A frameshift mutation in the SCNN1B gene in a family with Liddle syndrome: A case report and systematic review.

Liddle syndrome is an autosomal dominant form of monogenic hypertension that is caused by mutations in SCNN1A, SCNN1B or SCNN1G, which respectively encode the α, β and γ subunits of the epithelial sodium channel. In the present study, DNA was extracted from leukocytes in peripheral blood obtained from all members of a family with Liddle syndrome. Whole‑exome sequencing and Sanger sequencing were performed to assess the candidate variant and a co‑segregation analysis was conducted. A frameshift mutation in SCNN1B (NM_ 000336: c.1806dupG, p.Pro603Alafs*5) in the family was identified, characterized by early‑onset hypertension and hypokalemia. The mutation led to the truncation of the β subunit of the epithelial sodium channel and a lack of the conservative PY motif. Furthermore, a systematic review of follow‑up data from patients with Liddle syndrome with SCNN1B mutations was performed. The follow‑up data of 108 patients with pathogenic SCNN1B mutations from 47 families were summarized. Phenotypic heterogeneity was evident in patients with Liddle syndrome and early‑onset hypertension was the most frequent symptom. Patients responded well to targeted amiloride therapy with significant improvements in blood pressure and serum potassium concentration. The present study demonstrates that confirmatory genetic testing and targeted therapy can prevent premature onset of clinical endpoint events in patients with Liddle syndrome.

Childhood-Onset Refractory Hypertension Results from Neurofibromatosis Type 1 Caused by a Splicing NF1 Mutation.

INTRODUCTION:Neurofibromatosis type 1 (NF-1) is caused by mutations in the NF1 gene that encodes neurofibromin, a negative regulator of RAS proto-oncogene. Approximately one-third of the reported pathogenic mutations in NF1 are splicing mutations, but most consequences are unclear. The objective of this study was to identify the pathogenicity of splicing mutation in a Chinese family with NF-1 and determine the effects of the pre-mRNA splicing mutation by in vitro functional analysis.METHODS:Next-generation sequencing was used to screen candidate mutations. We performed a minigene splicing assay to determine the effect of the splicing mutation on NF1 expression, and three-dimensional structure models of neurofibromin were generated using SWISS-MODEL and PROCHECK methods, respectively.RESULTS:A pathogenic splicing mutation c.479+1G>C in NF1 was found in the proband characterized by childhood-onset refractory hypertension. In vitro analysis demonstrated that c.479+1G>C mutation caused the skipping of exon 4, leading to a glutamine-to-valine substitution at position 97 in neurofibromin and an open reading frame shift terminating at codon 108. Protein modeling showed that several major domains were missing in the truncated neurofibromin protein.CONCLUSION:The splicing mutation c.479+1G>C identified in a Chinese patient with NF-1 and childhood-onset refractory hypertension caused the skipping of exon 4 and a truncated protein. Our findings offer new evidence for the molecular diagnosis of NF-1.

Monogenic hypertension-a type of "curable" hypertension.

Identification of a novel frameshift mutation in the SCNN1B causing Liddle syndrome.

Predicting stroke and myocardial infarction risk in Takayasu arteritis with automated machine learning models.

Few models exist for predicting severe ischemic complications (SIC) in patients with Takayasu arteritis (TA). We conducted a retrospective analysis of 703 patients with TA from January 2010 to December 2019 to establish an SIC prediction model for TA. SIC was defined as ischemic stroke and myocardial infarction. SIC was present in 97 of 703 (13.8%) patients with TA. Common iliac artery, coronary artery, internal carotid artery, subclavian artery, vertebral artery, renal artery involvement, chest pain, hyperlipidemia, absent pulse, higher BMI, vascular occlusion, asymmetric blood pressure in both upper limbs, visual disturbance, and older age were selected as predictive risk factors. Considering both discrimination and calibration performance, the Weighted Subspace Random Forest model was the most optimal model, boasting an area under the curve of 0.773 (95% confidence interval [0.652, 0.894]) in the validation cohort. Effective models for predicting SIC in TA may help clinicians identify high-risk patients and make targeted interventions.

Relationship of triglyceride-glucose index with cardiometabolic multi-morbidity in China: evidence from a national survey.

BACKGROUND:Cardiometabolic multi-morbidity (CMM) is emerging as a global healthcare challenge and a pressing public health concern worldwide. Previous studies have principally focused on identifying risk factors for individual cardiometabolic diseases, but reliable predictors of CMM have not been identified. In the present study, we aimed to characterize the relationship of triglyceride-glucose (TyG) index with the incidence of CMM.METHODS:We enrolled 7,970 participants from the China Health and Retirement Longitudinal Study (CHARLS) and placed them into groups according to quartile of TyG index. The endpoint of interest was CMM, defined as the presence of at least two of the following: stroke, heart disease, and diabetes mellitus. Cox regression models and multivariable-adjusted restricted cubic spline (RCS) curves were used to evaluate the relationship between TyG index and CMM.RESULTS:In total, 638 (8.01%) incident cases of CMM were recorded among the participants who did not have CMM at baseline (2011) during a median follow-up of 84 months (interquartile range, 20‒87 months). The incidences of CMM for the participants in quartiles (Q) 1-4 of TyG index were 4.22%, 6.12%, 8.78%, and 12.60%, respectively. A fully adjusted Cox model showed that TyG index was closely associated with the incidence of CMM: the hazard ratio (HR) [95% confidence interval (CI)] for each 1.0-unit increment in TyG index for CMM was 1.54 (1.29-1.84); and the HRs (95% CIs) for Q3 and Q4 (Q1 as reference) of the TyG index for CMM were 1.41 (1.05-1.90) and 1.61 (1.18-2.20), respectively. The association of TyG index with the incidence of CMM was present in almost all the subgroups, and persisted in the sensitivity analyses and additional analyses. Multivariable-adjusted RCS analysis revealed a significant dose-response relationship of TyG index with the risk of CMM (overall P < 0.001; non-linear P = 0.129).CONCLUSIONS:We found that a high TyG index is associated with a higher risk of incident CMM. This finding may have significance for clinical practice and facilitate the creation of a personalized prevention strategy that involves monitoring the TyG index.

Clinical characteristics and management of coexistent cardiomyopathy in patients with bicuspid aortic valve.

BACKGROUND:Bicuspid aortic valve (BAV) is the most common congenital heart disease. However, the prevalence, clinical characteristics, and current management of BAV associated with inherited cardiomyopathy, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular noncompaction (LVNC) have not been well described.METHODS:Consecutive patients diagnosed with BAV at a large tertiary cardiovascular referral center between 2009 and 2018 were retrospectively assessed for HCM, DCM, and LVNC based on clinical and echocardiographic criteria. Patients with coexistent conditions were investigated further.RESULTS:Of 3533 patients with BAV screened, 57 (1.6%) had concomitant cardiomyopathy. BAV was combined with HCM in 30 of these patients, with DCM in 19, and with LVNC in eight. Forty-six patients (80.7%) were male, and the mean age at first diagnosis was 47 years for BAV with HCM, 49 years for BAV with DCM, and 35 years for BAV with LVNC. Heart failure and aortic valve dysfunction were common in these patients, and the prevalence of coexisting aortopathy was 43.3%, 26.3% and 25.0%, respectively, for BAV with HCM, DCM and LVNC. During the index hospitalization, 24 of the 57 patients (42.1%) underwent surgery, 16 (28%) underwent aortic valve and/or aortic surgery, and 16 of the 30 patients with HCM had a Morrow procedure. There were no deaths or other major adverse cardiovascular events.CONCLUSIONS:The prevalence of inherited cardiomyopathy was higher in our patients with BAV than in the general population. Aortopathy and heart failure were common, with almost half of patients requiring surgery at diagnosis.

Association between non-insulin-based insulin resistance indices and cardiovascular events in patients undergoing percutaneous coronary intervention: a retrospective study.

BACKGROUND:Insulin resistance (IR) has been confirmed that getting involved in the pathophysiological process of cardiovascular diseases (CVD). Recently, increasing evidence suggests metabolic score for insulin resistance (METS-IR), triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, triglyceride and glucose (TyG) index, triglyceride glucose-body mass (TyG-BMI) index are simple and reliable surrogates for IR. However, their abilities in predicting cardiovascular outcomes in patients undergoing percutaneous coronary intervention (PCI) are not well explored. Therefore, this study aimed to investigate the association and evaluate the predictive performance of each index.METHODS:A total of 2533 consecutive participants undergoing PCI were included in this study, and the data from 1461 patients were used to determine the correlation of these non-insulin-based IR indices with major adverse cardiac and cerebrovascular events (MACCEs) via performing the multivariate logistic models and restricted cubic splines (RCS).RESULTS:During a median of 29.8 months follow-up, 195 cases of 1461 patients experienced incident MACCEs. In the overall population, both univariate and multivariate logistic regression analyses indicated no statistically significant connection between these IR indices and MACCEs. Subgroup analyses revealed significant interactions between age subgroups and TyG-BMI index, as well as METS-IR, and between sex subgroups and TyG index. In elderly patients, per 1.0-SD increment in TyG-BMI index and METS-IR had a significant association with MACCEs, with odds ratios (ORs) [95% confidence interval (CI)] of 1.24 (1.02-1.50) and 1.27 (1.04-1.56), respectively (both P < 0.05). Moreover, in female patients, all the IR indices showed significant associations with MACCEs. Multivariable-adjusted RCS curves demonstrated a linear relationship between METS-IR and MACCEs in elderly and female patients, respectively. However, all the IR indices failed to enhance the predictive performance of the basic risk model for MACCEs.CONCLUSION:All the four IR indices showed a significant association with MACCEs in female individuals, whereas only TyG-BMI index and METS-IR showed associations in elderly patients. Although the inclusion of these IR indices did not improve the predictive power of basic risk model in either female or elderly patients, METS-IR appears to be the most promising index for secondary prevention of MACCEs and risk stratification in patients undergoing PCI.

Association between Chinese visceral adiposity index and risk of stroke incidence in middle-aged and elderly Chinese population: evidence from a large national cohort study.

BACKGROUND:Abdominal obesity has long been considered as a crucial risk factor of stroke. Chinese visceral adiposity index (CVAI), a novel surrogate indicator of abdominal obesity, has been confirmed as a better predictor for coronary heart disease than other indicators in Asian population. However, the data on the relationship of CVAI with stroke is limited. The objective of our study is evaluating the relationship between CVAI and stroke incidence.METHODS:In the present study, we enrolled 7242 middle-aged and elderly residents from the China Health and Retirement Longitudinal Study (CHARLS) and placed them into groups according to quartile of CVAI. The outcome of interest was stroke. Kaplan-Meier curves were used to estimate the cumulative incidences of stroke. Cox regression analyses and multivariable-adjusted restricted cubic spline (RCS) curves were performed to evaluate the relationship between CVAI and incident stroke. Multiple sensitivity analyses and subgroups analyses were performed to test the robustness of the findings.RESULTS:During a median 84 months of follow-up, 612 (8.45%) participants experienced incident stroke, and the incidences of stroke for participants in quartiles (Q) 1-4 of CVAI were 4.42%, 7.29%, 9.06% and 13.04%, respectively. In the fully adjusted model, per 1.0-SD increment in CVAI has a significant increased risk of incident stroke: hazard ratio (HR) [95% confidence interval (CI)] was 1.17 (1.07-1.28); compared with participants in Q1 of CVAI, the HRs (95% CI) of incident stroke among those in Q2-4 were 1.47 (1.10-1.95), 1.62 (1.22-2.15), and 1.70 (1.28-2.27), respectively. Subgroups analyses suggested the positive association was significant in male participants, without diabetes, hypertension and heart disease. The findings were robust in all the sensitivity analyses. Additional, RCS curves showed a significant dose-response relationship of CVAI with risk of incident stroke (P for non-linear trend = 0.319).CONCLUSION:Increased CVAI is significantly associated with higher risk of stroke incidence, especially in male individuals, without hypertension, diabetes and heart disease. The findings suggest that baseline CVAI is a reliable and effective biomarker for risk stratification of stroke, which has far-reaching significance for primary prevention of stroke and public health.

A Novel Frame-Shift Mutation in SCNN1B Identified in a Chinese Family Characterized by Early-Onset Hypertension.

Background:Liddle syndrome is a form of monogenic hypertension caused by mutations in the three homologous subunits of the epithelial sodium channels (ENaCs), α, β, and γ. It is characterized by early-onset refractory hypertension, hypokalemia, low renin activity, and hypoaldosteronism. In this study, we report a novel frame-shift mutation in SCNN1B responsible for Liddle syndrome in a Chinese family.Methods:DNA samples were collected from all participants. Whole-exome sequencing was performed in the proband to detect possible causative variants. Sanger sequencing was then conducted in the other family members to verify the candidate variant, and in 100 patients with hypertension and 100 normotensive controls to exclude population genetic polymorphism.Results:We identified a novel frame-shift mutation (c.1691_1693delinsG) in SCNN1B that was responsible for Liddle syndrome in this family. This mutation leads to the substitution of Arg in place of Gln at codon site 564 and generates a new stop codon at 592, influencing the crucial PY motif and resulting in reduced inactivation of the ENaCs. Aside from the proband, eight family members carried the mutation. Intra-familial phenotypic heterogeneity was observed in the blood pressure and serum potassium levels. Amiloride therapy combined with a low sodium diet is effective to alleviate the symptoms of patients with Liddle syndrome.Conclusion:c.1691_1693delinsG, a novel frame-shift mutation in the β subunit of ENaC, was identified in a Chinese family with Liddle syndrome by whole-exome sequencing. Phenotypic heterogeneity can make diagnosis of Liddle syndrome difficult on the basis of clinical or biochemical characteristics alone. Genetic analysis is a useful tool allowing timely and accurate diagnosis of Liddle syndrome and playing a guiding role in precise treatment of the disease.

A frameshift mutation in the SCNN1B gene in a family with Liddle syndrome: A case report and systematic review.

Liddle syndrome is an autosomal dominant form of monogenic hypertension that is caused by mutations in SCNN1A, SCNN1B or SCNN1G, which respectively encode the α, β and γ subunits of the epithelial sodium channel. In the present study, DNA was extracted from leukocytes in peripheral blood obtained from all members of a family with Liddle syndrome. Whole‑exome sequencing and Sanger sequencing were performed to assess the candidate variant and a co‑segregation analysis was conducted. A frameshift mutation in SCNN1B (NM_ 000336: c.1806dupG, p.Pro603Alafs*5) in the family was identified, characterized by early‑onset hypertension and hypokalemia. The mutation led to the truncation of the β subunit of the epithelial sodium channel and a lack of the conservative PY motif. Furthermore, a systematic review of follow‑up data from patients with Liddle syndrome with SCNN1B mutations was performed. The follow‑up data of 108 patients with pathogenic SCNN1B mutations from 47 families were summarized. Phenotypic heterogeneity was evident in patients with Liddle syndrome and early‑onset hypertension was the most frequent symptom. Patients responded well to targeted amiloride therapy with significant improvements in blood pressure and serum potassium concentration. The present study demonstrates that confirmatory genetic testing and targeted therapy can prevent premature onset of clinical endpoint events in patients with Liddle syndrome.

Childhood-Onset Refractory Hypertension Results from Neurofibromatosis Type 1 Caused by a Splicing NF1 Mutation.

INTRODUCTION:Neurofibromatosis type 1 (NF-1) is caused by mutations in the NF1 gene that encodes neurofibromin, a negative regulator of RAS proto-oncogene. Approximately one-third of the reported pathogenic mutations in NF1 are splicing mutations, but most consequences are unclear. The objective of this study was to identify the pathogenicity of splicing mutation in a Chinese family with NF-1 and determine the effects of the pre-mRNA splicing mutation by in vitro functional analysis.METHODS:Next-generation sequencing was used to screen candidate mutations. We performed a minigene splicing assay to determine the effect of the splicing mutation on NF1 expression, and three-dimensional structure models of neurofibromin were generated using SWISS-MODEL and PROCHECK methods, respectively.RESULTS:A pathogenic splicing mutation c.479+1G>C in NF1 was found in the proband characterized by childhood-onset refractory hypertension. In vitro analysis demonstrated that c.479+1G>C mutation caused the skipping of exon 4, leading to a glutamine-to-valine substitution at position 97 in neurofibromin and an open reading frame shift terminating at codon 108. Protein modeling showed that several major domains were missing in the truncated neurofibromin protein.CONCLUSION:The splicing mutation c.479+1G>C identified in a Chinese patient with NF-1 and childhood-onset refractory hypertension caused the skipping of exon 4 and a truncated protein. Our findings offer new evidence for the molecular diagnosis of NF-1.

Monogenic hypertension-a type of "curable" hypertension.

Identification of a novel frameshift mutation in the SCNN1B causing Liddle syndrome.

Predicting stroke and myocardial infarction risk in Takayasu arteritis with automated machine learning models.

Few models exist for predicting severe ischemic complications (SIC) in patients with Takayasu arteritis (TA). We conducted a retrospective analysis of 703 patients with TA from January 2010 to December 2019 to establish an SIC prediction model for TA. SIC was defined as ischemic stroke and myocardial infarction. SIC was present in 97 of 703 (13.8%) patients with TA. Common iliac artery, coronary artery, internal carotid artery, subclavian artery, vertebral artery, renal artery involvement, chest pain, hyperlipidemia, absent pulse, higher BMI, vascular occlusion, asymmetric blood pressure in both upper limbs, visual disturbance, and older age were selected as predictive risk factors. Considering both discrimination and calibration performance, the Weighted Subspace Random Forest model was the most optimal model, boasting an area under the curve of 0.773 (95% confidence interval [0.652, 0.894]) in the validation cohort. Effective models for predicting SIC in TA may help clinicians identify high-risk patients and make targeted interventions.

Relationship of triglyceride-glucose index with cardiometabolic multi-morbidity in China: evidence from a national survey.

BACKGROUND:Cardiometabolic multi-morbidity (CMM) is emerging as a global healthcare challenge and a pressing public health concern worldwide. Previous studies have principally focused on identifying risk factors for individual cardiometabolic diseases, but reliable predictors of CMM have not been identified. In the present study, we aimed to characterize the relationship of triglyceride-glucose (TyG) index with the incidence of CMM.METHODS:We enrolled 7,970 participants from the China Health and Retirement Longitudinal Study (CHARLS) and placed them into groups according to quartile of TyG index. The endpoint of interest was CMM, defined as the presence of at least two of the following: stroke, heart disease, and diabetes mellitus. Cox regression models and multivariable-adjusted restricted cubic spline (RCS) curves were used to evaluate the relationship between TyG index and CMM.RESULTS:In total, 638 (8.01%) incident cases of CMM were recorded among the participants who did not have CMM at baseline (2011) during a median follow-up of 84 months (interquartile range, 20‒87 months). The incidences of CMM for the participants in quartiles (Q) 1-4 of TyG index were 4.22%, 6.12%, 8.78%, and 12.60%, respectively. A fully adjusted Cox model showed that TyG index was closely associated with the incidence of CMM: the hazard ratio (HR) [95% confidence interval (CI)] for each 1.0-unit increment in TyG index for CMM was 1.54 (1.29-1.84); and the HRs (95% CIs) for Q3 and Q4 (Q1 as reference) of the TyG index for CMM were 1.41 (1.05-1.90) and 1.61 (1.18-2.20), respectively. The association of TyG index with the incidence of CMM was present in almost all the subgroups, and persisted in the sensitivity analyses and additional analyses. Multivariable-adjusted RCS analysis revealed a significant dose-response relationship of TyG index with the risk of CMM (overall P < 0.001; non-linear P = 0.129).CONCLUSIONS:We found that a high TyG index is associated with a higher risk of incident CMM. This finding may have significance for clinical practice and facilitate the creation of a personalized prevention strategy that involves monitoring the TyG index.

Clinical characteristics and management of coexistent cardiomyopathy in patients with bicuspid aortic valve.

BACKGROUND:Bicuspid aortic valve (BAV) is the most common congenital heart disease. However, the prevalence, clinical characteristics, and current management of BAV associated with inherited cardiomyopathy, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular noncompaction (LVNC) have not been well described.METHODS:Consecutive patients diagnosed with BAV at a large tertiary cardiovascular referral center between 2009 and 2018 were retrospectively assessed for HCM, DCM, and LVNC based on clinical and echocardiographic criteria. Patients with coexistent conditions were investigated further.RESULTS:Of 3533 patients with BAV screened, 57 (1.6%) had concomitant cardiomyopathy. BAV was combined with HCM in 30 of these patients, with DCM in 19, and with LVNC in eight. Forty-six patients (80.7%) were male, and the mean age at first diagnosis was 47 years for BAV with HCM, 49 years for BAV with DCM, and 35 years for BAV with LVNC. Heart failure and aortic valve dysfunction were common in these patients, and the prevalence of coexisting aortopathy was 43.3%, 26.3% and 25.0%, respectively, for BAV with HCM, DCM and LVNC. During the index hospitalization, 24 of the 57 patients (42.1%) underwent surgery, 16 (28%) underwent aortic valve and/or aortic surgery, and 16 of the 30 patients with HCM had a Morrow procedure. There were no deaths or other major adverse cardiovascular events.CONCLUSIONS:The prevalence of inherited cardiomyopathy was higher in our patients with BAV than in the general population. Aortopathy and heart failure were common, with almost half of patients requiring surgery at diagnosis.

Association between non-insulin-based insulin resistance indices and cardiovascular events in patients undergoing percutaneous coronary intervention: a retrospective study.

BACKGROUND:Insulin resistance (IR) has been confirmed that getting involved in the pathophysiological process of cardiovascular diseases (CVD). Recently, increasing evidence suggests metabolic score for insulin resistance (METS-IR), triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, triglyceride and glucose (TyG) index, triglyceride glucose-body mass (TyG-BMI) index are simple and reliable surrogates for IR. However, their abilities in predicting cardiovascular outcomes in patients undergoing percutaneous coronary intervention (PCI) are not well explored. Therefore, this study aimed to investigate the association and evaluate the predictive performance of each index.METHODS:A total of 2533 consecutive participants undergoing PCI were included in this study, and the data from 1461 patients were used to determine the correlation of these non-insulin-based IR indices with major adverse cardiac and cerebrovascular events (MACCEs) via performing the multivariate logistic models and restricted cubic splines (RCS).RESULTS:During a median of 29.8 months follow-up, 195 cases of 1461 patients experienced incident MACCEs. In the overall population, both univariate and multivariate logistic regression analyses indicated no statistically significant connection between these IR indices and MACCEs. Subgroup analyses revealed significant interactions between age subgroups and TyG-BMI index, as well as METS-IR, and between sex subgroups and TyG index. In elderly patients, per 1.0-SD increment in TyG-BMI index and METS-IR had a significant association with MACCEs, with odds ratios (ORs) [95% confidence interval (CI)] of 1.24 (1.02-1.50) and 1.27 (1.04-1.56), respectively (both P < 0.05). Moreover, in female patients, all the IR indices showed significant associations with MACCEs. Multivariable-adjusted RCS curves demonstrated a linear relationship between METS-IR and MACCEs in elderly and female patients, respectively. However, all the IR indices failed to enhance the predictive performance of the basic risk model for MACCEs.CONCLUSION:All the four IR indices showed a significant association with MACCEs in female individuals, whereas only TyG-BMI index and METS-IR showed associations in elderly patients. Although the inclusion of these IR indices did not improve the predictive power of basic risk model in either female or elderly patients, METS-IR appears to be the most promising index for secondary prevention of MACCEs and risk stratification in patients undergoing PCI.

Association between Chinese visceral adiposity index and risk of stroke incidence in middle-aged and elderly Chinese population: evidence from a large national cohort study.

BACKGROUND:Abdominal obesity has long been considered as a crucial risk factor of stroke. Chinese visceral adiposity index (CVAI), a novel surrogate indicator of abdominal obesity, has been confirmed as a better predictor for coronary heart disease than other indicators in Asian population. However, the data on the relationship of CVAI with stroke is limited. The objective of our study is evaluating the relationship between CVAI and stroke incidence.METHODS:In the present study, we enrolled 7242 middle-aged and elderly residents from the China Health and Retirement Longitudinal Study (CHARLS) and placed them into groups according to quartile of CVAI. The outcome of interest was stroke. Kaplan-Meier curves were used to estimate the cumulative incidences of stroke. Cox regression analyses and multivariable-adjusted restricted cubic spline (RCS) curves were performed to evaluate the relationship between CVAI and incident stroke. Multiple sensitivity analyses and subgroups analyses were performed to test the robustness of the findings.RESULTS:During a median 84 months of follow-up, 612 (8.45%) participants experienced incident stroke, and the incidences of stroke for participants in quartiles (Q) 1-4 of CVAI were 4.42%, 7.29%, 9.06% and 13.04%, respectively. In the fully adjusted model, per 1.0-SD increment in CVAI has a significant increased risk of incident stroke: hazard ratio (HR) [95% confidence interval (CI)] was 1.17 (1.07-1.28); compared with participants in Q1 of CVAI, the HRs (95% CI) of incident stroke among those in Q2-4 were 1.47 (1.10-1.95), 1.62 (1.22-2.15), and 1.70 (1.28-2.27), respectively. Subgroups analyses suggested the positive association was significant in male participants, without diabetes, hypertension and heart disease. The findings were robust in all the sensitivity analyses. Additional, RCS curves showed a significant dose-response relationship of CVAI with risk of incident stroke (P for non-linear trend = 0.319).CONCLUSION:Increased CVAI is significantly associated with higher risk of stroke incidence, especially in male individuals, without hypertension, diabetes and heart disease. The findings suggest that baseline CVAI is a reliable and effective biomarker for risk stratification of stroke, which has far-reaching significance for primary prevention of stroke and public health.

A Novel Frame-Shift Mutation in SCNN1B Identified in a Chinese Family Characterized by Early-Onset Hypertension.

Background:Liddle syndrome is a form of monogenic hypertension caused by mutations in the three homologous subunits of the epithelial sodium channels (ENaCs), α, β, and γ. It is characterized by early-onset refractory hypertension, hypokalemia, low renin activity, and hypoaldosteronism. In this study, we report a novel frame-shift mutation in SCNN1B responsible for Liddle syndrome in a Chinese family.Methods:DNA samples were collected from all participants. Whole-exome sequencing was performed in the proband to detect possible causative variants. Sanger sequencing was then conducted in the other family members to verify the candidate variant, and in 100 patients with hypertension and 100 normotensive controls to exclude population genetic polymorphism.Results:We identified a novel frame-shift mutation (c.1691_1693delinsG) in SCNN1B that was responsible for Liddle syndrome in this family. This mutation leads to the substitution of Arg in place of Gln at codon site 564 and generates a new stop codon at 592, influencing the crucial PY motif and resulting in reduced inactivation of the ENaCs. Aside from the proband, eight family members carried the mutation. Intra-familial phenotypic heterogeneity was observed in the blood pressure and serum potassium levels. Amiloride therapy combined with a low sodium diet is effective to alleviate the symptoms of patients with Liddle syndrome.Conclusion:c.1691_1693delinsG, a novel frame-shift mutation in the β subunit of ENaC, was identified in a Chinese family with Liddle syndrome by whole-exome sequencing. Phenotypic heterogeneity can make diagnosis of Liddle syndrome difficult on the basis of clinical or biochemical characteristics alone. Genetic analysis is a useful tool allowing timely and accurate diagnosis of Liddle syndrome and playing a guiding role in precise treatment of the disease.