest pain due to other causes. The assay demonstrates high reproducibility and correlate with clinical findings. Strong correlations were found for several of the apolipoproteins and their respective lipid subfractions (LDL, HDL or triglycerides). APOC1, APOC2 and APOE were elevated in patients with STEMI. Biological significance An MRM assay were developed for putative cardiovascular disease markers as target proteins, and applied to biobanking sample material. The comparative analysis of patients with ST-segment elevation myocardial infarction and chest pain due to other causes showed elevated levels of APOC1, APOC2 and APOE in patients with STEMI. These observations raise interesting novel hypotheses about the role of apolipoproteins C1, C2 and E in the pathophysiology of acute myocardial infarction, which merits further studies.

Aim To investigate serial serum concentrations of procalcitonin (PCT) and C-reactive protein (CRP) in patients treated with mild hypothermia after cardiac arrest, and to study their association to severe infections, post cardiac arrest syndrome (PCAS) and long-term outcome. Methods Serum samples from cardiac arrest patients treated with mild hypothermia were collected serially at admission, 2, 6, 12, 24, 36, 48 and 72 h after cardiac arrest. PCT and CRP concentrations were determined and tested for association with three definitions of infection, two surrogate markers of PCAS (circulation-SOFA and time to return of spontaneous circulation (ROSC)) and cerebral performance category (CPC) at six months. Results Eighty-four patients were included. PCT displayed an earlier release pattern than CRP with a significant increase within 2 h, increasing further at 6 h and onwards in patients with poor outcome. CRP increased later and continued to rise during the study period. PCT was strongly associated with circulation-SOFA and time to ROSC, and predicted a poor neurologic outcome with high accuracy (area under the receiver operating characteristic curve of 0.88, 0.86 and 0.87 at 12, 24 and 48 h respectively). No association of PCT or CRP to infection was observed. Conclusion Our results suggest that PCT is released early after resuscitation following cardiac arrest, is associated with markers of PCAS but not with infection, and is an accurate predictor of poor outcome. Validation of these findings in larger studies is warranted.

Background— Aortic valvular stenosis (AS) is the most common cause of cardiac valvular replacement surgery. During the last century, the pathogenesis of AS has undergone transitions in developed countries, from rheumatic heart disease to a degenerative calcific pathogenesis. Although a familial component has been described for a subset of cases with a bicuspid valve, data are limited on the overall familial aggregation of this disease. Methods and Results— Contemporary information on 6 117 263 Swedish siblings, of which 13 442 had a clinical diagnosis of AS, was collected from the nationwide Swedish Multi-Generation Register and the National Patient Register. A total of 4.8% of AS cases had a sibling history of AS. Having at least 1 sibling with AS was associated with a hazard ratio of 3.41 (95% confidence interval, 2.23–5.21) to be diagnosed with AS in an adjusted model. Individuals with >1 sibling with AS had an exceptionally high risk (hazard ratio, 32.84) but were uncommon (34 siblings from 11 sibships). In contrast, spouses of subjects with AS were only slightly more likely to be diagnosed with AS compared with subjects without spousal AS (hazard ratio 1.16 for husbands and 1.18 for wives). Conclusions— A sibling history of clinically diagnosed AS was associated with increased risk of AS. Spouses of patients with AS only had a modest risk increase, suggesting that shared adult environmental factors contribute less to the development of AS than genetic factors.

AIMS: Atrial fibrillation (AF) is a frequent co-morbidity in heart failure (HF) associated with increased mortality, but little is known about the mechanisms underlying AF onset in HF patients. We evaluated the association of cardiovascular and genetic risk factors with AF in HF patients. METHODS AND RESULTS: Individuals hospitalized for HF (n = 1040; 500 with AF) were identified from a large, population-based cohort study (n = 30 447; 2339 with AF). Genetic polymorphisms in the chromosomal regions 4q25 (rs2200733) and 16q22 (rs2106261) associated with AF in genome-wide association studies were genotyped. Association of cardiovascular risk factors and polymorphisms with AF was tested in HF patients and the entire cohort using both prospective and non-time-dependent models. Cardiovascular risk factors-hypertension, body mass index, sex, smoking, diabetes, and myocardial infarction-were associated with AF in the entire cohort but not in HF patients. In contrast, polymorphisms on chromosomes 16q22 and 4q25 were associated with AF both in the entire cohort and in HF patients, conferring 75% [95% confidence interval (CI) 35-126, P = 2 × 10(-5)] and 57% (95% CI 18-109, P = 0.002) increased risk of AF per copy in HF patients, respectively. In the entire cohort, AF risk in the presence of HF was multiplicatively magnified by genotype for 16q22 (P for interaction = 7 × 10(-4)) but not 4q25 (P = 0.83). In prospective analyses excluding patients with AF diagnosis prior to or simultaneously with HF diagnosis, 16q22 but not 4q25 remained robustly associated with AF (hazard ratio 1.96, 95% CI 1.40-2.73, P = 8 × 10(-5)). The proportion of AF diagnoses in HF patients attributable to polymorphisms was 19% and 12%, respectively. CONCLUSIONS: A polymorphism in the ZFHX3 gene, encoding a cardiac transcription factor, was associated with increased AF risk in HF patients, and the genetic association with AF was more pronounced in HF patients than in the general population.

Previous reports have shown ambiguous findings regarding the possible associations between ischaemic stroke (IS) and single nucleotide polymorphisms (SNPs) in the phosphodiesterase 4D (PDE4D) gene region. The SNP rs12188950 (or SNP45) has often been studied in this context. We performed a multi-centre study involving a large sample of 2599 IS patients and 2093 control subjects from the south and west regions of Sweden to replicate previous studies regarding IS risk and rs12188950. Subjects from Lund Stroke Register (LSR), Malmö Diet and Cancer Study (MDC) and Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) were enroled. Subgroups of participants with hypertension and participants

OBJECTIVES: the purpose of this study was to assess the predictive accuracy of conventional cardiovascular risk factors for incident heart failure and atrial fibrillation, and the added benefit of multiple biomarkers reflecting diverse pathophysiological pathways. BACKGROUND: heart failure and atrial fibrillation are interrelated cardiac diseases associated with substantial morbidity and mortality and increasing incidence. Data on prediction and prevention of these diseases in healthy individuals are limited. METHODS: in 5,187 individuals from the community-based MDCS (Malmo Diet and Cancer Study), we studied the performance of conventional risk factors and 6 biomarkers including midregional pro-atrial natriuretic peptide (MR-proANP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional pro-adrenomedullin, cystatin C, C-reactive protein (CRP), and copeptin. RESULTS: during a mean follow-up of 14 years, 112 individuals were diagnosed with heart failure and 284 individuals with atrial fibrillation. NT-proBNP (hazard ratio [HR]: 1.63 per SD, 95% confidence interval [CI]: 1.29 to 2.06, p < 0.001), CRP (HR: 1.57 per SD, 95% CI: 1.28 to 1.94, p < 0.001), and MR-proANP (HR: 1.26 per SD, 95% CI: 1.02 to 1.56, p = 0.03) predicted incident heart failure independently of conventional risk factors and other biomarkers. MR-proANP (HR: 1.62, 95% CI: 1.42 to 1.84, p < 0.001) and CRP (HR: 1.18, 95% CI: 1.03 to 1.34, p = 0.01) independently predicted atrial fibrillation. Addition of biomarkers to conventional risk factors improved c-statistics from 0.815 to 0.842 for heart failure and from 0.732 to 0.753 for atrial fibrillation and the integrated discrimination improvement for both diseases (p < 0.001). Net reclassification improvement (NRI) with biomarkers was observed in 22% of individuals for heart failure (NRI, p < 0.001) and in 7% for atrial fibrillation (NRI, p = 0.06), mainly due to up-classification of individuals who developed disease (heart failure: 29%, atrial fibrillation: 19%). Addition of CRP to natriuretic peptides did not improve discrimination or reclassification. CONCLUSIONS: conventional cardiovascular risk factors predict incident heart failure and atrial fibrillation with reasonable accuracy in middle-age individuals free from disease. Natriuretic peptides, but not other biomarkers, improve discrimination modestly for both diseases above and beyond conventional risk factors and substantially improve risk classification for heart failure. (Less)

Background— Epidemiological studies indicate a genetic contribution to ischemic stroke risk, but specific genetic variants remain unknown, with the exception of a few rare variants. Recent genome-wide association studies identified and replicated common genetic variants on chromosome 9p21 to confer risk of coronary heart disease. We examined whether these variants are associated with ischemic stroke. Methods and Results— We genotyped 6 common genetic variants on chromosome 9p21, previously associated with coronary artery disease in genome-wide association studies, in 2 population-based studies in southern Sweden, the Lund Stroke Register (n=1837 cases, 947 controls) and the Malmö Diet and Cancer study (MDC; n=888 cases, 893 controls). We examined association in each study and in the pooled dataset. Adjustments were made for cardiovascular risk factors and further for previous myocardial infarction in MDC. We found a modest increase in ischemic stroke risk for 2 common (minor allele frequencies 0.46 to 0.49) variants, rs2383207 ( P =0.04 in Lund Stroke Register, P =0.01 in MDC) and rs10757274 ( P =0.03 in Lund Stroke Register, P =0.03 in MDC), in each sample independently. The strength of the association increased when samples were pooled with an odds ratio of 1.15 (95% CI, 1.05 to 1.25; P =0.002) for the strongest variant rs2383207. Results were similar after adjustment for clinical covariates. rs1333049 also showed significant association in MDC, which increased in the pooled sample ( P =0.004). Conclusions— In this large sample (n=4565), we detected common genetic determinants for ischemic stroke on chromosome 9p21. Our findings indicate that ischemic stroke shares pathophysiological determinants with coronary heart disease and other arterial diseases and highlight the need for large sample sizes in stroke genetics.

OBJECTIVE: High concentrations of leukocytes in blood have been associated with diabetes mellitus. This prospective study aimed to explore whether total and differential leukocyte counts are associated with incidence of diabetes. A missense variant R262W in the SH2B3 (SH2B adaptor protein 3) gene, coding for a protein that negatively regulates hematopoietic cell proliferation, was also studied in relation to incidence of diabetes. METHODS AND RESULTS: Leukocyte count and its subtypes (neutrophils, lymphocytes and mixed cells) were analyzed in 26,667 men and women, 45-73 years old, from the population-based Malmo Diet and Cancer study. Information about the R262W polymorphism (rs3184504) in SH2B3 was genotyped in 24,489 subjects. Incidence of diabetes was studied during a mean follow-up of 14 years. Cox proportional hazards regression was used to examine incidence of diabetes by total and differential leukocyte counts. Mendelian randomization analysis using R262W as an instrumental variable was performed with two-stage least squares regression. A total of 2,946 subjects developed diabetes during the follow-up period. After taking several possible confounders into account, concentrations of total leukocyte count, neutrophils and lymphocytes were all significantly associated with incidence of diabetes. The adjusted hazard ratios (95% confidence interval; quartile 4 vs quartile 1) were 1.37 (1.22-1.53) for total leukocytes, 1.33 (1.19-1.49) for neutrophils and 1.29 (1.15-1.44) for lymphocytes. The R262W polymorphism was strongly associated with leukocytes (0.11x109 cells/l per T allele, p = 1.14 x10-12), lymphocytes (p = 4.3 x10-16), neutrophils (p = 8.0 x10-6) and mixed cells (p = 3.0 x10-6). However, there was no significant association between R262W and fasting glucose, HbA1c or incidence of diabetes. CONCLUSIONS: Concentrations of total leukocytes, neutrophils and lymphocytes are associated with incidence of diabetes. However, the lack of association with the R262W polymorphism suggests that the associations may not be causal, although limitations in statistical power and balancing pleiotropic effects cannot be excluded.

Pulmonary vein isolation (PVI) is a recommended treatment for patients with atrial fibrillation, but it is unclear whether it results in a lower risk of stroke.To investigate the proportion of patients discontinuing anticoagulation treatment after PVI in association with the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, stroke [doubled], vascular disease, age 65-74 years, sex category [female]) score, identify factors predicting stroke after PVI, and explore the risk of cardiovascular events after PVI in patients with and without guideline-recommended anticoagulation treatment.A retrospective cohort study was conducted using Swedish national health registries from January 1, 2006, to December 31, 2012, with a mean-follow up of 2.6 years. A total of 1585 patients with atrial fibrillation undergoing PVI from the Swedish Catheter Ablation Register were included, with information about exposure to warfarin in the national quality register Auricula. Data analysis was performed from January 1, 2015, to April 30, 2016.Warfarin treatment.Ischemic stroke, intracranial hemorrhage, and death.In this cohort of 1585 patients, 73.0% were male, the mean (SD) age was 59.0 (9.4) years, and the mean (SD) CHA2DS2-VASc score was 1.5 (1.4). Of the 1585 patients, 1175 were followed up for more than 1 year after PVI. Of these, 360 (30.6%) discontinued warfarin treatment during the first year. In patients with a CHA2DS2-VASc score of 2 or more, patients discontinuing warfarin treatment had a higher rate of ischemic stroke (5 events in 312 years at risk [1.6% per year]) compared with those continuing warfarin treatment (4 events in 1192 years at risk [0.3% per year]) (P = .046). Patients with a CHA2DS2-VASc score of 2 or more or those who had previously experienced an ischemic stroke displayed a higher risk of stroke if warfarin treatment was discontinued (hazard ratio, 4.6; 95% CI, 1.2-17.2; P = .02 and hazard ratio, 13.7; 95% CI, 2.0-91.9; P = .007, respectively).These findings indicate that discontinuation of warfarin treatment after PVI is not safe in high-risk patients, especially those who have previously experienced an ischemic stroke.

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.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.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).Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS.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).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.

AIM:To gain a better understanding of the impact of chronic obstructive pulmonary disease (COPD) on long-term mortality in patients with myocardial infarction (MI) and identify areas where the clin ...

Atrial fibrillation (AF) is a common cardiac disease and major risk factor for stroke, heart failure and death. Tools for prediction of AF have been developed to identify individuals who might benefit from preventive therapies, incorporating conventional cardiovascular risk factors, and the effects of such risk factors have been evaluated across several cohorts.1,2 Recently, a heritable component to AF has been reported and polymorphisms in three genetic regions have been reproducibly associated with AF: chromosome 4q25, located 150 kb from the closest gene - a transcription factor (PITX2) involved in cardiac development; chromosome 16q22, intronic to another transcription factor of unknown function, expressed in cardiac tissue (ZFHX3); and an amino acid-altering variant in KCNH2, one of the major cardiac voltage-gated potassium channels.3–5 Rare genetic variants segregating with AF are typically exclusive to individual families and unlikely to contribute to AF prediction at the population level but genetic polymorphisms could provide important predictive information.

Background: Despite advances in anti-platelet treatments, there still exists an early increase in both ischemic as well as bleeding events following primary PCI in patients with ST-elevation myocardial infarction (STEMI). Platelet inhibition data of different anti-platelet treatments in the acute phase of a myocardial infarction might offer some insight into these problems. The aim of this study was to evaluate the pharmacodynamic profile of 5 different anti-platelet treatments in the acute phase of STEMI in patients undergoing primary PCI. Methods: A total of 223 STEMI patients undergoing primary PCI were prospectively included. Patients received either pre-hospital clopidogrel only, pre-hospital clopidogrel followed by prasugrel switch in the cath lab, prasugrel treatment only, pre-hospital clopidogrel followed by ticagrelor switch in the cath lab or pre-hospital ticagrelor only. Platelet reactivity was measured serially using vasodilator-stimulated phosphoprotein (VASP). Results: Patients receiving pre-hospital clopidogrel followed by prasugrel switch showed similar platelet inhibition data as patients receiving prasugrel only, with more than 90% being good responders the day after PCI. Average time from prasugrel administration to a VASP value of

Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 × 10−22) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 × 10−13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 × 10−10) and aortic root diameter (P = 1.30 × 10−8), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 × 10−3) and coronary artery disease (OR = 1.05, P = 9.3 × 10−5). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases., This research has been conducted using the UK Biobank Resource under Application Number 15293. We thank all participants of the Cardiovascular Health Improvement Project (CHIP) and BAV registry at the University of Michigan for their contribution to research. We appreciate the valuable efforts from the CHIP and BAV registry collection team. The University of Michigan Health System—Cardiovascular Health Improvement Project was supported by the Frankel Cardiovascular Center. We appreciate the Aikens Fund for Aortic Research (to C.J.W., B.Y.) and McKay research award for supporting this project (to B.Y.). B.Y. is supported by American Association of Thoracic Surgery (AATS) Graham Foundation and Thoracic Surgery Foundation of Research and Education (TSFRE). C.J.W. is supported by HL109946, HL130705, and HL127564. W.Z. is supported by the Rackham Predoctoral Fellowship of the University of Michigan.