The Prevalence and Risk Factors of Blepharoptosis in an Elderly Asian Population.

BACKGROUND: Age-related blepharoptosis, or ptosis, affects vision and appearance. Associations with age, gender, BMI, and diabetes have been explored, but the link to blood lipids remains unclear. The impact on refraction also lacks consensus. This study addresses gaps by investigating ptosis prevalence and factors in a representative Chinese population, aiming for a comprehensive understanding. METHODS: A cross-sectional study was conducted among individuals aged 50 and above who were willing to participate in comprehensive systemic check-ups, behavioral questionnaires, and ophthalmic examinations at Yaoxi Community Health Center in Wenzhou City, Zhejiang Province. RESULTS: The prevalence of blepharoptosis among the elderly participants at this health center was 27.16%. Individuals with blepharoptosis tended to be older, male, exhibited slightly higher body mass index, wider waist circumference, engaged in lower exercise frequency, and had a higher prevalence of hypertension, diabetes, and with-the-rule astigmatism compared to their counterparts without these conditions. Adjusting for all other confounding variables, older age, being male, higher fasting plasma glucose (FPG), and lower exercise frequency displayed statistically significant relationships with blepharoptosis. After examining the distribution of blepharoptosis degrees within relevant factor subgroups, we noted a higher prevalence of severe ptosis in subgroups associated with older age, male gender, higher FPG, and against-the-rule astigmatism. CONCLUSION: The notable associations with age, gender, FPG, and exercise level suggest a multifactorial etiology for blepharoptosis. The observed link between with-the-rule astigmatism and blepharoptosis implies a potential contributory role in the refractive aspect of blepharoptosis. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

IMPACT OF PENETRATION AND IMAGE ANALYSIS IN OPTICAL COHERENCE TOMOGRAPHY ON THE MEASUREMENT OF CHOROIDAL VASCULARITY PARAMETERS.

PURPOSE: To investigate the impact of penetration and image analysis in different optical coherence tomography (OCT) instruments on the measurement of choroidal vascularity parameters. METHODS: Twenty-three healthy volunteers were imaged using two swept-source OCTs and one spectral-domain OCT. A fully automatic segmentation method based on ResNet-UNet and Niblack local threshold binarization was performed to quantify the relevant choroidal vascular parameters, including choroidal vascularity index, total choroidal volume, and luminal volume. The intraclass correlation coefficient (ICC) and coefficient of repeatability (COR) were used to analyze the repeatability and consistency of automatic and manual segmentation, respectively. RESULTS: Both swept-source OCT devices showed good consistency of luminal volume and total choroidal volume measurements (all ICC value >0.98 with COR% < 8.53%) based on manual segmentation, whereas the consistency of the spectral-domain OCT was lower (ICC value <0.60 with COR% > 40%), which was greatly improved after using the automatic algorithm (ICC value >0.99 with COR% < 4%). The repeatability of choroidal vascularity index obtained from different OCT images using manual or automatic segmentation showed good agreement (all ICC values >0.85), whereas the choroidal vascularity index measurement from the spectral-domain OCT was larger than the other two swept-source OCT devices (ICC value <0.65). CONCLUSION: For healthy youngsters, the penetration of OCT plays a role in the measurement precision for choroidal vascularity parameters, and automatic segmentation can improve the ability of choroidal boundary identification with deficient penetration, suggesting these factors need to be considered in clinical work.

A novel block at chromosome 12q24.1 is associated with coronary artery disease in Han Chinese populations.

OBJECTIVE: The aim of this study was to refine the chromosomal region 12q24.1 associated with coronary artery disease in Han Chinese populations. METHODS AND RESULTS: Twenty tagging single nucleotide polymorphisms covering 1.2 Mb of chromosomal 12q24.1 were selected and genotyped in three geographically isolated case-control populations consisting of 7076 coronary artery disease (CAD) patients and non-CAD participants. In addition to replication of the previous block (block 1), we identified a novel block (block 2) associated with CAD. In a combined analysis, the odds ratio (95% confidence interval, permuted P value) were 0.79 (0.72-0.86, 8.358×10) and 1.24 (1.13-1.36, 2.576×10) for haplotypes ATGGG and GCACA in block 1 and 1.22 (1.14-1.30, 6.484×10) and 0.82 (0.77-0.88, 6.484×10) for haplotypes GA and AG in block 2, respectively. Protective alleles of two index single nucleotide polymorphisms decreased the expression of NAA25 (P=0.034), but did not alter the expression of other genes within block 2. CONCLUSION: We identified a novel block associated with CAD at chromosomal 12q24.

Mutant LRP6 Impairs Endothelial Cell Functions Associated with Familial Normolipidemic Coronary Artery Disease.

Mutations in the genes low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) and myocyte enhancer factor 2A (MEF2A) were reported in families with coronary artery disease (CAD). We intend to determine the mutational spectrum of these genes among hyperlipidemic and normolipidemic CAD families. Forty probands with early-onset CAD were recruited from 19 hyperlipidemic and 21 normolipidemic Chinese families. We sequenced all exons and intron-exon boundaries of LRP6 and MEF2A, and found a novel heterozygous variant in LRP6 from a proband with normolipidemic CAD. This variant led to a substitution of histidine to tyrosine (Y418H) in an evolutionarily conserved domain YWTD in exon 6 and was not found in 1025 unrelated healthy individuals. Co-segregated with CAD in the affected family, LRP6Y418H significantly debilitated the Wnt3a-associated signaling pathway, suppressed endothelial cell proliferation and migration, and decreased anti-apoptotic ability. However, it exhibited no influences on low-density lipoprotein cholesterol uptake. Thus, mutation Y418H in LRP6 likely contributes to normolipidemic familial CAD via impairing endothelial cell functions and weakening the Wnt3a signaling pathway.

Outer retina and choroid as potential imaging markers for evaluation of neural impairment in early type 2 diabetic patients.

PURPOSE: To quantify the presence of early structural alterations in the outer retinal layer and choroid among healthy subjects and diabetic patients with no or mild diabetic retinopathy, and to establish the correlation between the measured structural parameters and retinal sensitivity. METHODS: In total, 31 eyes from subjects with type 2 diabetes and 29 eyes from healthy subjects were enrolled. Optical coherence tomography was used to measure outer retina layers and choroid, while microperimetry was used to characterize the changes of visual function in a 6-mm diameter area at macula. Quantitative analysis of structural and functional changes was performed between groups and the structure-function correlations were determined. RESULTS: The thickness of myoid and ellipsoid zone, choroid and the mean retinal sensitivity were significantly smaller in diabetic group than that in controls (all P values < 0.05). Besides, thinner choroid and outer retina was associated with the decreased retinal sensitivity，especially in diabetic patients (r = 0.377, P = 0.048; r = 0.401, P = 0.034; respectively). Final multiple regression models showed the outer retinal thickness (ORT) (P = 0.033), choroidal thickness (P = 0.003) and the interaction between ORT and choroidal thickness (P = 0.001) were significant predictors to retinal sensitivity. CONCLUSIONS: Thinning of choroid and outer retina were significantly correlated with reduced retinal sensitivity, which indicate outer retina and choroid might be potential imaging markers for evaluation of visual function related to neural impairment in type 2 diabetic patients without or in the early stage of diabetic retinopathy.

Using a dual-stream attention neural network to characterize mild cognitive impairment based on retinal images.

Mild cognitive impairment (MCI) is a critical transitional stage between normal cognition and dementia, for which early detection is crucial for timely intervention. Retinal imaging has been shown as a promising potential biomarker for MCI. This study aimed to develop a dual-stream attention neural network to classify individuals with MCI based on multi-modal retinal images. Our approach incorporated a cross-modality fusion technique, a variable scale dense residual model, and a multi-classifier mechanism within the dual-stream network. The model utilized a residual module to extract image features and employed a multi-level feature aggregation method to capture complex context information. Self-attention and cross-attention modules were utilized at each convolutional layer to fuse features from optical coherence tomography (OCT) and fundus modalities, resulting in multiple output losses. The neural network was applied to classify individuals with MCI, Alzheimer's disease, and control participants with normal cognition. Through fine-tuning the pre-trained model, we classified community-dwelling participants into two groups based on cognitive impairment test scores. To identify retinal imaging biomarkers associated with accurate prediction, we used the Gradient-weighted Class Activation Mapping technique. The proposed method achieved high precision rates of 84.96% and 80.90% in classifying MCI and positive test scores for cognitive impairment, respectively. Notably, changes in the optic nerve head on fundus photographs or OCT images among patients with MCI were not used to discriminate patients from the control group. These findings demonstrate the potential of our approach in identifying individuals with MCI and emphasize the significance of retinal imaging for early detection of cognitive impairment.

Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations.

FOXO1A and FOXO3A are two members of the FoxO family. FOXO3A has recently been linked to human longevity in Japanese, German and Italian populations. Here we tested the genetic contribution of FOXO1A and FOXO3A to the longevity phenotype in Han Chinese population. Six tagging SNPs from FOXO1A and FOXO3A were selected and genotyped in 1817 centenarians and younger individuals. Two SNPs of FOXO1A were found to be associated with longevity in women (P = 0.01-0.005), whereas all three SNPs of FOXO3A were associated with longevity in both genders (P = 0.005-0.001). One SNP from FOXO1A was found not to be associated with longevity. In haplotype association tests, the OR (95% CI) for haplotypes TTG and CCG of FOXO1A in association with female longevity were 0.72 (0.58-0.90) and 1.38 (1.08-1.76), P = 0.0033 and 0.0063, respectively. The haplotypes of FOXO3A were associated with longevity in men [GTC: OR (95% CI) = 0.67 (0.51-0.86), P = 0.0014; CGT: OR (95% CI) = 1.48 (1.12-1.94), P = 0.0035] and in women [GTC: OR (95% CI) = 0.75 (0.60-0.94), P = 0.0094; CGT: OR (95% CI) = 1.47 (1.16-1.86), P = 0.0009]. The haplotype association tests were validated by permutation analysis. The association of FOXO1A with female longevity was replicated in 700 centenarians and younger individuals that were sampled geographically different from the original population. Thus, we demonstrate that, unlike FOXO3A, FOXO1A is more closely associated with human female longevity, suggesting that the genetic contribution to longevity trait may be affected by genders.

Diurnal variation of corneal elasticity in healthy young human using air-puff optical coherence elastography.

Due to the disruption of intraocular pressure (IOP) and central corneal thickness (CCT), diurnal variation in normal young human corneal elasticity is not clear. Using the custom-built air-puff optical coherence elastography, one eye of 21 normal subjects is enrolled randomly to measure the central corneal elasticity, IOP, and CCT in different time points within a day. Based on the multi-level model, the corneal elastic modulus is found to have a linear positive relation with IOP (P < .01) but not CCT (P = .175) and time point (P = .174-.686). A new indicator, corneal elasticity change rate, is proposed to present the magnitude of corneal elasticity change caused by 1 mmHg IOP, which can correct the interference effect of IOP. The results show that the corneal elasticity in the normal young human does not have the characteristics of diurnal variation under IOP control. Furthermore, IOP plays an important role in the corneal elasticity, and corneal elasticity change rate can increase the comparability of results between individuals.

Relationships Between Anxiety Symptoms, Hopelessness and Suicidal Ideation Among Parental Caregivers of Mandarin-Speaking Children With Speech Impairment: The Mediating Effect of Depressive Symptoms.

Background: Determining the mental health status of parents who chronically care for a child with speech impairment is important for developing appropriate interventions to improve both parents' and children's health and achieve a win-win situation. Unfortunately, no study in China has explored this issue. This study investigated the differences in four aspects of mental health between maternal and paternal caregivers for the Mandarin-speaking children with speech impairment and determine whether depressive symptoms mediate the relationships between anxiety symptoms and suicidal ideation, hopelessness and suicidal ideation. Methods: This cross-sectional questionnaire survey was conducted in February 2020 by sending a link to the predesigned electronic questionnaire in WeChat. Standardized assessment tools were employed. Hierarchical multiple logistic regression was conducted to examine the associations between various factors and suicidal ideation, and two separate structural equation models were performed to evaluate the mediating effects of depressive symptoms in the relationship between anxiety symptoms and suicidal ideation as well as between hopelessness and suicidal ideation. Results: This study included 446 parental caregivers of Mandarin-speaking children with speech impairment. Paternal caregivers had greater score than maternal caregivers on loss of motivation (one of the subdomains of hopelessness). Somatic complications of the child (OR = 2.73, 95% CI: 1.09-6.67) and depressive symptoms (OR = 3.38, 95% CI: 1.83-6.30) were positively associated with caregivers' suicidal ideation. Having speech therapy of child (OR = 0.54, 95% CI: 0.29-0.98) was negatively correlated with caregivers' suicidal ideation. There was direct effect of depressive symptoms on suicidal ideation. Depressive symptoms play mediating roles on the relationships between anxiety symptoms (ß = 0.171, p < 0.001) as well as between hopelessness and suicidal ideation (ß = 0.187, p < 0.001). Conclusions: Paternal and maternal caregivers of Mandarin-speaking children with speech impairment suffered from mental health problems. Preventive strategies and interventions to ameliorate parental psychological well-being, and health care policies to increase the accessibility to speech therapy care of children with speech impairment are imperative.

Visual acuity is correlated with ischemia and neurodegeneration in patients with early stages of diabetic retinopathy.

PURPOSE: We investigated the effects of retinal ischemia, neurodegeneration, and subclinical edema on best-corrected visual acuity (BCVA) in the early stages of diabetic retinopathy (DR). METHODS: Ischemia was evaluated by the microvascular parameters measured by optical coherence tomography angiography. Neurodegeneration and subclinical edema were identified by the intraretinal layer thickness obtained by optical coherence tomography. Eyes with nonproliferative diabetic retinopathy (n = 132) from 89 patients were analyzed. Eyes were classified as having normal BCVA (n = 88 [66.7%], Snellen equivalent ≥ 20/20) or decreased BCVA (n = 44 [33.3%], Snellen equivalent < 20/20). The prevalence of ischemia, neurodegeneration, and subclinical edema was explored in patients with and without decreased BCVA, and correlations between BCVA and these pathological pathways were determined. RESULTS: Vessel density in the deep retinal capillary plexus (DRCP) and thickness of ganglion cell layer plus inner plexiform layer (GCL-IPL) were significantly lower in eyes with decreased BCVA compared with eyes with normal BCVA (both P < 0.05). In the final multiple regression predictive model, age, DRCP vessel density, and GCL-IPL thickness (all P ≤ 0.044) were predictors of BCVA. DRCP vessel density and GCL-IPL thickness have an interactive effect on visual acuity. The proportions of ischemia and neurodegeneration were significantly higher in eyes with decreased BCVA than in eyes with normal BCVA (P = 0.001 and P = 0.004, respectively). CONCLUSION: During the natural course of the early stages of DR, ischemia and neurodegeneration were the main disease pathways associated with visual acuity, and the mechanisms varied among patients.

NFAT5-mediated CACNA1C expression is critical for cardiac electrophysiological development and maturation.

UNLABELLED: Entry of calcium into cardiomyocyte via L-type calcium channel (LTCC) is fundamental to cardiac contraction. CACNA1C, a type of LTCC and a hallmark of a matured ventricular myocyte, is developmentally regulated. Here, we identified 138 potential transcription factors by a comparative genomic study on 5-kb promoter regions of CACNA1C gene across eight vertebrate species, and showed that six factors were developmentally regulated with the expression of Cacna1c in mouse P19cl6 in vitro cardiomyocyte differentiation model. We further demonstrated that the nuclear factor of activated T cells 5 (Nfat5) bound to a consensus sequence TGGAAGCGTTC and activated the transcription of Cacna1c. The siRNA-mediated knockdown of Nfat5 suppressed the expression of Cacna1c and decreased L-type calcium current in mouse neonatal cardiomyocytes. Furthermore, morpholino-mediated knockdown of nfat5 in zebrafish prohibited the expression of cacna1c and resulted in a non-contractile ventricle, while over-expression of either cacna1c or nfat5 rescued this impaired phenotype. Thus, NFAT5-mediated expression of CACNA1C is evolutionarily conserved and critical for cardiac electrophysiological development and maturation of cardiomyocyte. KEY MESSAGE: Nfat5 binds to a consensus sequence TGGAAGCGTTC in the promoter of Cacna1c. Nfat5 activates the transcription of Cacna1c. Nfat5 knockdown suppresses Cacna1c expression, decreases L-type calcium current, and results in non-beating ventricle. NFAT5-mediated expression of CACNA1C is evolutionarily conserved. NFAT5-mediated CACNA1C expression is critical for cardiac electrophysiological development and maturation.

TBX5 mutations contribute to early-onset atrial fibrillation in Chinese and Caucasians.

AIMS: Atrial fibrillation (AF) is a common arrhythmia with an important heritable aspect. The genetic factors underlying AF have not been fully elucidated. METHODS AND RESULTS: We screened six candidate genes (CAV1, KCNJ2, KCNQ1, NKX2.5, PITX2, and TBX5) for novel mutations in 139 patients of Chinese descent with early-onset AF and 576 controls. Four missense TBX5 mutations, p.R355C, p.Q376R, p.A428S, and p.S372L, were identified in evolutionarily conserved regions. We did not find any mutations in CAV1, KCNJ2, KCNQ1, NKX2.5, and PITX2. These mutations increased the expression of atrial natriuretic peptide (ANP) and connexin-40 (CX40) in the primarily cultured rat atrial myocytes but did not alter the expression of cardiac structural genes, atrial myosin heavy chain-α (MHC-α) and myosin light chain-2α (MLC-2α). Overexpression of p.R355C developed an atrial arrhythmia suggestive of paroxysmal AF in the zebrafish model. To replicate our findings, we screened TBX5 in 527 early-onset AF cases from the Massachusetts General Hospital AF study. A novel TBX5 deletion (ΔAsp118, p.D118del) was identified, while no TBX5 mutations were identified in 1176 control subjects. CONCLUSION: Our results provide both genetic and functional evidence to support the contribution of TBX5 gene in the pathogenesis of AF. The potential mechanism of arrhythmia may be due in part to the disturbed expression of ANP and CX40.

Novel loci and pathways significantly associated with longevity.

Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10(-5)). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity.

Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension.

Essential hypertension is a complex disease affected by genetic and environmental factors and serves as a major risk factor for cardiovascular diseases. Serum lysophosphatidic acid correlates with an elevated blood pressure in rats, and lysophosphatidic acid interacts with 6 subtypes of receptors. In this study, we assessed the genetic association of lysophosphatidic acid receptors with essential hypertension by genotyping 28 single-nucleotide polymorphisms from genes encoding for lysophosphatidic acid receptors, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 and their flanking sequences, in 3 Han Chinese cohorts consisting of 2630 patients and 3171 controls in total. We identified a single-nucleotide polymorphism, rs531003 in the 3'-flanking genomic region of LPAR1, associated with hypertension (the Bonferroni corrected P=1.09×10(-5), odds ratio [95% confidence interval]=1.23 [1.13-1.33]). The risk allele C of rs531003 is associated with the increased expression of LPAR1 and the susceptibility of hypertension, particularly in those with a shortage of sleep (P=4.73×10(-5), odds ratio [95% confidence interval]=1.75 [1.34-2.28]). We further demonstrated that blood pressure elevation caused by sleep deprivation and phenylephrine-induced vasoconstriction was both diminished in LPAR1-deficient mice. Together, we show that LPAR1 is a novel susceptibility gene for human essential hypertension and that stress, such as shortage of sleep, increases the susceptibility of patients with risk allele to essential hypertension.

NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans.

AIMS: Cardiac structural genes have been implicated as causative factors for congenital heart diseases (CHDs). NEXN is an F-actin binding protein and previously identified as a disease gene causing cardiomyopathies. Whether NEXN contributes to CHDs aetiologically remains unknown. Here, we explored the function of NEXN in cardiac development. METHODS AND RESULTS: First, we determine the role of NEXN in cardiac differentiation using mouse P19cl6 in vitro model; we demonstrated that NEXN inhibited cardiac contractile markers, serving as a negative regulator. Interestingly, we found this effect was mediated by GATA4, a crucial transcription factor that controls cardiac development by knockdown, overexpression, and rescue experiment, respectively. We then generated transgenic mouse models and surprisingly, we discovered cardiac-selective expression of the NEXN gene caused atrial septal defects (ASDs). Next, to search for the mutations in NEXN gene in patients suffering from ASDs, we sequenced the exon and exon-intron joint regions of the NEXN gene in 150 probands with isolated ASDs and identified three mutations in the conserved region of NEXN (c.-52-78C>A, K199E, and L227S), which were not found in 500 healthy controls. Finally, we characterize the related mechanisms and found all mutations inhibited GATA4 expression. CONCLUSION: We identify NEXN as a novel gene for ASD and its function to inhibit GATA4 established a critical regulation of an F-actin binding protein on a transcription factor in cardiac development.

NEXN is a novel susceptibility gene for coronary artery disease in Han Chinese.

Coronary artery disease (CAD) is the leading cause of death and disability in the world. Genome-wide association studies have implicated the importance of the genetic contribution of vascular smooth muscle cells (VSMCs) function in CAD susceptibility. The aberrant phenotypic modulation of VSMC is responsible for the pathological vascular intima hyperplasia that is the hallmark for atherosclerotic morphology. NEXN is a muscle-specific F-actin binding protein and is regulated by inflammatory cytokines in VSMCs. Whether NEXN contributes to human vascular disorders is still unknown. In this study, we genotyped 5 SNPs, tagging all of the 17 common SNPs within 54 kilobases (kb) covering NEXN gene and its flanking region, in 1883 patients with CAD and 1973 healthy individuals from Han Chinese, and identified one SNP, rs1780050, which was strongly associated with CAD trait. The Bonferroni corrected P-value was 7.65×10(-5). The odds ratio (95% confidence interval) was 1.23 (1.12-1.36) with statistical power of 0.994. Functional analysis showed that NEXN promotes VSMC to a contractile phenotype in vitro and inhibits balloon-injury induced neointima formation in vivo. Further eQTL analysis demonstrated that the risk allele T of rs1780050 is associated with decreased expression of NEXN, thus contributing to a higher risk of CAD susceptibility in the population. This is, to our knowledge, the first study to identify NEXN as a novel CAD susceptibility gene with both genetic and functional evidence.

Exon 47 skipping of fibrillin-1 leads preferentially to cardiovascular defects in patients with thoracic aortic aneurysms and dissections.

Excessive activation of the transforming growth factor beta signaling pathway and disorganized cellular skeleton caused by genetic mutations are known to be responsible for the inherited thoracic aortic aneurysms and dissections (TAAD), a life-threatening vascular disease. To investigate the genotype-phenotype correlation, we screened genetic mutations of fibrillin-1 (FBN1), transforming growth factor-ß receptor-1 (TGFBR1) and transforming growth factor-ß receptor-2 (TGFBR2) for TAAD in 7 affected families and 22 sporadic patients. Of 19 potential mutations identified in FBN1, 11 appeared novel while the others were recurrent. Two mutations were detected in TGFBR2. Eight patients carried no mutation in either of these genes. Characterization of FBN1 c.5917+6T>C in transfected HEK293 cells demonstrated that it caused skipping of exon 47, leading to the loss of the 33th calcium binding epidermal growth factor-like domain associated with Marfan syndrome. Compared with exon 46, skipping of 47 did not cause patients ectopia lentis in all carriers. To correlate genotypes with phenotypes in different human ancestries, we reviewed the published mutational studies on FBN1 and found that the probability of cardiovascular defects were significantly increased in Chinese patients with premature termination codon or splicing mutations than those with missense mutations (91.7 % vs 54.2 %, P = 0.0307) or with noncysteine-involved point mutations than those with cysteine-involved mutations (88.9 % vs 33.3 %, P = 0.0131). Thus, we conclude that exon 47 skipping of FBN1 leads preferentially to cardiovascular defects and human ancestries influence genotype-phenotype correlation in TAAD.

Common genetic variants of the ß2-adrenergic receptor affect its translational efficiency and are associated with human longevity.

ß-adrenoceptors are the common pharmacological targets for the treatment of cardiovascular diseases and asthma. Genetic modifications of ß-adrenergic system in engineered mice affect their lifespan. Here, we tested whether genes encoding for key components of the ß-adrenergic signaling pathway are associated with human longevity. We performed a 10-year follow-up study of the Chinese longitudinal healthy longevity survey. The Han Chinese population in this study consisted of 963 long-lived and 1028 geography-matched young individuals. Sixteen SNPs from ADRB1, ADRB2, ADCY5, ADCY6, and MAPK1 were selected and genotyped. Two SNPs, rs1042718 (C/A) and rs1042719 (G/C), of ADRB2 in linkage disequilibrium (D' = 1.0; r2 = 0.67) were found to be associated with enhanced longevity in men in two geographically isolated populations. Bonferroni-corrected P-values in a combined analysis were 0.00053-0.010. Men with haplotype A-C showed an increased probability to become centenarians (the frequency of A-C in long-lived and young individuals are 0.332 and 0.250, respectively, OR = 1.49, CI 95% = 1.17-1.88, P = 0.0007), in contrast to those with haplotype C-G (the frequency of C-G in long-lived and young individuals are 0.523 and 0.635, respectively, OR = 0.63, CI 95% = 0.51-0.78, P = 0.000018). The permuted P-values were 0.00005 and 0.0009, respectively. ADRB2 encodes the ß2-adrenergic receptor; the haplotype A-C markedly reduced its translational efficiency compared with C-G (P = 0.002) in transfected HEK293 cells. Thus, our data indicate that enhanced production of ß2-adrenergic receptors caused by genetic variants is inversely associated with human lifespan.

STK39 is an independent risk factor for male hypertension in Han Chinese.

BACKGROUND: STK39 interacts with OXSR1 and phosphorylates the sodium-chloride co-transporter (SLC12A3), which plays a critical role in regulating the salt/water balance and blood pressure. Here we tested whether STK39, OXSR1, and SLC12A3 genetically contribute to hypertension in the Han Chinese population and how the SNP to SNP or SNP to other risk factors interacts in the pathogenesis of hypertension. METHODS AND RESULTS: Eleven tagging SNPs from STK39, OXSR1, and SLC12A3 were selected and first genotyped in 1210 hypertensive and healthy individuals by sequencing. Two SNPs of STK39, rs6433027 and rs3754777, were found to be associated with hypertension in males (P=0.008-0.024). All other SNPs were not associated with hypertension in either gender. The association of rs6433027 and rs3754777 with male hypertension was validated by genotyping another 4598 hypertensive and healthy individuals. The odds ratios (95% confidence interval, P value) in males were 1.269 (1.13-1.43; P=0.0001) and 1.231 (1.078-1.41; P=0.004) of rs6433027 and rs3754777, respectively. The allele T of rs6433027 presented a strong epistatic effect on the allele A of rs3754777 in hypertensive trait. The minor allele frequencies of two SNPs were not stratified by age, BMI, or diabetes, the three major risk factors for hypertension. CONCLUSION: Our results suggest that STK39 is an independent risk factor for hypertension in men and that its intragenic SNPs can interact and function in the control of blood pressure.

Fine mapping of chromosome 3q22.3 identifies two haplotype blocks in ESYT3 associated with coronary artery disease in female Han Chinese.

OBJECTIVE: Genome-wide association study recently identified the chromosome 3q22.3 as a novel locus associated with coronary artery disease (CAD). This study was designed to identify the critical haplotype blocks within this region in Han Chinese populations. METHODS: We selected 1920 CAD patients and healthy participants from Han Chinese and genotyped 22 single nucleotide polymorphisms (SNPs) spanning 150 kilobases (kb) chromosomal region flanking rs9818870, a SNP associated with CAD at 3q22.3 in Caucasian. RESULTS: Seven SNPs were found to be strongly associated with CAD in females and clustered in two haplotype blocks of ESYT3 gene. This was validated in two geographically isolated case-control populations. The two blocks were 14 and 25kb long, respectively. In a combined haplotype analysis, the odds ratios (95% confidence interval, permuted P value) were 0.70 (0.58-0.83, 2×10(-5)) and 1.44 (1.20-1.72, 5×10(-5)) for haplotypes TTG and CCA in block 1 as well as 0.73 (0.61-0.87, 3×10(-4)) and 1.35 (1.13-1.62, 0.0013) for haplotypes TCG and CTT in block 2, respectively. ESYT3 was expressed in human lymphocyte, vascular endothelial cell, and smooth muscle cell. The risk factors including gender, obesity, hypertension, diabetes, and hyperlipidemia exhibited strong effects on the genetic contribution to CAD. CONCLUSION: We identified two haplotype blocks of ESYT3 gene in 3q22.3 region that likely harbor functional variants, which cooperate with other risk factors and play a role in the pathogenesis of coronary artery disease in females.