Analysis of the Synergistic Effects of Fasting Plasma Glucose and Hypertension on Cardiovascular Autonomic Neuropathy.

BACKGROUND: The purpose of this study was to evaluate the associations of fasting plasma glucose (FPG) and hypertension (HTN) with cardiovascular autonomic neuropathy (CAN) and to estimate the extent to which the synergistic effects of FPG and HTN affect outcomes in a Chinese population. METHOD: We conducted a large-scale, population-based study to analyze the association and interaction of the two factors with CAN in a sample of 2,092 Chinese people. Univariate and multiple linear regression (MLR) analyses were employed to detect these relationships. Interaction on an additive scale can be calculated by using the relative excess risk due to interaction, the proportion attributable to interaction (AP), and the synergy index (S). RESULT: After adjusting for confounding factors, MLR showed that FPG and HTN were independently associated with CAN (p < 0.001 for both). A significant synergistic effect of FPG and HTN on CAN was detected (p = 0.046, RETI = 0.733, 95% CI 0.059-1.450; AP = 0.167, 95% CI -0.033 to 0.367; S = 1.275, 95% CI 0.140-2.410). CONCLUSION: Our findings suggest that FPG and HTN are independently associated with CAN, and they offer evidence to support the hypothesis that FPG and HTN have synergistic effects that influence the progression of CAN.

Human genetics of diabetic nephropathy.

Diabetic vascular complications (DVCs) affecting several important organ systems of human body such as cardiovascular system contribute a major public health problem. Genetic factors contribute to the risk of diabetic nephropathy (DN). Genetics variants, structural variants (copy number variation) and epigenetic changes play important roles in the development of DN. Apart from nucleus genome, mitochondrial DNA (mtDNA) plays critical roles in regulation of development of DN. Epigenetic studies have indicated epigenetic changes in chromatin affecting gene transcription in response to environmental stimuli, which provided a large body of evidence of regulating development of diabetes mellitus. This review focused on the current knowledge of the genetic and epigenetic basis of DN. Ultimately, identification of genes or genetic loci, structural variants and epigenetic changes contributed to risk or protection of DN will benefit uncovering the complex mechanism underlying DN, with crucial implications for the development of personalized medicine to diabetes mellitus and its complications.

Association and interaction analysis of excess weight and chronic kidney disease for cardiovascular autonomic neuropathy in the general Chinese population.

BACKGROUND: The purpose of this study was to evaluate the associations of excess weight (EW) and/or chronic kidney disease (CKD) with cardiovascular autonomic neuropathy (CAN), and to detect the extent to which interaction of EW and CKD has on the outcome in a Chinese sample. METHOD: We conducted a large-scale, population-based study to analyze the association and interaction of the two factors on CAN in a sample of 2092 Chinese people. Multiple linear regression analysis to include the two main factors and its interaction were employed to detect these relationships. Relative excess risk due to interaction (RERI), the proportion attributable to interaction (AP) and the synergy index (S) were used to estimate the effect of interaction on an additive scale can. RESULT: Multivariable logistic regression (MLR) indicated that body mass index (BMI) was independently associated with CAN (p = 0.006). In addition, a significant positive interaction between BMI and CKD on CAN was estimated (p = 0.042, RETI = 0.473, 95% CI: 0.0615-0.884, AP = 0.203, 95% CI: -0.055 to 0.461 and S = 1.550, 95% CI: 0.667-2.589). CONCLUSION: Our findings suggest that BMI is independently associated with CAN and offer evidence to support the hypothesis that excess weight and CKD have significant positive interactions on CAN.

Association and predictive value analysis for metabolic syndrome on systolic and diastolic heart failure in high-risk patients.

BACKGROUND: The purpose of this study was, in high-risk patients, to simultaneously estimate the effect of metabolic syndrome (MetS) on diastolic or systolic heart failure (DHF or SHF), to evaluate MetS predictive value for both outcomes. METHOD: We retrospective enrolled 347 high-risk patients who were scheduled to undergo coronary angiography. They were categorized into DHF cases, SHF cases and reference group. The association of MetS with DHF or SHF was assessed by multinomial logistic regression model. The shared contributor to both outcomes was estimated by bivariate association analysis. The predictive performance of MetS severity score was evaluated using the area under the receiver-operating characteristic curve (AUC). RESULT: Hypertension (HT) and triglycerides (TG) were detected to independently associate with DHF (P = 0.044 and 0.049, respectively), while HT and fasting plasma glucose (FPG) independently associate with SHF (P = 0.036 and 0.016, respectively). Bivariate association analysis showed that HT as a shared predictor to both outcomes (P = 0.028). MetS severity score significantly associated with DHF or SHF independently (P = 0.004 and 0.043, respectively), and was a shared predictor to both outcomes (P = 0.049), and showed a high value in predicting DHF and SHF (AUC = 0.701 and 0.722, respectively). CONCLUSION: Our findings signify that MetS is an independently shared predictor of DHF and SHF, and HT is also independently associated with both outcomes in high-risk patients. Prevalence of DHF or SHF trends to increase with increasing MetS severity showing high predictive value for both outcomes.

Artificial neural network models for prediction of cardiovascular autonomic dysfunction in general Chinese population.

BACKGROUND: The present study aimed to develop an artificial neural network (ANN) based prediction model for cardiovascular autonomic (CA) dysfunction in the general population. METHODS: We analyzed a previous dataset based on a population sample consisted of 2,092 individuals aged 30-80 years. The prediction models were derived from an exploratory set using ANN analysis. Performances of these prediction models were evaluated in the validation set. RESULTS: Univariate analysis indicated that 14 risk factors showed statistically significant association with CA dysfunction (P < 0.05). The mean area under the receiver-operating curve was 0.762 (95% CI 0.732-0.793) for prediction model developed using ANN analysis. The mean sensitivity, specificity, positive and negative predictive values were similar in the prediction models was 0.751, 0.665, 0.330 and 0.924, respectively. All HL statistics were less than 15.0. CONCLUSION: ANN is an effective tool for developing prediction models with high value for predicting CA dysfunction among the general population.

Genome-wide association and follow-up replication studies identified ADAMTS18 and TGFBR3 as bone mass candidate genes in different ethnic groups.

To identify and validate genes associated with bone mineral density (BMD), which is a prominent osteoporosis risk factor, we tested 379,319 SNPs in 1000 unrelated white U.S. subjects for associations with BMD. For replication, we genotyped the most significant SNPs in 593 white U.S. families (1972 subjects), a Chinese hip fracture (HF) sample (350 cases, 350 controls), a Chinese BMD sample (2955 subjects), and a Tobago cohort of African ancestry (908 males). Publicly available Framingham genome-wide association study (GWAS) data (2953 whites) were also used for in silico replication. The GWAS detected two BMD candidate genes, ADAMTS18 (ADAM metallopeptidase with thrombospondin type 1 motif, 18) and TGFBR3 (transforming growth factor, beta receptor III). Replication studies verified the significant findings by GWAS. We also detected significant associations with hip fracture for ADAMTS18 SNPs in the Chinese HF sample. Meta-analyses supported the significant associations of ADAMTS18 and TGFBR3 with BMD (p values: 2.56 x 10(-5) to 2.13 x 10(-8); total sample size: n = 5925 to 9828). Electrophoretic mobility shift assay suggested that the minor allele of one significant ADAMTS18 SNP might promote binding of the TEL2 factor, which may repress ADAMTS18 expression. The data from NCBI GEO expression profiles also showed that ADAMTS18 and TGFBR3 genes were differentially expressed in subjects with normal skeletal fracture versus subjects with nonunion skeletal fracture. Overall, the evidence supports that ADAMTS18 and TGFBR3 might underlie BMD determination in the major human ethnic groups.

Evidence for major pleiotropic effects on bone size variation from a principal component analysis of 451 Caucasian families.

AIM: To identify pleiotropic quantitative trait loci (QTL) influencing bone size (BS) at different skeletal sites in Caucasians. METHODS: In a sample containing 3899 Caucasians from 451 pedigrees, 410 microsatellite markers spaced approximately 8.9 cM apart across the human genome were genotyped. Phenotypical and genetic correlations of BS at lumbar spine, hip (femoral neck, trochanter, and intertrochanter regions), and wrist (ultradistal, mid-distal, and one-third distal sites) were determined using bivariate quantitative genetic analysis. A principal component analysis (PCA) was performed to obtain principal component (PC) factors that were then subjected to variance components linkage analysis to identify regions linked to the PC. RESULTS: Genetic correlations of BS at different skeletal sites ranged from 0.40 to 0.79 (P<0.001). The PCA yielded a PC named PCtotal, which explained up to 76% of the total (co)variation of all the BS at the 7 skeletal sites for the whole sample. We identified a QTL influencing the BS of multiple skeletal sites on chromosome 7 at 140 cM [logarithm of odds (LOD)=2.85] in the overall sample. Sex-specific evidence for linkage was observed on chromosome 11 at 53 cM (LOD =2.82) in the male-only data subset. CONCLUSION: Our study identified several genomic regions that may have pleiotropic effects on different skeletal sites. These regions may contain genes that play a critical role in overall bone development and osteoporosis at multiple skeletal sites, hence are biologically and clinically important.

Bivariate whole genome linkage analysis for femoral neck geometric parameters and total body lean mass.

UNLABELLED: A genome-wide bivariate analysis was conducted for femoral neck GPs and TBLM in a large white sample. We found QTLs shared by GPs and TBLM in the total sample and the sex-specific samples. QTLs with potential pleiotropy were also disclosed. INTRODUCTION: Previous studies have suggested that femoral neck cross-section geometric parameters (FNCS-GPs), including periosteal diameter (W), cross-sectional area (CSA), cortical thickness (CT), buckling ratio (BR), and section modulus (Z), are genetically correlated with total body lean mass (TBLM). However, the shared genetic factors between them are unknown. MATERIALS AND METHODS: To identify the specific QTLs shared by FNCS-GPs and TBLM, we performed bivariate whole genome linkage analysis (WGLA) in a large sample of 451 white families made up of 4498 subjects. RESULTS: Multipoint bivariate linkage analyses for 22 autosomes showed evidence of suggestive or significant linkages (thresholds of LOD = 2.3 and 3.7, respectively) to chromosomes 3q12 and 20q13 in the entire sample, 6p25 and 10q24 in women, and 4p15, 5q34-35 and 7q21 in men. Two-point linkage analyses for chromosome X showed strong linkage to Xp22.13, Xp11.4, Xq22.3, Xq23-24, and Xq25. Complete pleiotropy was identified on 10q24 and 5q35 for TBLM and BR in women and for TBLM and CT in men, respectively. Furthermore, chromosomes 5q34-35, 7q21, 10q24, 20q13, Xp22.13, Xp11.4, and Xq25 are also of importance because of their linkage to multiple trait pairs. For example, linkage to chromosome 10q24 was found for TBLM x W (LOD = 2.31), TBLM x CT (LOD = 2.51), TBLM x CSA (LOD = 2.51), TBLM x BR (LOD = 2.64), and TBLM x Z (LOD = 2.55) in women. CONCLUSIONS: In this study, we identified several genomic regions (e.g., 3q12 and 20q13) that seem to be linked to both FNCS-GPs and TBLM. These regions are of interesting because they may harbor genes that may contribute to variation in both FNCS-GPs and TBLM.

A bivariate whole-genome linkage scan suggests several shared genomic regions for obesity and osteoporosis.

CONTEXT: A genome-wide bivariate analysis was conducted for body fat mass (BFM) and bone mineral density (BMD) in a large Caucasian sample. We found some quantitative trait loci shared by BFM and BMD in the total sample and the gender-specific subgroups, and quantitative trait loci with potential pleiotropy were disclosed. BFM and BMD, as the respective measure for obesity and osteoporosis, are phenotypically and genetically correlated. However, specific genomic regions accounting for their genetic correlation are unknown. OBJECTIVE: To identify systemically the shared genomic regions for BFM and BMD, we performed a bivariate whole-genome linkage scan in 4498 Caucasian individuals from 451 families for BFM and BMD at the hip, spine, and wrist, respectively. Linkage analyses were performed in the total sample and the male and female subgroups, respectively. RESULTS: In the entire sample, suggestive linkages were detected at 7p22-p21 (LOD 2.69) for BFM and spine BMD, 6q27 (LOD 2.30) for BFM and hip BMD, and 11q13 (LOD 2.64) for BFM and wrist BMD. Male-specific suggestive linkages were found at 13q12 (LOD 3.23) for BFM and spine BMD and at 7q21 (LOD 2.59) for BFM and hip BMD. Female-specific suggestive LOD scores were 3.32 at 15q13 for BFM and spine BMD and 3.15 at 6p25-24 for BFM and wrist BMD. CONCLUSIONS: Several shared genomic regions for BFM and BMD were identified here. Our data may benefit further positional and functional studies, aimed at eventually uncovering the complex mechanism underlying the shared genetic determination of obesity and osteoporosis.

Erratum to: Diagnostic performance analysis for diabetic cardiovascular autonomic neuropathy based on short-term heart rate variability using Bayesian methods: preliminary analysis.

[This corrects the article DOI: 10.1186/s13098-015-0070-z.].

Correction: Comparison of Prediction Model for Cardiovascular Autonomic Dysfunction Using Artificial Neural Network and Logistic Regression Analysis.

[This corrects the article DOI: 10.1371/journal.pone.0070571.].

Salty food preference is associated with osteoporosis among Chinese men.

BACKGROUND AND OBJECTIVES: The main purpose of this study was to evaluate the associations between salty food preference and osteoporosis (OP) in general Chinese men. METHODS AND STUDY DESIGN: We conducted a largescale, community-based, cross-sectional study to estimate the associations by using self-report questionnaire to evaluate the salty food preference. The total of 1,092 men was available to data analysis in this study. Multiple regression models controlling for confounding factors to include salty food preference variables were employed to explore the relationships for OP. RESULTS: We found negative correlations between preference for salty food and T-score (p=0.006). Multiple regression analysis showed that the preference for salty food was significantly positively associated with OP (p<0.05 for all). The men with preference for salty food habits had a higher prevalence of OP. CONCLUSION: The findings indicated that salty food preference was independently and significantly associated with OP. The prevalence of OP was more frequent in Chinese men preferring salty food habits.

The association and interaction analysis of hypertension and diabetes mellitus on diastolic heart failure in a high-risk population.

OBJECTIVE: The purpose of this study was to evaluate the extent to which hypertension (HT) interacts with diabetes mellitus (DM) to affect diastolic heart failure (DHF) in a high-risk population. METHODS: We conducted a hospital-based case-control study to investigate the relationship between HT or DM and DHF in 251 patients (case: 133 patients with DHF; control: 118 patients without DHF). Echocardiography was used to assess left ventricular (LV) diastolic function. The association between HT or DM and DHF was assessed by multivariate logistic regression (MLR) analysis controlling for confounders. The effect of the interaction between HT and DM on DHF was assessed in MLR models. Interaction on an additive scale can be calculated by using the relative excess risk due to interaction (RERI), the proportion attributable to interaction (AP), and the synergy index (S). RESULTS: The MLR analyses showed that HT and DM were independent predictors of DHF after adjustment for potential confounders (OR = 2.35-3.14, P<0.05 for all models). DHF was affected by the interaction between HT and DM (ORInt = 3.11-4.31, P Int<0.1, RETI = 2.13-2.69, AP = 0.38-0.49 and S = 4.11-6.80). CONCLUSION: The findings provide evidence that HT and DM are independent predictors of DHF and that both risk factors act synergistically to influence DHF in a Chinese high-risk population.

Diagnostic performance analysis for diabetic cardiovascular autonomic neuropathy based on short-term heart rate variability using Bayesian methods: preliminary analysis.

OBJECTIVES: This study aimed to estimate the performance of diabetic cardiovascular autonomic neuropathy (DCAN) diagnostic tests in the absence of a gold standard. BACKGROUND: The DCAN prevalence is rapidly growing in all populations worldwide. No document has been reported about diagnostic performance for DCAN based on short-term HRV without a gold standard. METHODS: We conducted a cross-sectional study to perform diagnostic test in Chinese diabetic patients. A dataset contained 56 subjects who completed both the short-term HRV test and Ewing's test. Simultaneous inferences about the population prevalence and the performance of each diagnostic test were possible using the Bayesian approach. RESULTS: The HRV test had a high sensitivity (0.837 and 0.821 for independence model) and specificity (0.838 and 0.797 for dependence model) to DCAN. In addition, the non-inferiority test rejected the hypothesis that the performance of the HRV test was inferior to that of Ewing's test (P < 0.05). The estimated DCAN prevalence in our study sample was more than 0.400. CONCLUSION: Our findings provided evidence that short-term HRV were used for the DCAN diagnostic test with a high sensitivity and specificity. ClinicalTrial.org ID: NCT02461381.

Association between rheumatoid arthritics and osteoporosis among Chinese men, a community based study.

BACKGROUND: The main purpose of this study was to estimate the associations between rheumatoid arthritics (RA) and osteoporosis (OP) in general Chinese men. METHODS: We conducted a large-scale, community-based, cross-sectional study to investigate the associations by using self-report questionnaire to access medical history. A total of 1041 men were recruited sis in this study. Multiple regression models controlling for confounding factors to include RA were performed to investigate the relationships for OP. RESULTS: Univariate analysis indicated there was no significant association between RA and T-score (P = 0.103), however, significant association between RA and OP was reported (P = 0.005). Multiple regression analysis indicated that RA was significantly associated with OP (P = 0.013, OR = 3.191 95% CI: 1.284-7.932). The men with RA had a significant higher prevalence of OP. CONCLUSION: The findings indicated that RA was independently and significantly associated with OP. The prevalence of OP was less frequent in Chinese men without RA.

The relationship of frequency of meat consumption and osteoporosis in Chinese postmenopausal women.

BACKGROUND: This study was aimed at evaluating the associations between frequency of meat food intake and osteoporosis (OP) in general Chinese postmenopausal women. METHODS: We conducted a large-scale, community-based, cross-sectional study to investigate the associations by using self-report questionnaire to access frequency of meat food intake. The total of 1905 participants was available to data analysis in this study. Multiple regression models controlling for confounding factors to include frequency of meat food intake variable were performed to investigate the relationships for OP. RESULTS: Positive correlations between frequency of meat food intake and T-score were reported (ß = 0.12, P value < 0.001). Multiple regression analysis indicated that the frequency of meat food intake was significantly associated with OP (P < 0.1 for model 1 and model 2). The postmenopausal women with high frequency of meat food intake had a lower prevalence of OP. CONCLUSION: The findings indicated that frequency of meat food intake was independently and significantly associated with OP. The prevalence of OP was less frequent in Chinese postmenopausal women preferring meat food habits.

The analysis of a reference value for baroreflex sensitivity and cardiovascular autonomic neuropathy prevalence in a Chinese population.

BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is rapidly growing in all populations worldwide. Baroreflex sensitivity (BRS) is easily applied as a diagnostic test to a large number of individuals in the general population. However, no study has reported the normal reference values of BRS for the CAN diagnostic test in a Chinese population. The aim of this study was to estimate the normative reference value of BRS, and assess CAN prevalence in our cross-sectional dataset. METHODS: We conducted a large-scale, community-based, cross-sectional study in a Chinese population. We performed data analysis on 2,092 subjects. Cardiovascular autonomic function was assessed using spontaneous BRS. A total of 349 healthy subjects were used to perform analysis for the reference value for BRS. The CAN prevalence was calculated in the overall sample, and in patients with diabetes mellitus, patients with hypertension and patients with metabolic syndrome. RESULTS: In the overall sample, the reference value for total power (TP.brs) was more than 1.96 ms/mmHg. The cut-off points of 1.74 ms/mmHg and 2.53 ms/mmHg were set as high frequency (HF.brs) and low frequency (LF.brs), respectively. CAN diagnostic tests based on the reference value were performed. The estimated CAN prevalence in the overall sample was 20.41% using the BRS test. CAN prevalence was 33.18%, 28.69% and 28.57% in patients with diabetes mellitus, patients with hypertension and patients with metabolic syndrome, respectively. CONCLUSIONS: Our findings provided reference values for BRS. Estimated CAN prevalence was high in this Chinese population, which has become a major public health problem in China.

Association and predictive value analysis for resting heart rate and diabetes mellitus on cardiovascular autonomic neuropathy in general population.

BACKGROUND: The purpose of this study was to evaluate the predictive value of DM and resting HR on CAN in a large sample derived from a Chinese population. MATERIALS AND METHODS: We conducted a large-scale, population-based, cross-sectional study to explore the relationships of CAN with DM and resting HR. A total of 387 subjects were diagnosed with CAN in our dataset. The associations of CAN with DM and resting HR were assessed by a multivariate logistic regression (MLR) analysis (using subjects without CAN as a reference group) after controlling for potential confounding factors. The area under the receiver-operating characteristic curve (AUC) was used to evaluate the predictive performance of resting HR and DM. RESULTS: A tendency toward increased CAN prevalence with increasing resting HR was reported (P for trend <0.001). MLR analysis showed that DM and resting HR were very significantly and independently associated with CAN (P < 0.001 for both). Resting HR alone or combined with DM (DM-HR) both strongly predicted CAN (AUC = 0.719, 95% CI 0.690-0.748 for resting HR and AUC = 0.738, 95% CI 0.710-0.766 for DM-HR). CONCLUSION: Our findings signify that resting HR and DM-HR have a high value in predicting CAN in the general population.

Bayesian estimation of cardiovascular autonomic neuropathy diagnostic test based on short-term heart rate variability without a gold standard.

OBJECTIVE: To evaluate the reference values for short-term heart rate variability (HRV), estimate the performance of cardiovascular autonomic neuropathy (CAN) diagnostic tests in the absence of a gold standard, and assess CAN prevalence in our dataset. SETTING: Community and hospital health centre. PARTICIPANTS: Of 2092 subjects available for data analysis, 371 healthy subjects were selected so the reference values for the short-term HRV test could be evaluated. An external dataset contained 88 subjects who completed both the short-term HRV test and Ewing's test. INTERVENTION: Collection of information on clinical outcome. PRIMARY AND SECOND OUTCOME MEASURES: Cardiovascular autonomic function evaluated by using the short-term HRV test and/or Ewing's test. RESULTS: Cut-off points of 356.13, 55.45 and 36.64 ms2 were set for total power, low frequency and high frequency (HF), respectively. The diagnostic test for CAN based on the mentioned reference value was created. The HRV test had a high sensitivity (80.01-85.09%) and specificity (82.30-85.20%) for CAN. In addition, the non-inferiority test rejected the null hypothesis that the performance of the HRV test was inferior to that of Ewing's test (p<0.05). The estimated CAN prevalence was 14.92% and 29.17% in the total sample and patients with diabetes, respectively. CONCLUSIONS: Our findings provided reference values for short-term HRV, which were used for the CAN diagnostic test with high sensitivity and specificity. The estimated CAN prevalence was high in the Chinese population.

A simple Chinese risk score model for screening cardiovascular autonomic neuropathy.

BACKGROUND: The purpose of the present study was to develop and evaluate a risk score to predict people at high risk of cardiovascular autonomic dysfunction neuropathy (CAN) in Chinese population. METHODS AND MATERIALS: A population-based sample of 2,092 individuals aged 30-80 years, without previously diagnosed CAN, was surveyed between 2011 and 2012. All participants underwent short-term HRV test. The risk score was derived from an exploratory set. The risk score was developed by stepwise backward multiple logistic regression. The coefficients from this model were transformed into components of a CAN score. This score was tested in a validation and entire sample. RESULTS: The final risk score included age, body mass index, hypertension, resting hear rate, items independently and significantly (P<0.05) associated with the presence of previously undiagnosed CAN. The area under the receiver operating curve was 0.726 (95% CI 0.686-0.766) for exploratory set, 0.784 (95% CI 0.749-0.818) for validation set, and 0.756 (95% CI 0.729-0.782) for entire sample. In validation set, at optimal cutoff score of 5 of 10, the risk score system has the sensitivity, specificity, and percentage that needed subsequent testing were 69, 78, and 30%, respectively. CONCLUSION: We developed a CAN risk score system based on a set of variables not requiring laboratory tests. The score system is simple fast, inexpensive, noninvasive, and reliable tool that can be applied to early intervention to delay or prevent the disease in China.