Erratum: Author correction to 'TMEM16A inhibits angiotensin II-induced basilar artery smooth muscle cell migration in a WNK1-dependent manner' [Acta Pharmaceutica Sinica B 11 (2021) 3994-4007].

[This corrects the article DOI: 10.1016/j.apsb.2021.04.013.].

[Progress in Development of Dose Verification System Software KylinRay-Dose4D].

Advanced radiotherapy technology enables the dose to more accurately conform to the tumor target area of the patient, providing accurate treatment for the patient, but the gradient of the patient's radiation dose at the tumor edge is getting larger, which putting forward higher requirements for radiotherapy dose verification. The dose verification system software KylinRay-Dose4D can verify the patient's pre-treatment plan and the in vivo/on-line dose during the patient's treatment, providing important reference for the physicist to modify the radiotherapy plan and ensuring that the patient receives accurate treatment. This study introduces the overall design and key technologies of KylinRay-Dose4D, and tests the pre-treatment plan dose checking calculation and 2D/3D dose verification through clinical cases. The test results showed that the 2D/3D gamma pass rate (3 mm/3%) of KylinRay-Dose4D reconstructed dose compared with TPS plan dose and measured dose is larger than 95%, which indicating that the reconstructed dose of KylinRay-Dose4D meets the requirement of clinical application.

CT-CBCT deformable registration using weakly-supervised artifact-suppression transfer learning network.

Objective.Computed tomography-cone-beam computed tomography (CT-CBCT) deformable registration has great potential in adaptive radiotherapy. It plays an important role in tumor tracking, secondary planning, accurate irradiation, and the protection of at-risk organs. Neural networks have been improving CT-CBCT deformable registration, and almost all registration algorithms based on neural networks rely on the gray values of both CT and CBCT. The gray value is a key factor in the loss function, parameter training, and final efficacy of the registration. Unfortunately, the scattering artifacts in CBCT affect the gray values of different pixels inconsistently. Therefore, the direct registration of the original CT-CBCT introduces artifact superposition loss.Approach. In this study, a histogram analysis method for the gray values was used. Based on an analysis of the gray value distribution characteristics of different regions in CT and CBCT, the degree of superposition of the artifact in the region of disinterest was found to be much higher than that in the region of interest. Moreover, the former was the main reason for artifact superposition loss. Consequently, a new weakly supervised two-stage transfer-learning network based on artifact suppression was proposed. The first stage was a pre-training network designed to suppress artifacts contained in the region of disinterest. The second stage was a convolutional neural network that registered the suppressed CBCT and CT.Main Results. Through a comparative test of the thoracic CT-CBCT deformable registration, whose data were collected from the Elekta XVI system, the rationality and accuracy after artifact suppression were confirmed to be significantly improved compared with the other algorithms without artifact suppression.Significance. This study proposed and verified a new deformable registration method with multi-stage neural networks, which can effectively suppress artifacts and further improve registration by incorporating a pre-training technique and an attention mechanism.

Erratum: Author correction to "TMEM16A inhibits angiotensin II-induced basilar artery smooth muscle cell migration in a WNK1-dependent manner" [Acta Pharm Sin B 11(12) (2021) 3994-4007].

[This corrects the article DOI: 10.1016/j.apsb.2021.04.013.].

Mutagenesis of the cleavage site of (pro)renin receptor abrogates aldosterone-salt-induced hypertension and renal injury in mice.

Soluble (pro)renin receptor (sPRR), the extracellular domain of (pro)renin receptor (PRR), is primarily generated by site-1 protease and furin. It has been reported that sPRR functions as an important regulator of intrarenal renin contributing to angiotensin II (ANG II)-induced hypertension. Relatively, less is known for the function of sPRR in ANG II-independent hypertension such as mineralocorticoid excess. In the present study, we used a novel mouse model with mutagenesis of the cleavage site in PRR (termed as PRRR279V/L282V or mutant) to examine the phenotype during aldosterone (Aldo)-salt treatment. The hypertensive response of mutant mice to Aldo-salt treatment was blunted in parallel with the attenuated response of plasma volume expansion and renal medullary α-epithelial Na+ channel expression. Moreover, Aldo-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied by blunted polydipsia and polyuria. Together, these results represent strong evidence favoring endogenous sPRR as a mediator of Aldo-salt-induced hypertension and renal injury.NEW & NOTEWORTHY We used a novel mouse model with mutagenesis of the cleavage site of PRR to support soluble PRR as an essential mediator of aldosterone-salt-induced hypertension and also as a potential therapeutic target for patients with mineralocorticoid excess. We firstly report that soluble PRR-dependent pathway medicates the Na+-retaining action of aldosterone in the distal nephron, which opens up a new area for a better understanding of the molecular basis of renal handling of Na+ balance and blood pressure.

Nonlinear motor-mechanism coupling tank gun control system based on adaptive radial basis function neural network optimised computed torque control.

This study investigates the spatial pointing control of a motor-mechanism coupling tank gun. The tank gun control system (TGCS) is driven and stabilised by the motor servo system. However, complicated nonlinearities in the TGCS are inevitable, such as friction, parameter uncertainty, and modelling errors. To solve this problem, the TGCS is regarded as a coupling system composed of mechanical, motor, and control systems. Accordingly, the mechanical and motor models of the marching tank gun are developed first in this paper. The motor-mechanism coupling dynamics model is established based on the principle of equivalent torque. On this basis, a computed torque controller, whose uncertainty was estimated using a radial basis function neural network (RBFNN), is constructed. A modified adaptive algorithm is used to estimate the weights of the RBFNN, and the estimation error of the uncertain observer is compensated by a compensation controller. Simulation results under different conditions validated the effectiveness of the proposed control system, revealing that the proposed control system has good tracking accuracy, strong adaptability, and robustness.

TMEM16A inhibits angiotensin II-induced basilar artery smooth muscle cell migration in a WNK1-dependent manner.

Vascular smooth muscle cell (VSMC) migration plays a critical role in the pathogenesis of many cardiovascular diseases. We recently showed that TMEM16A is involved in hypertension-induced cerebrovascular remodeling. However, it is unclear whether this effect is related to the regulation of VSMC migration. Here, we investigated whether and how TMEM16A contributes to migration in basilar artery smooth muscle cells (BASMCs). We observed that AngII increased the migration of cultured BASMCs, which was markedly inhibited by overexpression of TMEM16A. TMEM16A overexpression inhibited AngII-induced RhoA/ROCK2 activation, and myosin light chain phosphatase (MLCP) and myosin light chain (MLC20) phosphorylation. But AngII-induced myosin light chain kinase (MLCK) activation was not affected by TMEM16A. Furthermore, a suppressed activation of integrinß3/FAK pathway, determined by reduced integrinß3 expression, FAK phosphorylation and F-actin rearrangement, was observed in TMEM16A-overexpressing BASMCs upon AngII stimulation. Contrary to the results of TMEM16A overexpression, silencing of TMEM16A showed the opposite effects. These in vitro results were further demonstrated in vivo in basilar arteries from VSMC-specific TMEM16A transgenic mice during AngII-induced hypertension. Moreover, we observed that the inhibitory effect of TMEM16A on BASMC migration was mediated by decreasing the activation of WNK1, a Cl--sensitive serine/threonine kinase. In conclusion, this study demonstrated that TMEM16A suppressed AngII-induced BASMC migration, thus contributing to the protection against cerebrovascular remodeling during AngII-infused hypertension. TMEM16A may exert this effect by suppressing the RhoA/ROCK2/MLCP/MLC20 and integrinß3/FAK signaling pathways via inhibiting WNK1. Our results suggest that TMEM16A may serve as a novel therapeutic target for VSMC migration-related diseases, such as vascular remodeling.

An improved beam splitting method for intensity modulated proton therapy.

The pencil beam algorithm (PBA) has become the predominant dose calculation method in proton therapy, due to its high level of efficiency. However, density heterogeneity decreases the accuracy of PBA. To improve PBA's accuracy, a beam splitting method is used to divide the original scanning beam into multiple thinner beamlets. Beam splitting should ensure that the beamlets' summed fluence is as close to the original beam fluence as possible, while keeping the spatial variance of beamlets small, and minimizing the number of beamlets. In this work, the generalized differential evolution (GDE) algorithm is utilized for the optimal scheme. Under reasonable constraints for the radius and weight of beamlets, several schemes are optimized via the GDE algorithm. In order to achieve a trade-off between accuracy and calculation speed, three hexagon-based schemes, which split the original beam into 7, 13, and 19 beamlets, respectively, are proposed and compared with the scheme of Raystation 4.5. The fluence distribution calculated by the schemes with 13 beamlets and 19 beamlets are demonstrated to be more accurate than the Raystation scheme, which has 19 beamlets, with a maximum absolute difference between the summed beamlets fluence and the original beam fluence of 2.12%, and 0.93%, respectively. Furthermore, beam splitting schemes are implemented into a proton dose calculation algorithm based on the KylinRay-IMPT TPS. These schemes, based on the dose algorithm, are compared with the Monte Carlo program TOPAS 3.2 in slab geometry with lateral heterogeneity. The dose, calculated by the dose algorithm using a scheme of 13 beamlets, shows a good agreement with the dose from TOPAS. In addition, an abdominal geometry is used for further verification. Gamma analysis passing rates greater than 99.7% are observed, with a 2%/2 mm criterion. Thus, the accuracy and effectiveness of the improved beam splitting method are preliminarily verified.

TMEM16A ameliorates vascular remodeling by suppressing autophagy via inhibiting Bcl-2-p62 complex formation.

Rationale: Transmembrane member 16A (TMEM16A) is a component of calcium-activated chloride channels that regulate vascular smooth muscle cell (SMC) proliferation and remodeling. Autophagy, a highly conserved cellular catabolic process in eukaryotes, exerts important physiological functions in vascular SMCs. In the current study, we investigated the relationship between TMEM16A and autophagy during vascular remodeling. Methods: We generated a transgenic mouse that overexpresses TMEM16A specifically in vascular SMCs to verify the role of TMEM16A in vascular remodeling. Techniques employed included immunofluorescence, electron microscopy, co-immunoprecipitation, and Western blotting. Results: Autophagy was activated in aortas from angiotensin II (AngII)-induced hypertensive mice with decreased TMEM16A expression. The numbers of light chain 3B (LC3B)-positive puncta in aortas correlated with the medial cross-sectional aorta areas and TMEM16A expression during hypertension. SMC-specific TMEM16A overexpression markedly inhibited AngII-induced autophagy in mouse aortas. Moreover, in mouse aortic SMCs (MASMCs), AngII-induced autophagosome formation and autophagic flux were blocked by TMEM16A upregulation and were promoted by TMEM16A knockdown. The effect of TMEM16A on autophagy was independent of the mTOR pathway, but was associated with reduced kinase activity of the vacuolar protein sorting 34 (VPS34) enzyme. Overexpression of VPS34 attenuated the effect of TMEM16A overexpression on MASMC proliferation, while the effect of TMEM16A downregulation was abrogated by a VPS34 inhibitor. Further, co-immunoprecipitation assays revealed that TMEM16A interacts with p62. TMEM16A overexpression inhibited AngII-induced p62-Bcl-2 binding and enhanced Bcl-2-Beclin-1 interactions, leading to suppression of Beclin-1/VPS34 complex formation. However, TMEM16A downregulation showed the opposite effects. Conclusion: TMEM16A regulates the four-way interaction between p62, Bcl-2, Beclin-1, and VPS34, and coordinately prevents vascular autophagy and remodeling.

SGK1 mediates the hypotonic protective effect against H2O2-induced apoptosis of rat basilar artery smooth muscle cells by inhibiting the FOXO3a/Bim signaling pathway.

Serum- and glucocorticoid-inducible kinease-1 (SGK1) is a serine/threonine kinase regulated by hypotonic stimuli, which is involved in regulation of cell cycle and apoptosis. Our previous study shows that activation of volume-regulated Cl- channels (VRCCs) protects rat basilar artery smooth muscle cells (BASMCs) against hydrogen peroxide (H2O2)-induced apoptosis. In the present study, we investigated whether SGK1 was involved in the protective effect of VRCCs in BASMCs. We showed that hypotonic challenge significantly reduced H2O2-induced apoptosis, and increased SGK1 phosphorylation, but did not affect SGK1 protein expression. The protective effect of hypotonic challenge against H2O2-induced apoptosis was mediated through inhibiting mitochondria-dependent apoptotic pathway, evidenced by increased Bcl-2/Bax ratio, stabilizing mitochondrial membrane potential (MMP), decreased cytochrome c release from the mitochondria to the cytoplasm, and inhibition of the activation of caspase-9 and caspase-3. These protective effects of hypotonic challenge against H2O2-induced apoptosis was diminished and enhanced, respectively, by SGK1 knockdown and overexpression. We further revealed that SGK1 activation significantly increased forkhead box O3a (FOXO3a) phosphorylation, and then inhibited the translocation of FOXO3a into nucleus and the subsequent expression of Bcl-2 interacting mediator of cell death (Bim). In conclusion, SGK1 mediates the protective effect of VRCCs against H2O2-induced apoptosis in BASMCs via inhibiting FOXO3a/Bim signaling pathway. Our results provide compelling evidences that SGK1 is a critical link between VRCCs and apoptosis, and shed a new light on the treatment of vascular apoptosis-associated diseases, such as vascular remodeling, angiogenesis, and atherosclerosis.

Smooth muscle-specific TMEM16A expression protects against angiotensin II-induced cerebrovascular remodeling via suppressing extracellular matrix deposition.

Cerebrovascular remodeling is the leading factor for stroke and characterized by increased extracellular matrix deposition, migration and proliferation of vascular smooth muscle cells, and inhibition of their apoptosis. TMEM16A is an important component of Ca2+-activated Cl- channels. Previously, we showed that downregulation of TMEM16A in the basilar artery was negatively correlated with cerebrovascular remodeling during hypertension. However, it is unclear whether TMEM16A participates in angiotensin II (Ang II)-induced vascular remodeling in mice that have TMEM16A gene modification. In this study, we generated a transgenic mouse that overexpresses TMEM16A specifically in vascular smooth muscle cells. We observed that vascular remodeling in the basilar artery during Ang II-induced hypertension was significantly suppressed upon vascular smooth muscle-specific overexpression of TMEM16A relative to control mice. Specifically, we observed a large reduction in the deposition of fibronectin and collagen I. The expression of matrix metalloproteinases (MMP-2, MMP-9, and MMP-14), and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were upregulated in the basilar artery during Ang II-induced hypertension, but this was suppressed upon overexpression of TMEM16A in blood vessels. Furthermore, TMEM16A overexpression alleviated the overactivity of the canonical TGF-ß1/Smad3, and non-canonical TGF-ß1/ERK and JNK pathways in the basilar artery during Ang II-induced hypertension. These in vivo results were similar to the results derived in vitro with basilar artery smooth muscle cells stimulated by Ang II. Moreover, we observed that the inhibitory effect of TMEM16A on MMPs was mediated by decreasing the activation of WNK1, which is a Cl--sensitive serine/threonine kinase. In conclusion, this study demonstrates that TMEM16A protects against cerebrovascular remodeling during hypertension by suppressing extracellular matrix deposition. We also showed that TMEM16A exerts this effect by reducing the expression of MMPs via inhibiting WNK1, and decreasing the subsequent activities of TGF-ß1/Smad3, ERK, and JNK. Accordingly, our results suggest that TMEM16A may serve as a novel therapeutic target for vascular remodeling.

Combined Direct Posterior Split-Gastrocnemius Approach for the Posterolateral Tibial Plateau Involved Fractures.

BACKGROUND: Several approaches of fracture reduction and fixation are employed in complex tibial plateau fractures. However, there is a lack of consensus regarding reduction and fixation for fractures to the posterolateral part of the tibial plateau. HYPOTHESIS: The combined direct posterior split-gastrocnemius approach may be a choice of the posterior part involved comminuted tibial plateau fractures. PATIENTS AND METHODS: We review cases of 216 patients with tibial plateau fracture and subsequent operation from 2012/1/1 to 2017/1/1. Fifty-six cases involved posterolateral plateau damage. For these 56 patients, we use anteromedial and direct posterior split-gastrocnemius approaches or anterolateral and direct posterior split-gastrocnemius approaches to fix the posterolateral and medial or lateral segments. RESULTS: From the radiography films, all patients (56/56) achieved a good reduction of the articular surface after surgery (31 patients were anatomic reduction, 25 patients were acceptable reduction). After 12 months follow up, only 2 patients showed poor reduction and no significant difference between <3 days after surgery and 12 months follow up. All patients acquired good knee functions at 12 months' time-point of the fracture surgery. These patients have less pain and other related symptoms in daily living according to the Knee Injury and Osteoarthritis Scores. CONCLUSION: The direct posterior split-gastrocnemius approach provides efficient and less invasive access to the posterolateral tibial plateau, which is suitable for direct reduction and rigid fixation to the fragments of posterolateral tibial fractures. It is a valuable choice when mapping a surgical approach to tibial plateau fracture reduction involving the posterior tibial plateau and its implementation may offer better post-operative functionality relative to alternative approaches.

Transmembrane member 16A participates in hydrogen peroxide-induced apoptosis by facilitating mitochondria-dependent pathway in vascular smooth muscle cells.

BACKGROUND AND PURPOSE: Transmembrane member 16A (TMEM16A), an intrinsic constituent of the Ca2+ -activated Cl- channel, is involved in vascular smooth muscle cell (VSMC) proliferation and hypertension-induced cerebrovascular remodelling. However, the functional significance of TMEM16A for apoptosis in basilar artery smooth muscle cells (BASMCs) remains elusive. Here, we investigated whether and how TMEM16A contributes to apoptosis in BASMCs. EXPERIMENTAL APPROACH: Cell viability assay, flow cytometry, Western blot, mitochondrial membrane potential assay, immunogold labelling and co-immunoprecipitation (co-IP) were performed. KEY RESULTS: Hydrogen peroxide (H2 O2 ) induced BASMC apoptosis through a mitochondria-dependent pathway, including by increasing the apoptosis rate, down-regulating the ratio of Bcl-2/Bax and potentiating the loss of the mitochondrial membrane potential and release of cytochrome c from the mitochondria to the cytoplasm. These effects were all reversed by the silencing of TMEM16A and were further potentiated by the overexpression of TMEM16A. Endogenous TMEM16A was detected in the mitochondrial fraction. Co-IP revealed an interaction between TMEM16A and cyclophilin D, a component of the mitochondrial permeability transition pore (mPTP). This interaction was up-regulated by H2 O2 but restricted by cyclosporin A, an inhibitor of cyclophilin D. TMEM16A increased mPTP opening, resulting in the activation of caspase-9 and caspase-3. The results obtained with cultured BASMCs from TMEM16A smooth muscle-specific knock-in mice were consistent with those from rat BASMCs. CONCLUSIONS AND IMPLICATIONS: These results suggest that TMEM16A participates in H2 O2 -induced apoptosis via modulation of mitochondrial membrane permeability in VSMCs. This study establishes TMEM16A as a target for therapy of several remodelling-related diseases.

[Development and Validation of Dynamic Intensity Modulated Accurate Radiotherapy System KylinRay-IMRT].

KylinRay-IMRT is the advanced radiotherapy treatment planning module of accurate radiotherapy system (KylinRay) aiming to provide accurate and efficient plan design platform. In this paper the system design, main functions and key technologies of KylinRay-IMRT were introduced. KylinRay-IMRT supports three dimensional conformal radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT) and many other types of treatment plan design with function modules including patient data management, image registration and fusion, image contouring, image three dimensional reconstruction and visualization, three dimensional conformal radiotherapy planning, intensity modulated radiotherapy planning, plan evaluation and comparison, and report print. KylinRay-IMRT has been tested by the national standard YY/T 0889-2013, the results showed that the performance of KylinRay-IMRT can fully meet the standard requirements.

WNK1 is required for proliferation induced by hypotonic challenge in rat vascular smooth muscle cells.

Hypotonic challenge evoked vascular cell proliferation through activation of volume-regulated Cl- channel (VRCC), leading to a decrease in the intracellular Cl- concentration ([Cl-]i). We hypothesize that the decrease in [Cl-]i may activate one or several Cl--sensitive kinases, resulting in a subsequent signaling cascade. In this study we demonstrated that WNK1, a Cl--sensitive kinase, was involved in VRCC-induced proliferative signaling pathway in A10 vascular smooth muscle cells in vitro. A10 cells were exposed to a hypotonic challenge (225 mosmol·kg-1·H20), which caused significantly increase in WNK1 phosphorylation without altering WNK1 protein expression. WNK1 overexpression significantly increased hypotonic-induced A10 cell proliferation, whereas silencing of WNK1 caused an opposite action. WNK1 mutation did not affect hypotonic-induced WNK1 phosphorylation and cell proliferation. Silencing of WNK1 caused cell cycle arrest at G0/G1 phase and prevented transition from G1 to S phase, whereas the WNK1 overexpression accelerated cell cycle transition from G1 to S phase. Silencing of WNK1 significantly inhibited cyclin D1/cyclin E1 expression and increased p27kip/p21cip expression. WNK1 overexpression significantly increased cyclin D1/cyclin E1 expression and reduced p27KIP/p21CIP expression. In addition, WNK1 knockdown or overexpression significantly attenuated or increased the hypotonic-induced phosphorylation of Akt and PI3K respectively.In conclusion, the reduction in [Cl-]i caused by hypotonic challenge-induced VRCC opening evokes WNK1 phosphorylation in A10 VSMCs, which mediates cell cycle transition from G0/G1 to S phase and proliferation through the PI3K-Akt signaling pathway.

Body mass index and risk of knee osteoarthritis: systematic review and meta-analysis of prospective studies.

OBJECTIVES: Obesity is suggested to be a risk factor for knee osteoarthritis (OA). This meta-analysis aimed to examine the relationship between body mass index (BMI) and the risk of knee OA in published prospective studies. DESIGN: Meta-analysis. STUDIES REVIEWED: An extensive literature review was performed, and relevant studies published in English were retrieved from the computerised databases MEDLINE, EMBASE and Cochrane. METHODS: The effect estimate (RR or HR) and its 95% CI are investigated on the basis of the evaluation of differences of knee OR risk in overweight or obesity versus those with normal weight. Category-specific risk estimates were further transformed into estimates of the RR in terms of per increase of 5 in BMI by using the generalised least-squares method for trend estimation. Studies were independently reviewed by two investigators. Subgroup analysis was performed. Heterogeneity and publication bias were assessed. Data from eligible studies were extracted, and the meta-analysis was performed by using the STATA software V.12.0. RESULTS: 14 studies were finally included in the analysis. The results showed that overweight and obesity were significantly associated with higher knee OA risks of 2.45 (95% CI 1.88 to 3.20, p<0.001) and 4.55 (95% CI 2.90 to 7.13, p<0.001), respectively. The risk of knee OA increases by 35% (95% CI 1.18 to 1.53, p<0.001) with a 5 kg/m(2) increase in BMI. Subgroup analysis showed that obesity was an independent predictor of knee OA risk regardless of the study country, sample size, gender proportion of participants, duration of follow-up, presence of adjusted knee injury and assessed study quality above or below an NOS score of 8. No publication bias was detected. CONCLUSIONS: Obesity was a robust risk factor for knee OA. Professionals should take a possible weight reduction into account for the treatment of knee OA whenever a patient is significantly overweight.

[A1166C polymorphism of the angiotensin II type 1 receptor gene and essential hypertension in Han, Tibetan and Yi populations].

OBJECTIVE: To clarify whether A1166C polymorphism of the angiotensin II type 1 receptor (AT(1)R) gene is associated with susceptibility to essential hypertension in Han, Tibetan and Yi populations in China. METHODS: This study involved 302 normotensive and 446 hypertensive subjects. The polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism in genomic DNA. The data were analyzed by ANCOVA, chi-square test, and multiple logistic regression. RESULTS: In normotensive controls, the A1166 allele frequencies were 0.979, 0.939 and 0.965 in Han, Tibetan and Yi participants, respectively. There was no significant intergroup variation in frequency of the allele in normotensives (chi-square=4.166, P=0.125). The frequency of the A1166 allele in Tibetan male hypertensives was significantly higher than that in normotensives (chi-square=11.46, P=0.001). There was no significant difference in A1166C genotype distribution and allele frequency between normotensives and hypertensives either in the Han (P=0.465) or Yi (P=0.357) populations. Body mass index in the Han and Yi populations (P=0.0001), age in the Tibetan and Yi populations (P=0.0001), and AA genotype in the Tibetan male population (P=0.0034) all were independent risk factors for hypertension. Diastolic blood pressure levels were significantly higher in Tibetan male subjects with the AA genotype than in those with the AC+CC genotype (P=0.0040). CONCLUSION: The A1166 allele is very common in Han, Tibetan and Yi populations, approximately 1.35-fold more common than in Caucasians. The A1166 allele of the AT(1)R gene may be a predisposing factor for essential hypertension in Tibetan males. A1166C polymorphism of the AT(1)R gene is probably not involved in the pathogenesis of essential hypertension in Han and Yi populations.

A1166C polymorphism of the angiotensin II type 1 receptor gene and essential hypertension in Han, Tibetan and Yi populations.

Our aim was to clarify whether substitution of cytosine for adenine at position 1166 (A1166C) polymorphism of the angiotensin II type 1 receptor (AT1R) gene is associated with susceptibility to essential hypertension in Han, Tibetan and Yi populations in China. This study involved 302 normotensive and 446 hypertensive subjects. The polymorphism was detected by polymelase chain reaction of genomic DNA and restriction fragment length polymorphism (PCR-RFLP) in genomic DNA. The data were analyzed by analysis of covariance (ANCOVA), X2 test, and multiple logistic regression. In normotensive controls, the A1166 allele frequencies were 0.979, 0.939 and 0.965 in Han, Tibetan and Yi participants, respectively. There was no significant intergroup variation in frequency of the allele in normotensives (X2=4.166, p=0.125). The frequency of the A1166 allele was significantly higher in Tibetan male hypertensives than that in normotensives (X2=11.46, p=0.001). There was no significant difference in A1166C genotype distribution and allele frequency between normotensives and hypertensives either in the Han (p=0.465) or Yi (p=0.357) populations. Body mass index in the Han and Yi populations (p=0.0001), age in the Tibetan and Yi populations (p=0.0001), and AA genotype in the Tibetan male population (p=0.0034) all were independent risk factors for hypertension. Diastolic blood pressure levels were significantly higher in Tibetan male subjects with the AA genotype than in those with the AC+CC genotype (p=0.0040). We concluded that the A1166 allele is very common in Han, Tibetan and Yi populations, approximately 1.35-fold more common than in Caucasians. The A1166 allele of the AT1R gene may be a predisposing factor for essential hypertension in Tibetan males. A1166C polymorphism of the AT1R gene is probably not involved in the pathogenesis of essential hypertension in Han or Yi populations.