Pub Date : 2017-10-01DOI: 10.1161/CIRCGENETICS.117.001917
Michael A Portman, Sadeep Shrestha
{"title":"One Size Does Not Fit All: Genetic Prediction of Kawasaki Disease Treatment Response in Diverse Populations.","authors":"Michael A Portman, Sadeep Shrestha","doi":"10.1161/CIRCGENETICS.117.001917","DOIUrl":"10.1161/CIRCGENETICS.117.001917","url":null,"abstract":"","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661947/pdf/nihms903256.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35601882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-10-01DOI: 10.1161/CIRCGENETICS.117.001918
Chloe Reuter, Julia Platt
Our understanding of Fabry disease continues to evolve since its first description as a dermatologic disorder over a century ago, and the more we learn, the more it becomes clear that this complex disorder defies simple categorizations. A progressive inborn error of lysosomal glycosphingolipid metabolism caused by disruption of the X-linked GLA gene, Fabry disease exhibits a wide spectrum of severity and clinical findings. The phenotype that is most likely to be recognized clinically is the well-described classic form that manifests in boys or young men with neuropathic pain and paresthesia, angiokeratomas, hypohydrosis or anhydrosis, corneal verticillata, hypertrophic cardiomyopathy, renal failure, and cerebrovascular strokes.1 However, the diagnosis remains challenging in people with nonclassic presentations, such as female heterozygotes, who may have a milder course or later onset but are still at risk for life-threatening complications of the disease, and cases of variant Fabry, where clinical involvement is largely confined to a single organ. For example, cardiac variant Fabry can mimic sarcomeric hypertrophic cardiomyopathy.1 These diagnostic challenges are of particular concern to providers who are likely to encounter nonclassic presentations, such as those working in cardiology clinics. Fabry disease-specific treatments, such as enzyme replacement therapy or chaperone treatment, can only be initiated after an accurate diagnosis is established, and the efficacy of treatment may be limited in those with advanced disease.2 See Article by Oder et al In this issue, Oder et al3 describe a cohort of patients who were referred for evaluation of apparently isolated hypertrophic cardiomyopathy but who on further workup and genetic testing were diagnosed with nonclassic Fabry disease. This article describes 26 patients (13 men and 13 women) with the N215S (c.644A>G, p.Asn215Ser) variant in the GLA gene. The N215S variant is a common cause of Fabry, occurring in 4.8% of people in …
{"title":"Clinical Characteristics of the <i>GLA</i> N215S Variant and Implications for the Diagnosis and Management of Nonclassic Fabry Disease.","authors":"Chloe Reuter, Julia Platt","doi":"10.1161/CIRCGENETICS.117.001918","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001918","url":null,"abstract":"Our understanding of Fabry disease continues to evolve since its first description as a dermatologic disorder over a century ago, and the more we learn, the more it becomes clear that this complex disorder defies simple categorizations. A progressive inborn error of lysosomal glycosphingolipid metabolism caused by disruption of the X-linked GLA gene, Fabry disease exhibits a wide spectrum of severity and clinical findings. The phenotype that is most likely to be recognized clinically is the well-described classic form that manifests in boys or young men with neuropathic pain and paresthesia, angiokeratomas, hypohydrosis or anhydrosis, corneal verticillata, hypertrophic cardiomyopathy, renal failure, and cerebrovascular strokes.1 However, the diagnosis remains challenging in people with nonclassic presentations, such as female heterozygotes, who may have a milder course or later onset but are still at risk for life-threatening complications of the disease, and cases of variant Fabry, where clinical involvement is largely confined to a single organ. For example, cardiac variant Fabry can mimic sarcomeric hypertrophic cardiomyopathy.1 These diagnostic challenges are of particular concern to providers who are likely to encounter nonclassic presentations, such as those working in cardiology clinics. Fabry disease-specific treatments, such as enzyme replacement therapy or chaperone treatment, can only be initiated after an accurate diagnosis is established, and the efficacy of treatment may be limited in those with advanced disease.2\u0000\u0000See Article by Oder et al \u0000\u0000In this issue, Oder et al3 describe a cohort of patients who were referred for evaluation of apparently isolated hypertrophic cardiomyopathy but who on further workup and genetic testing were diagnosed with nonclassic Fabry disease. This article describes 26 patients (13 men and 13 women) with the N215S (c.644A>G, p.Asn215Ser) variant in the GLA gene. The N215S variant is a common cause of Fabry, occurring in 4.8% of people in …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001918","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35594838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-10-01DOI: 10.1161/CIRCGENETICS.117.001951
Megan J Puckelwartz, Elizabeth M McNally
Heredity strongly influences multiple cardiovascular disorders, including arrhythmia syndromes, aortic aneurysms, dyslipidemias, cardiomyopathy, and heart failure. Genetic testing has emerged as an effective clinical tool, especially in the cardiomyopathies, because it provides information useful for diagnosis and stratification.1 Genetic testing for clinical diagnosis currently relies on gene panels, where many genes are sequenced simultaneously. With gene panel sequencing, the coding regions of specific genes are first captured and then sequenced. Most mutations detected with this method are single nucleotide polymorphisms or small insertions/deletions. It is also possible to detect larger exonic-level deletions or duplications. Most cardiomyopathy mutations are inherited in an autosomal dominant manner, and these methods can detect heterozygous variants. See Article by Cirino et al Cardiomyopathy gene panels have grown in size and scope, and it has now become commonplace to evaluate 50 to 120 genes in a single test, depending on the specific cardiomyopathy subtype and accompanying cardiac arrhythmias.2 Hypertrophic cardiomyopathy (HCM) is a more genetically restricted disease compared with dilated cardiomyopathy. The majority of HCM arises from heterozygous mutations in genes encoding sarcomere proteins with MYH7 and MYBPC3 accounting for 70% to 80% of familial HCM. The limited yield of larger panels combined with the enrichment of MYH7/MYBPC3 mutations has prompted the suggestion that genetic testing for HCM should first focus on these 2 genes.3,4 In contrast, dilated cardiomyopathy is linked to many more genes, with 1 gene, TTN , accounting for 20% of genetic dilated cardiomyopathy, and ≥80 genes explaining an additional fraction.5–7 This genetic heterogeneity has led some to suggest that >1 variant may contribute to disease onset, supporting an oligogenic pathogenesis. The sensitivity of genetic panels for cardiomyopathies ranges from 30% to 50%, depending on the subtype. The rate of variant discovery should improve as …
{"title":"Hypertrophic Cardiomyopathy Gene Testing: Go Big?","authors":"Megan J Puckelwartz, Elizabeth M McNally","doi":"10.1161/CIRCGENETICS.117.001951","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001951","url":null,"abstract":"Heredity strongly influences multiple cardiovascular disorders, including arrhythmia syndromes, aortic aneurysms, dyslipidemias, cardiomyopathy, and heart failure. Genetic testing has emerged as an effective clinical tool, especially in the cardiomyopathies, because it provides information useful for diagnosis and stratification.1 Genetic testing for clinical diagnosis currently relies on gene panels, where many genes are sequenced simultaneously. With gene panel sequencing, the coding regions of specific genes are first captured and then sequenced. Most mutations detected with this method are single nucleotide polymorphisms or small insertions/deletions. It is also possible to detect larger exonic-level deletions or duplications. Most cardiomyopathy mutations are inherited in an autosomal dominant manner, and these methods can detect heterozygous variants.\u0000\u0000See Article by Cirino et al \u0000\u0000Cardiomyopathy gene panels have grown in size and scope, and it has now become commonplace to evaluate 50 to 120 genes in a single test, depending on the specific cardiomyopathy subtype and accompanying cardiac arrhythmias.2 Hypertrophic cardiomyopathy (HCM) is a more genetically restricted disease compared with dilated cardiomyopathy. The majority of HCM arises from heterozygous mutations in genes encoding sarcomere proteins with MYH7 and MYBPC3 accounting for 70% to 80% of familial HCM. The limited yield of larger panels combined with the enrichment of MYH7/MYBPC3 mutations has prompted the suggestion that genetic testing for HCM should first focus on these 2 genes.3,4 In contrast, dilated cardiomyopathy is linked to many more genes, with 1 gene, TTN , accounting for 20% of genetic dilated cardiomyopathy, and ≥80 genes explaining an additional fraction.5–7 This genetic heterogeneity has led some to suggest that >1 variant may contribute to disease onset, supporting an oligogenic pathogenesis.\u0000\u0000The sensitivity of genetic panels for cardiomyopathies ranges from 30% to 50%, depending on the subtype. The rate of variant discovery should improve as …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001951","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35449460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-10-01DOI: 10.1161/CIRCGENETICS.117.001736
Francesca N Delling, Xinjun Li, Shuo Li, Qiong Yang, Vanessa Xanthakis, Andreas Martinsson, Pontus Andell, Birgitta T Lehman, Ewa W Osypiuk, Plamen Stantchev, Bengt Zöller, Emelia J Benjamin, Kristina Sundquist, Ramachandran S Vasan, J Gustav Smith
Background: Familial aggregation has been described for primary mitral regurgitation (MR) caused by mitral valve prolapse. We hypothesized that heritability of MR exists across different MR subtypes including nonprimary MR.
Methods and results: Study participants were FHS (Framingham Heart Study) Generation 3 (Gen 3) and Gen 2 cohort participants and all adult Swedish siblings born after 1932 identified in 1997 and followed through 2010. MR was defined as ≥ mild regurgitation on color Doppler in FHS and from International Classification of Diseases codes in Sweden. We estimated the association of sibling MR with MR in Gen 2/Gen 3/Swedish siblings. We also estimated heritability of MR in 539 FHS pedigrees (7580 individuals). Among 5132 FHS Gen 2/Gen 3 participants with sibling information, 1062 had MR. Of siblings with sibling MR, 28% (500/1797) had MR compared with 17% (562/3335) without sibling MR (multivariable-adjusted odds ratio, 1.20; 95% confidence interval [CI], 1.01-1.43; P=0.04). When we combined parental and sibling data in FHS pedigrees, heritability of MR was estimated at 0.15 (95% CI, 0.07-0.23), 0.12 (95% CI, 0.04-0.20) excluding mitral valve prolapse, and 0.44 (95% CI, 0.15-0.73) for ≥ moderate MR only (all P<0.05). In Sweden, sibling MR was associated with a hazard ratio of 3.57 (95% CI, 2.21-5.76; P<0.001) for development of MR.
Conclusions: Familial clustering of MR exists in the community, supporting a genetic susceptibility common to primary and nonprimary MR. Further studies are needed to elucidate the common regulatory pathways that may lead to MR irrespective of its cause.
{"title":"Heritability of Mitral Regurgitation: Observations From the Framingham Heart Study and Swedish Population.","authors":"Francesca N Delling, Xinjun Li, Shuo Li, Qiong Yang, Vanessa Xanthakis, Andreas Martinsson, Pontus Andell, Birgitta T Lehman, Ewa W Osypiuk, Plamen Stantchev, Bengt Zöller, Emelia J Benjamin, Kristina Sundquist, Ramachandran S Vasan, J Gustav Smith","doi":"10.1161/CIRCGENETICS.117.001736","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001736","url":null,"abstract":"<p><strong>Background: </strong>Familial aggregation has been described for primary mitral regurgitation (MR) caused by mitral valve prolapse. We hypothesized that heritability of MR exists across different MR subtypes including nonprimary MR.</p><p><strong>Methods and results: </strong>Study participants were FHS (Framingham Heart Study) Generation 3 (Gen 3) and Gen 2 cohort participants and all adult Swedish siblings born after 1932 identified in 1997 and followed through 2010. MR was defined as ≥ mild regurgitation on color Doppler in FHS and from <i>International Classification of Diseases</i> codes in Sweden. We estimated the association of sibling MR with MR in Gen 2/Gen 3/Swedish siblings. We also estimated heritability of MR in 539 FHS pedigrees (7580 individuals). Among 5132 FHS Gen 2/Gen 3 participants with sibling information, 1062 had MR. Of siblings with sibling MR, 28% (500/1797) had MR compared with 17% (562/3335) without sibling MR (multivariable-adjusted odds ratio, 1.20; 95% confidence interval [CI], 1.01-1.43; <i>P</i>=0.04). When we combined parental and sibling data in FHS pedigrees, heritability of MR was estimated at 0.15 (95% CI, 0.07-0.23), 0.12 (95% CI, 0.04-0.20) excluding mitral valve prolapse, and 0.44 (95% CI, 0.15-0.73) for ≥ moderate MR only (all <i>P</i><0.05). In Sweden, sibling MR was associated with a hazard ratio of 3.57 (95% CI, 2.21-5.76; <i>P</i><0.001) for development of MR.</p><p><strong>Conclusions: </strong>Familial clustering of MR exists in the community, supporting a genetic susceptibility common to primary and nonprimary MR. Further studies are needed to elucidate the common regulatory pathways that may lead to MR irrespective of its cause.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001736","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35491704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-10-01DOI: 10.1161/CIRCGENETICS.117.001767
Kamaldeep Panach, Abhimanyu Garg, Zahid Ahmad
Patients with familial hypercholesterolemia (FH; Online Mendelian Inheritance in Man #143890) have lifelong elevations in low-density lipoprotein cholesterol (LDL-C) that result in deposition of cholesterol in tendons— referred to as tendon xanthomas and occurring in ≈19% of heterozygous FH patients1—and an increased risk of premature cardiovascular disease. FH is an autosomal dominant disorder resulting from mutations in the LDL receptor ( LDLR ), APOB (apolipoprotein B), or PCSK9 (proprotein convertase subtilisin-like kexin type 9) genes.2 Heterozygous mutations in LDLR are the most common cause of FH. In addition to elevated LDL-C, patients harboring LDLR mutations may have lower levels of high-density lipoprotein cholesterol and only mild, if any, elevations in triglycerides.3–5 Severe hypertriglyceridemia is rarely seen in FH patients.5 We report an alcoholic patient who presented with severely elevated serum triglycerides and both tuberous and tendon xanthomas in whom the diagnosis of FH was confirmed by genetic testing. A 75-year-old Hispanic man was referred to us for genetic testing as part of a larger research protocol.6 His medical history included 3-vessel coronary artery bypass graft at age 47 and a myocardial infarction at age 60, hypothyroidism, osteoporosis, gastro-esophageal reflux, hypertension, recurrent major depressive disorder with a history of a suicide attempt, heavy alcohol and tobacco abuse, and Alzheimer dementia (initially diagnosed at age 72 with superimposed frontal lobe damage from prior alcohol use). Hyperlipidemia was first diagnosed at age 34, although his wife noted that he had Achilles tendon xanthomas and arcus senilis since age 22 (when they first met). He had been tried on multiple medications (he could not recall exact names) and ultimately underwent ileal bypass surgery at age 41 for treatment. The ileal bypass was reversed at age 60 because of multiple episodes of intestinal obstruction. At age 66, he was …
{"title":"Heterozygous Null <i>LDLR</i> Mutation in a Familial Hypercholesterolemia Patient With an Atypical Presentation Because of Alcohol Abuse.","authors":"Kamaldeep Panach, Abhimanyu Garg, Zahid Ahmad","doi":"10.1161/CIRCGENETICS.117.001767","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001767","url":null,"abstract":"Patients with familial hypercholesterolemia (FH; Online Mendelian Inheritance in Man #143890) have lifelong elevations in low-density lipoprotein cholesterol (LDL-C) that result in deposition of cholesterol in tendons— referred to as tendon xanthomas and occurring in ≈19% of heterozygous FH patients1—and an increased risk of premature cardiovascular disease. FH is an autosomal dominant disorder resulting from mutations in the LDL receptor ( LDLR ), APOB (apolipoprotein B), or PCSK9 (proprotein convertase subtilisin-like kexin type 9) genes.2\u0000\u0000Heterozygous mutations in LDLR are the most common cause of FH. In addition to elevated LDL-C, patients harboring LDLR mutations may have lower levels of high-density lipoprotein cholesterol and only mild, if any, elevations in triglycerides.3–5 Severe hypertriglyceridemia is rarely seen in FH patients.5 We report an alcoholic patient who presented with severely elevated serum triglycerides and both tuberous and tendon xanthomas in whom the diagnosis of FH was confirmed by genetic testing.\u0000\u0000A 75-year-old Hispanic man was referred to us for genetic testing as part of a larger research protocol.6 His medical history included 3-vessel coronary artery bypass graft at age 47 and a myocardial infarction at age 60, hypothyroidism, osteoporosis, gastro-esophageal reflux, hypertension, recurrent major depressive disorder with a history of a suicide attempt, heavy alcohol and tobacco abuse, and Alzheimer dementia (initially diagnosed at age 72 with superimposed frontal lobe damage from prior alcohol use).\u0000\u0000Hyperlipidemia was first diagnosed at age 34, although his wife noted that he had Achilles tendon xanthomas and arcus senilis since age 22 (when they first met). He had been tried on multiple medications (he could not recall exact names) and ultimately underwent ileal bypass surgery at age 41 for treatment. The ileal bypass was reversed at age 60 because of multiple episodes of intestinal obstruction. At age 66, he was …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001767","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35491705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-10-01DOI: 10.1161/CIRCGENETICS.117.001920
Daniel P Judge, Russell A Norris
As the field of cardiovascular genetics continues to evolve, traditional Mendelian disorders are more readily characterized by clinical genetic testing. These conditions are caused by rare DNA mutations with major effects for most, if not all carriers. The newest frontiers for genetic investigation include more common disorders in which the genetic variants are more prevalent and the effect sizes are smaller. The spectrum extends from severe neonatal disorders with high penetrance to more common diseases, such as familial mitral valve prolapse (MVP). Pushing this envelope, investigators in this issue of Circulation: Cardiovascular Genetics now report heritability of mitral regurgitation (MR).1 Starting with the well-characterized Framingham Heart Study participants in whom second- and third-generation cardiac data were available, they identified 1062 with ≥mild MR among 5132 (21%), in whom there was adequate parental and sibling information. The odds ratio of MR was 1.42 if parental MR was present after adjusting for age, sex, and risk factors and with restricting to ≥moderate MR. Likewise, the odds ratio of MR was 1.78 if sibling MR was present after adjusting for age, sex, and risk factors and restricting to ≥moderate MR. Strengthening their conclusions, the authors used the Swedish hospital registry to validate these findings. In Sweden, 1.2% (239 of 18 891) of siblings with sibling MR had MR compared with 0.2% (n=8389/5 138 298) without sibling MR, corresponding to a hazard ratio of 4.0 adjusted for age and sex. MR is more commonly seen in the context …
{"title":"Inheritance Impacts Mitral Valve Insufficiency.","authors":"Daniel P Judge, Russell A Norris","doi":"10.1161/CIRCGENETICS.117.001920","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001920","url":null,"abstract":"As the field of cardiovascular genetics continues to evolve, traditional Mendelian disorders are more readily characterized by clinical genetic testing. These conditions are caused by rare DNA mutations with major effects for most, if not all carriers. The newest frontiers for genetic investigation include more common disorders in which the genetic variants are more prevalent and the effect sizes are smaller. The spectrum extends from severe neonatal disorders with high penetrance to more common diseases, such as familial mitral valve prolapse (MVP). Pushing this envelope, investigators in this issue of Circulation: Cardiovascular Genetics now report heritability of mitral regurgitation (MR).1 Starting with the well-characterized Framingham Heart Study participants in whom second- and third-generation cardiac data were available, they identified 1062 with ≥mild MR among 5132 (21%), in whom there was adequate parental and sibling information. The odds ratio of MR was 1.42 if parental MR was present after adjusting for age, sex, and risk factors and with restricting to ≥moderate MR. Likewise, the odds ratio of MR was 1.78 if sibling MR was present after adjusting for age, sex, and risk factors and restricting to ≥moderate MR. Strengthening their conclusions, the authors used the Swedish hospital registry to validate these findings. In Sweden, 1.2% (239 of 18 891) of siblings with sibling MR had MR compared with 0.2% (n=8389/5 138 298) without sibling MR, corresponding to a hazard ratio of 4.0 adjusted for age and sex. MR is more commonly seen in the context …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001920","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35491706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-10-01DOI: 10.1161/CIRCGENETICS.117.001919
TyAnna L Lovato, Richard M Cripps
In 1925, Dr Carlos Monge presented to the National Academy of Medicine in Lima, Peru, his observations of a new disease. His patient had bluish skin, dizziness, and confusion when working at high altitudes, but symptoms were ameliorated once the patient returned to the coast.1 In a storied and impactful career, Monge went on to study the physiological differences between sufferers of Monge’s disease, those who were able to acclimatize to the altitude, and finally those who thrived in the low oxygen conditions.2 Today, we now know this condition as chronic mountain sickness (CMS). Caused by exposure to low oxygen conditions, CMS affects a significant proportion of high-altitude populations and can lead to pulmonary hypertension, cardiac hypertrophy, and eventual heart failure.3 See Article by Zarndt and Walls et al Today, CMS still afflicts a large number of individuals, including a striking one sixth of residents of Cerro de Pasco in Peru,4 designating CMS as a significant medical challenge in many high-altitude populations. Understanding the mechanisms by which hypertension and cardiac hypertrophy occur as a result of hypoxia is important not only …
{"title":"High Heart: A Role for Calcineurin Signaling in Hypoxia-Influenced Cardiac Growth.","authors":"TyAnna L Lovato, Richard M Cripps","doi":"10.1161/CIRCGENETICS.117.001919","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001919","url":null,"abstract":"In 1925, Dr Carlos Monge presented to the National Academy of Medicine in Lima, Peru, his observations of a new disease. His patient had bluish skin, dizziness, and confusion when working at high altitudes, but symptoms were ameliorated once the patient returned to the coast.1 In a storied and impactful career, Monge went on to study the physiological differences between sufferers of Monge’s disease, those who were able to acclimatize to the altitude, and finally those who thrived in the low oxygen conditions.2 Today, we now know this condition as chronic mountain sickness (CMS). Caused by exposure to low oxygen conditions, CMS affects a significant proportion of high-altitude populations and can lead to pulmonary hypertension, cardiac hypertrophy, and eventual heart failure.3\u0000\u0000See Article by Zarndt and Walls et al \u0000\u0000Today, CMS still afflicts a large number of individuals, including a striking one sixth of residents of Cerro de Pasco in Peru,4 designating CMS as a significant medical challenge in many high-altitude populations. Understanding the mechanisms by which hypertension and cardiac hypertrophy occur as a result of hypoxia is important not only …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001919","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35479281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-10-01DOI: 10.1161/CIRCGENETICS.117.001778
Aldi T Kraja, James P Cook, Helen R Warren, Praveen Surendran, Chunyu Liu, Evangelos Evangelou, Alisa K Manning, Niels Grarup, Fotios Drenos, Xueling Sim, Albert Vernon Smith, Najaf Amin, Alexandra I F Blakemore, Jette Bork-Jensen, Ivan Brandslund, Aliki-Eleni Farmaki, Cristiano Fava, Teresa Ferreira, Karl-Heinz Herzig, Ayush Giri, Franco Giulianini, Megan L Grove, Xiuqing Guo, Sarah E Harris, Christian T Have, Aki S Havulinna, He Zhang, Marit E Jørgensen, AnneMari Käräjämäki, Charles Kooperberg, Allan Linneberg, Louis Little, Yongmei Liu, Lori L Bonnycastle, Yingchang Lu, Reedik Mägi, Anubha Mahajan, Giovanni Malerba, Riccardo E Marioni, Hao Mei, Cristina Menni, Alanna C Morrison, Sandosh Padmanabhan, Walter Palmas, Alaitz Poveda, Rainer Rauramaa, Nigel William Rayner, Muhammad Riaz, Ken Rice, Melissa A Richard, Jennifer A Smith, Lorraine Southam, Alena Stančáková, Kathleen E Stirrups, Vinicius Tragante, Tiinamaija Tuomi, Ioanna Tzoulaki, Tibor V Varga, Stefan Weiss, Andrianos M Yiorkas, Robin Young, Weihua Zhang, Michael R Barnes, Claudia P Cabrera, He Gao, Michael Boehnke, Eric Boerwinkle, John C Chambers, John M Connell, Cramer K Christensen, Rudolf A de Boer, Ian J Deary, George Dedoussis, Panos Deloukas, Anna F Dominiczak, Marcus Dörr, Roby Joehanes, Todd L Edwards, Tõnu Esko, Myriam Fornage, Nora Franceschini, Paul W Franks, Giovanni Gambaro, Leif Groop, Göran Hallmans, Torben Hansen, Caroline Hayward, Oksa Heikki, Erik Ingelsson, Jaakko Tuomilehto, Marjo-Riitta Jarvelin, Sharon L R Kardia, Fredrik Karpe, Jaspal S Kooner, Timo A Lakka, Claudia Langenberg, Lars Lind, Ruth J F Loos, Markku Laakso, Mark I McCarthy, Olle Melander, Karen L Mohlke, Andrew P Morris, Colin N A Palmer, Oluf Pedersen, Ozren Polasek, Neil R Poulter, Michael A Province, Bruce M Psaty, Paul M Ridker, Jerome I Rotter, Igor Rudan, Veikko Salomaa, Nilesh J Samani, Peter J Sever, Tea Skaaby, Jeanette M Stafford, John M Starr, Pim van der Harst, Peter van der Meer, Cornelia M van Duijn, Anne-Claire Vergnaud, Vilmundur Gudnason, Nicholas J Wareham, James G Wilson, Cristen J Willer, Daniel R Witte, Eleftheria Zeggini, Danish Saleheen, Adam S Butterworth, John Danesh, Folkert W Asselbergs, Louise V Wain, Georg B Ehret, Daniel I Chasman, Mark J Caulfield, Paul Elliott, Cecilia M Lindgren, Daniel Levy, Christopher Newton-Cheh, Patricia B Munroe, Joanna M M Howson
Background: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.
Methods and results: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.
Conclusions: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
{"title":"New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals.","authors":"Aldi T Kraja, James P Cook, Helen R Warren, Praveen Surendran, Chunyu Liu, Evangelos Evangelou, Alisa K Manning, Niels Grarup, Fotios Drenos, Xueling Sim, Albert Vernon Smith, Najaf Amin, Alexandra I F Blakemore, Jette Bork-Jensen, Ivan Brandslund, Aliki-Eleni Farmaki, Cristiano Fava, Teresa Ferreira, Karl-Heinz Herzig, Ayush Giri, Franco Giulianini, Megan L Grove, Xiuqing Guo, Sarah E Harris, Christian T Have, Aki S Havulinna, He Zhang, Marit E Jørgensen, AnneMari Käräjämäki, Charles Kooperberg, Allan Linneberg, Louis Little, Yongmei Liu, Lori L Bonnycastle, Yingchang Lu, Reedik Mägi, Anubha Mahajan, Giovanni Malerba, Riccardo E Marioni, Hao Mei, Cristina Menni, Alanna C Morrison, Sandosh Padmanabhan, Walter Palmas, Alaitz Poveda, Rainer Rauramaa, Nigel William Rayner, Muhammad Riaz, Ken Rice, Melissa A Richard, Jennifer A Smith, Lorraine Southam, Alena Stančáková, Kathleen E Stirrups, Vinicius Tragante, Tiinamaija Tuomi, Ioanna Tzoulaki, Tibor V Varga, Stefan Weiss, Andrianos M Yiorkas, Robin Young, Weihua Zhang, Michael R Barnes, Claudia P Cabrera, He Gao, Michael Boehnke, Eric Boerwinkle, John C Chambers, John M Connell, Cramer K Christensen, Rudolf A de Boer, Ian J Deary, George Dedoussis, Panos Deloukas, Anna F Dominiczak, Marcus Dörr, Roby Joehanes, Todd L Edwards, Tõnu Esko, Myriam Fornage, Nora Franceschini, Paul W Franks, Giovanni Gambaro, Leif Groop, Göran Hallmans, Torben Hansen, Caroline Hayward, Oksa Heikki, Erik Ingelsson, Jaakko Tuomilehto, Marjo-Riitta Jarvelin, Sharon L R Kardia, Fredrik Karpe, Jaspal S Kooner, Timo A Lakka, Claudia Langenberg, Lars Lind, Ruth J F Loos, Markku Laakso, Mark I McCarthy, Olle Melander, Karen L Mohlke, Andrew P Morris, Colin N A Palmer, Oluf Pedersen, Ozren Polasek, Neil R Poulter, Michael A Province, Bruce M Psaty, Paul M Ridker, Jerome I Rotter, Igor Rudan, Veikko Salomaa, Nilesh J Samani, Peter J Sever, Tea Skaaby, Jeanette M Stafford, John M Starr, Pim van der Harst, Peter van der Meer, Cornelia M van Duijn, Anne-Claire Vergnaud, Vilmundur Gudnason, Nicholas J Wareham, James G Wilson, Cristen J Willer, Daniel R Witte, Eleftheria Zeggini, Danish Saleheen, Adam S Butterworth, John Danesh, Folkert W Asselbergs, Louise V Wain, Georg B Ehret, Daniel I Chasman, Mark J Caulfield, Paul Elliott, Cecilia M Lindgren, Daniel Levy, Christopher Newton-Cheh, Patricia B Munroe, Joanna M M Howson","doi":"10.1161/CIRCGENETICS.117.001778","DOIUrl":"10.1161/CIRCGENETICS.117.001778","url":null,"abstract":"<p><strong>Background: </strong>Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.</p><p><strong>Methods and results: </strong>Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (<i>P</i><5×10<sup>-</sup><sup>8</sup>) for BP, of which 4 are new BP loci: rs9678851 (missense, <i>SLC4A1AP</i>), rs7437940 (<i>AFAP1</i>), rs13303 (missense, <i>STAB1</i>), and rs1055144 (<i>7p15.2</i>). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, <i>SYNPO2L</i>) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at <i>DBH</i>) was genome-wide significant.</p><p><strong>Conclusions: </strong>We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776077/pdf/nihms905672.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10654491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-10-01DOI: 10.1161/CIRCGENETICS.116.001678
Christine M Willinger, Jian Rong, Kahraman Tanriverdi, Paul L Courchesne, Tianxiao Huan, Gregory A Wasserman, Honghuang Lin, Josée Dupuis, Roby Joehanes, Matthew R Jones, George Chen, Emelia J Benjamin, George T O'Connor, Joseph P Mizgerd, Jane E Freedman, Martin G Larson, Daniel Levy
Background: Cigarette smoking increases risk for multiple diseases. MicroRNAs regulate gene expression and may play a role in smoking-induced target organ damage. We sought to describe a microRNA signature of cigarette smoking and relate it to smoking-associated clinical phenotypes, gene expression, and lung inflammatory signaling.
Methods and results: Expression profiling of 283 microRNAs was conducted on whole blood-derived RNA from 5023 Framingham Heart Study participants (54.0% women; mean age, 55±13 years) using TaqMan assays and high-throughput reverse transcription quantitative polymerase chain reaction. Associations of microRNA expression with smoking status and associations of smoking-related microRNAs with inflammatory biomarkers and pulmonary function were tested with linear mixed effects models. We identified a 6-microRNA signature of smoking. Five of the 6 smoking-related microRNAs were associated with serum levels of C-reactive protein or interleukin-6; miR-1180 was associated with pulmonary function measures at a marginally significant level. Bioinformatic evaluation of smoking-associated genes coexpressed with the microRNA signature of cigarette smoking revealed enrichment for immune-related pathways. Smoking-associated microRNAs altered expression of selected inflammatory mediators in cell culture gain-of-function assays.
Conclusions: We characterized a novel microRNA signature of cigarette smoking. The top microRNAs were associated with systemic inflammatory markers and reduced pulmonary function, correlated with expression of genes involved in immune function, and were sufficient to modulate inflammatory signaling. Our results highlight smoking-associated microRNAs and are consistent with the hypothesis that smoking-associated microRNAs serve as mediators of smoking-induced inflammation and target organ damage. These findings call for further mechanistic studies to explore the diagnostic and therapeutic use of smoking-related microRNAs.
{"title":"MicroRNA Signature of Cigarette Smoking and Evidence for a Putative Causal Role of MicroRNAs in Smoking-Related Inflammation and Target Organ Damage.","authors":"Christine M Willinger, Jian Rong, Kahraman Tanriverdi, Paul L Courchesne, Tianxiao Huan, Gregory A Wasserman, Honghuang Lin, Josée Dupuis, Roby Joehanes, Matthew R Jones, George Chen, Emelia J Benjamin, George T O'Connor, Joseph P Mizgerd, Jane E Freedman, Martin G Larson, Daniel Levy","doi":"10.1161/CIRCGENETICS.116.001678","DOIUrl":"10.1161/CIRCGENETICS.116.001678","url":null,"abstract":"<p><strong>Background: </strong>Cigarette smoking increases risk for multiple diseases. MicroRNAs regulate gene expression and may play a role in smoking-induced target organ damage. We sought to describe a microRNA signature of cigarette smoking and relate it to smoking-associated clinical phenotypes, gene expression, and lung inflammatory signaling.</p><p><strong>Methods and results: </strong>Expression profiling of 283 microRNAs was conducted on whole blood-derived RNA from 5023 Framingham Heart Study participants (54.0% women; mean age, 55±13 years) using TaqMan assays and high-throughput reverse transcription quantitative polymerase chain reaction. Associations of microRNA expression with smoking status and associations of smoking-related microRNAs with inflammatory biomarkers and pulmonary function were tested with linear mixed effects models. We identified a 6-microRNA signature of smoking. Five of the 6 smoking-related microRNAs were associated with serum levels of C-reactive protein or interleukin-6; miR-1180 was associated with pulmonary function measures at a marginally significant level. Bioinformatic evaluation of smoking-associated genes coexpressed with the microRNA signature of cigarette smoking revealed enrichment for immune-related pathways. Smoking-associated microRNAs altered expression of selected inflammatory mediators in cell culture gain-of-function assays.</p><p><strong>Conclusions: </strong>We characterized a novel microRNA signature of cigarette smoking. The top microRNAs were associated with systemic inflammatory markers and reduced pulmonary function, correlated with expression of genes involved in immune function, and were sufficient to modulate inflammatory signaling. Our results highlight smoking-associated microRNAs and are consistent with the hypothesis that smoking-associated microRNAs serve as mediators of smoking-induced inflammation and target organ damage. These findings call for further mechanistic studies to explore the diagnostic and therapeutic use of smoking-related microRNAs.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683429/pdf/nihms906513.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35449484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-10-01DOI: 10.1161/CIRCGENETICS.117.001910
Kiran Musunuru, William R Lagor, Joseph M Miano
Genome editing has captured widespread attention because of its potential therapeutic applications. Early studies with human embryos have established the feasibility of human germline genome editing but raise complex social, ethical, and legal questions. In light of the potential impact of genome editing on the practice of cardiovascular medicine, we surveyed ≈300 attendees at a recent American Heart Association conference to elicit their opinions on somatic and germline genome editing. The results were revealing and highlight the need to broadly engage the public and solicit the opinions of various constituencies before proceeding with clinical germline genome editing. Genome editing with clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9 (CRISPR/Cas9) has proven so effective in vitro and in vivo that human therapeutic applications are already under pursuit. Clinical trials for somatic genome-editing therapies, that is, modification of cells, tissues, and organs in living people, have been announced in the United States and China. The first reports of human germline genome editing (GGE), that is, embryo modification, were published in 2015 and 2016, although those studies used nonviable embryos and relatively crude first-generation CRISPR/Cas9 tools. A more recent report in August 2017 of GGE to correct a disease-causing gene mutation in viable human embryos that, in principle, could have been carried to term and resulted in healthy offspring was widely heralded in the press as a breakthrough and drew considerable attention.1 What was particularly notable about this study was that the correction of the mutation was efficient and specific—unlike the earlier studies, unintended mutations were not observed elsewhere in the genome (off-target effects) in edited embryos, and mosaicism (mutations present in some cells in the embryo but not in …
{"title":"What Do We Really Think About Human Germline Genome Editing, and What Does It Mean for Medicine?","authors":"Kiran Musunuru, William R Lagor, Joseph M Miano","doi":"10.1161/CIRCGENETICS.117.001910","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001910","url":null,"abstract":"Genome editing has captured widespread attention because of its potential therapeutic applications. Early studies with human embryos have established the feasibility of human germline genome editing but raise complex social, ethical, and legal questions. In light of the potential impact of genome editing on the practice of cardiovascular medicine, we surveyed ≈300 attendees at a recent American Heart Association conference to elicit their opinions on somatic and germline genome editing. The results were revealing and highlight the need to broadly engage the public and solicit the opinions of various constituencies before proceeding with clinical germline genome editing. \u0000\u0000Genome editing with clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9 (CRISPR/Cas9) has proven so effective in vitro and in vivo that human therapeutic applications are already under pursuit. Clinical trials for somatic genome-editing therapies, that is, modification of cells, tissues, and organs in living people, have been announced in the United States and China. The first reports of human germline genome editing (GGE), that is, embryo modification, were published in 2015 and 2016, although those studies used nonviable embryos and relatively crude first-generation CRISPR/Cas9 tools. A more recent report in August 2017 of GGE to correct a disease-causing gene mutation in viable human embryos that, in principle, could have been carried to term and resulted in healthy offspring was widely heralded in the press as a breakthrough and drew considerable attention.1 What was particularly notable about this study was that the correction of the mutation was efficient and specific—unlike the earlier studies, unintended mutations were not observed elsewhere in the genome (off-target effects) in edited embryos, and mosaicism (mutations present in some cells in the embryo but not in …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001910","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35569344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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