[show abstract][hide abstract] ABSTRACT: Background:Solar ultraviolet (UV) exposure estimated based on residential history has been used as a sun exposure indicator in previous case-control and descriptive studies. However, the associations of cumulative UV exposure based on residential history with different skin cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), have not been evaluated simultaneously in prospective studies.Methods:We conducted a cohort study among 108 578 women in the Nurses' Health Study (1976-2006) to evaluate the relative risks of skin cancers with cumulative UV flux based on residential history in adulthood.Results:Risk of SCC and BCC was significantly lower for women in lower quintiles vs the highest quintile of cumulative UV flux (both P for trend <0.0001). The association between cumulative UV flux and risk of melanoma did not reach statistical significance. However, risk of melanoma appeared to be lower among women in lower quintiles vs the highest quintile of cumulative UV flux in lag analyses with 2-10 years between exposure and outcome. The multivariable-adjusted hazard ratios per 200 × 10(-4) Robertson-Berger units increase in cumulative UV flux were 0.979 (95% confidence interval (CI): 0.933, 1.028) for melanoma, 1.072 (95% CI: 1.041, 1.103) for SCC, and 1.043 (95% CI: 1.034, 1.052) for BCC.Conclusions:Associations with cumulative UV exposure in adulthood among women differed for melanoma, SCC, and BCC, suggesting a potential variable role of UV radiation in adulthood in the carcinogenesis of the three major skin cancers.British Journal of Cancer advance online publication, 4 March 2014; doi:10.1038/bjc.2014.43 www.bjcancer.com.
British Journal of Cancer 03/2014; · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
[show abstract][hide abstract] ABSTRACT: To develop concise, up-to-date, patient-focused, evidence-based, expert consensus guidelines for the management of knee osteoarthritis, intended to inform patients, physicians, and allied health care professionals worldwide.
Thirteen experts from relevant medical disciplines (primary care, rheumatology, orthopedics, physical therapy, physical medicine and rehabilitation, and evidence-based medicine), three continents and ten countries (USA, UK, France, Netherlands, Belgium, Sweden, Denmark, Australia, Japan, and Canada) and a patient representative comprised the Osteoarthritis Guidelines Development Group (OAGDG). Based on previous OA guidelines and a systematic review of the osteoarthritis (OA) literature, twenty-nine treatment modalities were considered for recommendation. Evidence published subsequent to the 2010 OARSI guidelines was based on a systematic review conducted by the OARSI evidence team at Tufts Medical Center, Boston, USA. Medline, EMBASE, Google Scholar, Web of Science, and the Cochrane Central Register of Controlled Trials were initially searched in first quarter 2012 and last searched in March 2013. Included evidence was assessed for quality using AMSTAR criteria, and published criticism of included evidence was also considered. To provide recommendations for individuals with a range of health profiles and OA burden, treatment recommendations were stratified into four clinical subphenotypes. Consensus recommendations were produced using the Rand/UCLA Appropriateness method and Delphi voting process. Treatments were recommended as Appropriate, Uncertain, or Not Appropriate, for each of four clinical subphenotypes and accompanied by 1-10 risk and benefit scores.
Appropriate treatment modalities for all individuals with knee OA included biomechanical interventions, intra-articular corticosteroids, exercise (land-based and water-based), self-management and education, strength training, and weight management. Treatments appropriate for specific clinical subphenotypes included acetaminophen (paracetamol), balneotherapy, capsaicin, cane (walking stick), duloxetine, oral NSAIDs (COX-2 selective and non-selective), and topical NSAIDs. Treatments of uncertain appropriateness for specific clinical subphenotypes included acupuncture, avocado soybean unsaponfiables, chondroitin, crutches, diacerein, glucosamine, intra-articular hyaluronic acid, opioids (oral and transdermal), rosehip, transcutaneous electrical nerve stimulation, and ultrasound. Treatments voted not appropriate included risedronate and electrotherapy (neuromuscular electrical stimulation).
These evidence-based consensus recommendations provide guidance to patients and practitioners on treatments applicable to all individuals with knee OA, as well as therapies that can be considered according to individualized patient needs and preferences.
Osteoarthritis and Cartilage 01/2014; · 4.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine the impact of arthritis pain and quality of life among adults with arthritis-related pain in Australia.
A cross-sectional survey was conducted on a convenience sample of adults with arthritis-related pain in Australia from an access research panel. The survey was administered to 1039 participants who reported experiencing pain or loss of mobility as a result of their arthritis. The survey covered details of their condition, descriptions of the pain, impacts of pain on their daily lives, information regarding pain management and medication, the Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP) tool, the EQ5D (a standardized measure of health tool) and demographic information.
Osteoarthritis (OA) was the most common form of arthritis (69% of respondents). The back (65%), knees (64%) and fingers (61%) were the regions in which pain was most commonly reported; 87% of respondents reported that their pain tended to change in intensity, with exercise and cold weather producing significantly increased levels of pain. Forty-seven percent of patients reported that the worst impact of arthritis was on their capacity to carry out activities of daily living. The majority of patients (71%) found their pain management programs to be of 'medium effectiveness' or 'fairly effective', although 17% described it as ineffective.
Persons with arthritis in Australia demonstrate marked pain-related functional impairment characterized by difficulty with many aspects of daily activity. The results suggest that a substantial benefit may be derived from increased awareness of the disease and increased knowledge about the potential for improved management.
International Journal of Rheumatic Diseases 11/2013; · 1.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Computed tomography-based depth-specific image processing is able to precisely identify regional differences between healthy patellae and patellae with osteoarthritis.
This study aims to assess the precision errors and potential differences in regional, depth-specific subchondral bone mineral density (BMD) in normal and osteoarthritic (OA) human patellae in vivo using CT-based density analyses.
Fourteen participants (2 men and 12 women; mean age, 51.4; SD, 11.8 years) were scanned using clinical quantitative CT (QCT) three times over 2 days. Participants were categorized as either normal (n = 7) or exhibiting radiographic OA (n = 7). Average subchondral BMD was assessed at three depths relative to the subchondral surface. Regional BMD analysis included: total lateral facet BMD, total medial facet BMD, and superior/middle/inferior BMD of lateral and medial facets at normalized depths of 0-2.5, 2.5-5, and 5-7.5 mm from the subchondral surface. We assessed precision using root mean square coefficients of variation (CV%). We evaluated differences between OA and normal BMD by (1) calculating percentage differences between the groups (in relation to normal BMD) (2) relating percentage differences to respective CV% errors and (3) determining effect sizes using Cohen's d.
Root mean square CV% precision errors ranged from 1.1 to 5.9 %. Percentage differences between OA and normal BMD varied from -1.6 to -30.1 % (BMD lower in OA patellae). In relation to precision errors, percentage differences were, on average, 5.5× greater than CV% errors. Cohen's d effect sizes ranged from -1.7 to -0.1. Largest differences were noted at depths of 2.5-5 and 5-7.5 mm from the subchondral surface.
Patellar subchondral BMD measures were precise (average CV%, ≤3 %). This region- and depth-specific CT-based imaging tool characterized regional standardized BMD differences between normal and OA patellae in vivo.
Osteoporosis International 11/2013; · 4.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine which subregions of the knee joint have a high prevalence of pre-radiographic osteoarthritic changes, i.e. cartilage damage and osteophytes that can only be detected by MRI, in radiographically normal knees.
Institutional review board approval and written informed consent from all participants was obtained. Data was collected from a community cohort in Framingham, MA, involving people aged 50-79. Participants underwent weight-bearing posteroanterior and lateral knee radiography with the fixed-flexion protocol, and 1.5T MRI. Knees without radiographic osteoarthritis (Kellgren Lawrence grade 0 for the tibiofemoral joint and absence of any osteophytes or joint space narrowing in the patellofemoral joint) were included. The knee joint was divided into 14 subregions for cartilage and 16 subregions for osteophytes, and prevalence and severity of cartilage damage (grade 0-6) and osteophytes (grade 0-7) were semiquantitatively assessed using the Whole Organ Magnetic Resonance Imaging Score.
The mean age of 696 participants was 62.3±8.4 years, and the mean body mass index was 27.9±5.1 kg/m(2). Women comprised 55.2% of the study sample (384/696). Prevalence of cartilage damage (grade ≥2) was 47.7% (332/696) in the medial patellar and 29.9% (208/696) in patellar lateral subregions, and 24.0% (167/696) in femoral medial anterior and 26.5% (184/696) in femoral medial central subregions. Prevalence of osteophytes (grade ≥2) was highest at 60.8% (423/696) in the medial femoral posterior subregion, followed by 34.0% (237/696) in patellar lateral and 24.6% (171/696) in patellar medial subregions. For all other subregions, prevalence of these lesions was lower than the aforementioned percentages.
MRI-detected cartilage damage and osteophytes are highly prevalent in the medial patellofemoral and medial posterior tibiofemoral joints in radiographically normal knees in persons aged 50-79.
Osteoarthritis and Cartilage 10/2013; · 4.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: Genetic predisposition plays a major role in the etiology of melanoma, but known genetic markers only account for a limited fraction of family-history-associated melanoma cases. Expression microarrays have offered the opportunity to identify further genomic profiles correlated with family history of melanoma. We aimed to distinguish mRNA expression signatures between melanoma cases with and without a family history of melanoma.
Based on the Nurses' Health Study, family history was defined as having one or more first-degree family members diagnosed with melanoma. Melanoma diagnosis was confirmed by reviewing pathology reports, and tumor blocks were collected by mail from across the USA. Genomic interrogation was accomplished through evaluating expression profiling of formalin-fixed paraffin-embedded tissues from 78 primary cutaneous invasive melanoma cases, on either a 6K or whole-genome (24K) Illumina gene chip. Gene set enrichment analysis was performed for each batch to determine the differentially enriched pathways and key contributing genes.
The CXC chemokine receptor 4 (CXCR4) pathway was consistently up-regulated within cases of familial melanoma in both platforms. Leading edge analysis showed four genes from the CXCR4 pathway, including MAPK1, PLCG1, CRK, and PTK2, were among the core members that contributed to the enrichment of this pathway. There was no association between the enrichment of CXCR4 pathway and NRAS, BRAF mutation, or Breslow thickness of the primary melanoma cases.
We found that the CXCR4 pathway might constitute a novel susceptibility pathway associated with family history of melanoma in first-degree relatives.
Cancer Causes and Control 10/2013; · 3.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: Increased risk of skin cancer by indoor tanning has drawn public attention. However, there are arguments that tanning bed use increases vitamin D production, which may therefore prevent internal cancers. Methods: We follow 73,358 female nurses for 20 years (1989-2009) in the Nurses' Health Study II and investigated the frequency of tanning bed use during high school/college and at ages 25-35 in relation to the incidence of total cancers (excluding skin cancers). We used multivariate Cox proportional hazards models to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of total cancers and each individual major cancer with more than 100 cases. Results: During follow-up, a total of 4,271 internal cancer cases were diagnosed. No association was found between tanning bed use and risk of total cancers (multivariable-adjusted HR, 0.99; 95% CI, 0.95-1.04 for every 4 times/year use on average during high school/college and at ages 25-35). In addition, no association was found for the risk of any individual major cancers, such as breast cancer, thyroid cancer, colorectal cancer, non-Hodgkin lymphoma, or endometrial cancer. Conclusions: Our data do not suggest any association between the use of tanning beds and risk of internal cancers. Impact: Based on the strong evidence of increase in skin cancer risk and no evidence of reduction in internal cancer risk by tanning bed use, it is important to warn the public against indoor tanning.
Cancer Epidemiology Biomarkers & Prevention 10/2013; · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: Despite the family aggregation of severe teenage acne, the genetic basis of this common skin condition remains unclear. We conducted a genome-wide association study (GWAS) on severe teenage acne in 928 European Americans. The SNP rs4133274 on chromosome 8q24 (72 kb upstream of MYC) revealed the most significant association with severe teenage acne (p value = 1.7 × 10(-6)). The variant allele of this SNP (G allele) was associated with an increased risk of severe teenage acne with odds ratio of 4.01 (95 % confidence interval = 2.37-6.82). Upon further replication, our findings suggest new genetic basis of acne and may explain the association between acne and cancer risk observed in the epidemiological studies.
[show abstract][hide abstract] ABSTRACT: Heterocyclic amines (HCAs) are mutagenic compounds generated when meats are cooked at high temperature and for long duration. The findings from previous studies on the relation between HCAs and breast cancer are inconsistent, possibly because of genetic variations in the enzymes metabolizing HCAs. To evaluate whether the associations of intakes of estimated HCAs, meat-derived mutagenicity (MDM), and red meat with risk of postmenopausal breast cancer were modified by N-acetyltransferase 2 (NAT2) acetylator genotype or cytochrome P450 1A2-164 A/C (CYP1A2) polymorphism, we conducted a nested case-control study with 579 cases and 981 controls within a prospective cohort, the Nurses' Health Study. HCAs and MDM intakes were derived using a cooking method questionnaire administered in 1996. NAT2acetylator genotype, the CYP1A2 polymorphism, and intakes of HCAs, MDM, and red meat were not associated with risk of postmenopausal breast cancer. There was also no interaction between NAT2 acetylator genotype or CYP1A2 polymorphism and HCAs and MDM and red meat intake in relation to breast cancer. These results do not support the hypothesis that genetic polymorphisms of xenobiotic enzymes involved in the metabolism of HCAs may modify the associations between intakes of red meat or meat-related mutagens and breast cancer risk.
Nutrition and Cancer 10/2013; · 2.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: Radiographic joint space width (JSW) is considered the reference standard for demonstrating structural therapeutic benefits in knee osteoarthritis. Our objective was to determine the proportion by which 3D (regional) meniscus and cartilage measures explain between-knee differences of JSW in the fixed flexion radiographs.
Segmentation of the medial meniscus and tibial and femoral cartilage was performed in double echo steady state (DESS) images. Quantitative measures of meniscus size and position, femorotibial cartilage thickness, and radiographic JSW (minimum, and fixed locations) were compared between both knees of 60 participants of the Osteoarthritis Initiative, with strictly unilateral medial joint space narrowing (JSN). Statistical analyses (between-knee, within-person comparison) were performed using regression analysis.
A strong relationship with side-differences in minimum and a central fixed location JSW was observed for percent tibial plateau coverage by the meniscus (r=.59 and .47; p<.01) and central femoral cartilage thickness (r=.69 and .75; p<.01); other meniscus and cartilage measures displayed lower coefficients. The correlation of central femoral cartilage thickness with JSW (but not that of meniscus measures) was greater (r=.78 and .85; p<.01) when excluding knees with non-optimal alignment between the tibia and X-ray beam.
3D measures of meniscus and cartilage provide significant, independent information in explaining side-differences in radiographic JSW in fixed flexion radiographs. Tibial coverage by the meniscus and central femoral cartilage explained two thirds of the variability in minimum and fixed location JSW. JSW provides a better representation of (central) femorotibial cartilage thickness, when optimal positioning of the fixed flexion radiographs is achieved.
European journal of radiology 09/2013; · 2.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: To describe the frequency of bone marrow lesions (BMLs) detected by magnetic resonance imaging (MRI), and to examine the association of BMLs with knee pain severity in community residents in Korea.
Participants were randomly chosen from the population-based Hallym Aging Study, irrespective of whether they had knee osteoarthritis (OA) or pain. Demographic and knee pain data were obtained by questionnaire. Radiographic evaluations consisted of weight-bearing knee anteroposterior radiographs and 1.5-T MRI scans. MRI was performed in the dominant knees of subjects without knee pain and in the more symptomatic knees of subjects with knee pain. BMLs were graded according to the whole-organ MRI score.
The mean age of the 358 study subjects was 71.8 years, and 34.5% of subjects had radiographically detected knee OA. The prevalences of BMLs and large BMLs in the tibiofemoral compartments were 80.3% and 40.4%, respectively. After adjusting for age, sex, and body mass index, total and medial compartment BML scores were significantly associated with the presence of knee pain, and the association was stronger as the summary score for BML increased. In proportional regression analysis, knee pain severity increased with BML severity in any compartment and in the medial compartment.
BMLs detected by MRI were highly prevalent in this elderly Asian population. BMLs were significantly linked to knee pain, and BML severity correlated with knee pain severity. BMLs may be important surrogate targets for monitoring pain and structure modification in OA therapeutics.
Osteoarthritis and Cartilage 09/2013; 21(9):1207-13. · 4.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine whether the presence and extent of severe lumbar facet joint osteoarthritis (OA) are associated with back pain in older adults, accounting for disc height narrowing and other covariates.
Two hundred and fifty-two older adults from the Framingham Offspring Cohort (mean age 67 years) were studied. Participants received standardized computed tomography (CT) assessments of lumbar facet joint OA and disc height narrowing at the L2-S1 interspaces using four-grade semi-quantitative scales. Severe facet joint OA was defined according to the presence and/or degree of joint space narrowing, osteophytosis, articular process hypertrophy, articular erosions, subchondral cysts, and intraarticular vacuum phenomenon. Severe disc height narrowing was defined as marked narrowing with endplates almost in contact. Back pain was defined as participant report of pain on most days or all days in the past 12 months. We used multivariable logistic regression to examine associations between severe facet joint OA and back pain, adjusting for key covariates including disc height narrowing, sociodemographics, anthropometrics, and health factors.
Severe facet joint OA was more common in participants with back pain than those without (63.2% vs 46.7%; P = 0.03). In multivariable analyses, presence of any severe facet joint OA remained significantly associated with back pain (odds ratio (OR) 2.15 [95% confidence interval (CI) 1.13-4.08]). Each additional joint with severe OA conferred greater odds of back pain [OR per joint 1.20 (95% CI 1.02-1.41)].
The presence and extent of severe facet joint OA on CT imaging are associated with back pain in community-based older adults, independent of sociodemographics, health factors, and disc height narrowing.
Osteoarthritis and Cartilage 09/2013; 21(9):1199-206. · 4.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: To describe the insights on the epidemiology of pain-structure association and the ramifications of these studies for clinical trials.
Narrative review summarizing the pertinent literature in this area, summarizing some of the methodologic challenges inherent and proposing some research initiatives to further understanding of this complex science.
The predominant symptom in most patients presenting with osteoarthritis (OA) is pain. Over recent years a number of imaging based studies have narrowed the discord between structural findings on imaging and symptoms. The interpretation of pain in OA is still enigmatic and difficult to deal with both for clinicians and scientists.
We would envisage that over the next few years many of the pressing questions pertaining to research into the structure pain relationship will continue to be addressed. With this, we can expect clinically appropriate therapeutic advance.
Osteoarthritis and Cartilage 09/2013; 21(9):1170-8. · 4.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is an important need to evaluate therapeutic approaches for osteoarthritis (OA) in terms of cost-effectiveness as well as efficacy.
The ESCEO expert working group met to discuss the epidemiological and economic evidence that justifies the increasing concern of the impact of this disease and reviewed the current state-of-the-art in health economic studies in this field.
OA is a debilitating disease; it is increasing in frequency and is associated with a substantial and growing burden on society, in terms of both burden of illness and cost of illness. Economic evaluations in this field are relatively rare, and those that do exist, show considerable heterogeneity of methodological approach (such as indicated population, comparator, decision context and perspective, time horizon, modeling and outcome measures used). This heterogeneity makes comparisons between studies problematic.
Better adherence to guidelines for economic evaluations is needed. There was strong support for the definition of a reference case and for what might constitute "standard optimal care" in terms of best clinical practice, for the control arms of interventional studies.
Seminars in arthritis and rheumatism 08/2013; · 4.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: Knee osteoarthritis is associated with structural changes in the joint. Despite its many drawbacks, radiography is the current standard for evaluating joint structure in trials of potential disease-modifying osteoarthritis drugs. MRI is a non-invasive alternative that provides comprehensive imaging of the whole joint. Frequently used MRI measurements in knee osteoarthritis are cartilage volume and thickness; others include synovitis, synovial fluid effusions, bone marrow lesions (BML) and meniscal damage. Joint replacement is considered a clinically relevant outcome in knee osteoarthritis; however, its utility in clinical trials is limited. An alternative is virtual knee replacement on the basis of symptoms and structural damage. MRI may prove to be a good alternative to radiography in definitions of knee replacement. One of the MRI parameters that predicts knee replacement is medial compartment cartilage volume/thickness, which correlates with radiographic joint space width, is sensitive to change, and predicts outcomes in a continuous manner. Other MRI parameters include BML and meniscal lesions. MRI appears to be a viable alternative to radiography for the evaluation of structural changes in knee osteoarthritis and prediction of joint replacement.
Annals of the rheumatic diseases 07/2013; · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: Osteoarthritis (OA), the most common of all arthropathies, is a leading cause of disability and has a large (and growing) worldwide socioeconomic cost. Despite its burgeoning importance, translation of disease-modifying OA therapies from the laboratory into clinical practice has slowed. Differences between the OA models studied preclinically and the disease evaluated in human clinical trials contribute to this failure. Most animal models of OA induce disease through surgical or mechanical disruption of joint biomechanics in young individuals rather than the spontaneous development of age-associated disease. This instability-induced joint disease in animals best models the arthritis that develops in humans after an injurious event, known as post-traumatic OA (PTOA). Studies in genetically modified mice suggest that PTOA has a distinct molecular pathophysiology compared with that of spontaneous OA, which might explain the poor translation from preclinical to clinical OA therapeutic trials. This Review summarizes the latest data on potential molecular targets for PTOA prevention and modification derived from studies in genetically modified mice, and describes their validation in preclinical therapeutic trials. This article focuses on how these findings might best be translated to humans, and identifies the potential challenges to successful implementation of clinical trials of disease-modifying drugs for PTOA.
[show abstract][hide abstract] ABSTRACT: The 6(th) OARSI Workshop on Imaging in Osteoarthritis combined with the 3(rd) OA Biomarkers Workshop is the first to bring together the imaging and molecular biomarker communities to focus on clinical validation and qualification of osteoarthritis biomarkers. The workshop was held in Hilton Head, SC, USA, from June 12-14, 2012; 138 attendees participated, including representatives from academia, pharmaceutical and MRI industries, FDA, and NIH. Presentations and discussions raised awareness, consolidated knowledge, and identified strategies to overcome challenges for the development and application of imaging and biochemical biomarkers in OA research studies and clinical trials. CONCLUSIONS: The OA research communities need to work alongside regulatory agencies across the world, to qualify and validate new chemical and imaging biomarkers for future research and clinical trials.
Osteoarthritis and Cartilage 04/2013; · 4.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.