Single nucleotide polymorphism rs3732860 in the 3'-untranslated region of CYP8B1 gene is associated with gallstone disease in Han Chinese.

BACKGROUND AND AIMS: Gallstone disease (GD) is a common disease of multigenetic origin; however, the major susceptibility loci for GD in human populations remain unidentified. This study aimed to identify the genetic factors contributing to gallstone development in Chinese. METHODS: A genome-wide scan was conducted in 12 Han Chinese GD families to identify linkage loci. The linkage region showing the highest logarithm of odds score encompasses the sterol 12α-hydroxylase gene (CYP8B1). Replication analysis with an independent sample of 192 GD patients and 192 unrelated, matched controls was carried out to verify the associations between CYP8B1 polymorphisms and GD. RESULTS: Three loci (D3S1266, D4S406, and D9S1682) showed suggestive or nominal evidence of linkage in all 12 GD families. The logarithm of odds score of D3S1266 reached 2.71 in the families with late-onset patients. The single nucleotide polymorphism rs3732860 in the 3'-untranslated region of CYP8B1 showed significant association to GD (P = 0.022), and carriers of the A allele had lower risk of GD (odds ratio = 1.46, 95% confidence interval: 1.055-2.034) compared with carriers of the G allele. CONCLUSIONS: The single nucleotide polymorphism rs3732860 in the 3'-untranslated region of the CYP8B1 gene is associated with risk of GD in Chinese Han and appears to be responsible for the observed linkage with D3S1266.

[Angiotensin(1-7) attenuates left ventricular dysfunction and myocardial apoptosis on rat model of adriamycin-induced dilated cardiomyopathy].

OBJECTIVE: To investigate the effect of Angiotensin(1-7) [Ang(1-7)] on left ventricular dysfunction and myocardial apoptosis on rat model of adriamycin-induced dilated cardiomyopathy (ADR-DCM). METHODS: Weight-matched adult male Wistar rats were randomly divided into 3 groups: (1) the ADR-DCM group (n = 25), in which 2.5 mg/kg of ADR was weekly intravenously injected for 10 weeks. (2) Ang(1-7) group (n = 25), in which ADR rats were simultaneously treated with angiotensin-(1-7) (24 µg×kg(-1)×h(-1), ip.) for 12 weeks. (3) normal control group (n = 10). Hemodynamics and echocardiography examination were performed at 12 weeks. The malondialdehyde (MDA) was measured by TBA methods. The plasma concentration of AngII was determined by immunoradiometric assay. The pathological change was analyzed by histological hematoxylin-eosin staining. Myocardial apoptosis was assessed by TUNEL method. The protein expression of pro-apoptotic protein caspase-3, Bax and anti-apoptotic protein Bcl-xl in cardiomyocytes were detected by Western blot. RESULTS: Mortality was significantly lower in Ang(1-7) group than in ADR-DCM group (16% vs. 40%, P < 0.01). Compared to the control group, left ventricular end-diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD) and left ventricular end-diastolic pressure (LVEDP) were significantly increased in ADR-DCM group (all P < 0.01) while fractional shorting (FS), +dp/dtmax and -dp/dtmax were significantly reduced in ADR-DCM group (all P < 0.01). LVEDD, LVESD and LVEDP were significantly reduced while FS, +dp/dtmax and -dp/dtmax were significantly higher in Ang(1-7) group compared to the ADR-DCM group, but still higher than the control group (all P < 0.01). The concentrations of AngII and MDA were higher in the ADR-DCM group than in the control group (P < 0.01), which were significantly reduced by Ang(1-7) treatment (P < 0.01). The TUNEL-positive cells and apoptosis index, the expression of pro-apoptotic protein caspase-3 and Bax were significantly higher while the expression of anti-apoptotic protein Bcl-xl was significantly lower in the ADR-DCM group than in the control group (all P < 0.01) which could all be partially reversed by Ang(1-7) treatment (all P < 0.01). CONCLUSION: Ang(1-7) could significantly attenuate left ventricular dysfunction and myocardial apoptosis in this model by downregulating pro-apoptotic protein caspase-3 and Bax and upregulating anti-apoptotic protein Bcl-xl expression.

[Association of single nucleotide polymorphism in human CYP8B1 gene with gallstone disease].

OBJECTIVE: To identify the single nucleotide polymorphisms of human CYP8B1gene and explore the association of some of these SNPs with gallstone disease in Chinese population. METHODS: The exon and part of promoter were sequenced by a fluorescent labeling automatic method to identify and characterize the SNPs in Chinese population. For SNPs with an allelic frequency of over 10%, a case-control study was performed in patients and controls. RESULTS: Eleven SNPs were found within a 5119 bp region. Among them, 1 was in coding region, 5 in promoter and 5 in 3'-UTR. There were 3 novel SNPs and 12 SNPs in SNP database were not found. The allelic frequency of rs3732860 polymorphism showed a significant difference (P = 0.022) in the association study. The subjects with A allele had a significantly lower frequency of gallstone disease than those with G allele (OR = 1.465, 95%CI 1.055 - 2.034, P = 0.023). CONCLUSION: SNP rs3732860 of CYP8B1 gene is associated with gallstone disease in Chinese population. And A allele may play a protective role in the pathogenesis of gallstone.

The association between the IL-20-1723C→G allele on the 1q chromosome and psoriasis triggered or exacerbated by an upper respiratory tract infection in the Chinese Han population.

BACKGROUND: Psoriasis is a cutaneous disorder of multifactorial etiology influenced by both genetic and environmental factors such as infection. METHODS: We conducted a genome analysis with 20 microsatellite markers spanning the long arm of chromosome 1 in 36 Chinese families with psoriasis and detected evidence for linkage at 1q21 with a nonparametric linkage score of 1.74, p=0.03, and 1q32 with one of 1.84, p=0.03. According to the positional and functional candidate principle, we further investigated the single-nucleotide polymorphisms of the HAX-1 gene (located in 1q21) and IL-20 gene (located in 1q32) in a case-control study including 340 sporadic patients and 199 controls. RESULTS: We determined that the frequency of the G allele of IL-20-1723C→G (rs1713239) was significantly higher among psoriatic patients (38.5% in cases vs. 31.2% in controls, p=0.015, odds ratio, OR=1.39, 95% confidence interval, CI=1.07-1.80). When we stratified our analysis by psoriasis triggered or exacerbated by infection of the upper respiratory tract, a significant difference was detected (42.4% in stratified cases vs. 31.2% in controls, p=0.005, OR=1.63, 95% CI=1.15-2.30). CONCLUSION: We assume that triggered or exacerbated by respiratory tract infection, the population with the G allele of IL-20-1723C→G are predisposed to psoriasis.

[Association between smoking status at follow-up and clinical outcomes in patients undergoing successful percutaneous coronary intervention].

OBJECTIVE: To assess the association between smoking status at follow-up and clinical outcomes in patients undergoing successful percutaneous coronary intervention (PCI). METHODS: The smoking status at follow-up was investigated in 592 patients undergoing successful PCI between Jan. 2003 and Nov. 2006. The patients were divided into three groups on the basis of their smoking status at follow-up: non-smokers (n = 272), quitters (n = 215) and current smokers (n = 105). Major adverse cardiac events were recorded. RESULTS: The average follow-up time was 19.0 months. At follow-up, current smokers were significantly younger (P < 0.01), more likely to be male (P < 0.01) than non-smokers and had more favorable clinical and angiographic characteristics: lower prevalence of hypertension (P < 0.05) and diabetes (P < 0.05), fewer diseased vessels (P < 0.05) and fewer implanted coronary stents (P < 0.01), larger target vessel diameter (P < 0.01). However, the incidence of non-fatal myocardial infarction (MI) in quitters (1.40%) was significantly higher than in nonsmokers (0.37%, P < 0.05), the incidence of nonfatal MI in current smokers (4.76%) was significantly higher than quitters (1.40%, P < 0.05) and nonsmokers (0.37%, P < 0.01). After adjustments for age, gender, hypertension, diabetes, dyslipidaemia, target vessel diameter, the number of diseased vessels, the kind and number of implanted stents, and the follow-up time, multi-variables logistic regression analysis showed that current smoking was a independent predictive factor for non-fatal MI (beta = 1.28, wald chi2 = 6.91, P < 0.01). CONCLUSIONS: Smokers, especially current smokers, were at increased risk for non-fatal MI post successful PCI. Therefore, all patients underwent PCI should be encouraged to stop smoking.

Gene expression profiling of porokeratosis.

BACKGROUND: Porokeratosis (PK) represents a heterogeneous group of disorders of keratinization and has a wide variety of clinical manifestations. PK may exhibit similarities with psoriasis at both clinical and molecular levels. The genetic basis and pathogenesis for PK remain elusive. METHODS: We studied the transcriptional profiles of three pairwise lesional and uninvolved skin biopsies from patients with different subtypes of PK using the Illumina BeadArray platform. RESULTS: A total of 37 upregulated genes were identified in our study, including wound-induced keratins, S100 calcium-binding protein genes involved in epidermal differentiation, as well as genes involved in mediating intercellular communication and the immune response. To our knowledge, this is the first study that characterizes the immune profile of PK lesions. CONCLUSIONS: Here, we report that keratinocytes (KCs)-harboring lesions have activated and overexpressed wound-induced keratin genes, which appear to be coregulated with other genes involved in mediating epidermal differentiation, intercellular communication and immunity. This study, from the perspective of gene profiling, supports that gene misregulation in PK mimics that of psoriasis. Our data indicate that the genes implicated in the T-cell-mediated immune response pathway and activation of KCs play a key role in the pathogenesis of PK.

[Effects of intracoronary autologous bone marrow mononuclear cells transplantation in patients with dilated cardiomyopathy].

OBJECTIVE: To evaluate the safety and efficacy of intracoronary autologous bone marrow mononuclear cells (BM-MNCs) transplantation in patients with dilated cardiomyopathy (DCM). METHODS: On top of standard therapy, DCM patients received BM-MNCs transplantation (n = 71) or saline injection (n = 187). The baseline clinical characteristics of two groups were comparable. Data on echocardiography, Holter, six-minute-walk test, cardiac SPECT and annual hospital days were obtained in all patients at baseline, 1, 3, 6, 12 and 24 months after transplantation. RESULTS: Six-minute-walk distance was significantly longer at one month [(345 +/- 76) m vs. (286 +/- 104) m, P < 0.05] and thereafter (all P < 0.05) in BM-MNCs group compared with saline group. Left ventri ocular ejection fraction (LVEF) at one month in BM-MNCs group was significantly higher compared with saline group [(41.5 +/- 9.4)% vs. (37.3 +/- 6.6)%, P < 0.05] and with pre-transplantation value [(41.5 +/- 9.4)% vs. (32.4 +/- 8.5)%, P < 0.05] while LVEF was similar at 24 months after transplantation between the two groups [(43.6 +/- 6.3)% vs. (43.2 +/- 6.0)%, P > 0.05]. Three months after transplantation, the number of ischemic segments of BM-MNCs group was significantly reduced compared with that of saline group (2.0 +/- 1.0 vs. 3.1 +/- 1.4, P < 0.05) and with baseline (2.0 +/- 1.0 vs. 3.1 +/- 1.2, P < 0.05) while the number of necrotic segments were similar in both groups during the follow-up. There were no significant difference in survival between two groups during 2 years follow-up (95.4% vs. 94.9%, P > 0.05) but the annual hospitalization days of BM-MNCs group was significantly lower than that of saline group [(23.6 +/- 13.4) d vs. (33.0 +/- 14.0) d, P > 0.05]. CONCLUSIONS: Intracoronary transplantation of autologous BM-MNCs was safe and could increase LVEF and the six-minute-walk distance and reduce hospitalization days for patients with dilated cardiomyopathy.

A novel MGST2 non-synonymous mutation in a Chinese pedigree with psoriasis vulgaris.

A balanced translocation was recently identified in a German psoriasis patient. One of the breakpoints was mapped immediately upstream of the microsomal glutathione S-transferase 2 (MGST2) gene, suggesting it as a candidate gene. Here, we report the identification of a novel non-synonymous mutation in MGST2 by a comprehensive sequence analysis of MGST2's coding region in Chinese psoriasis samples. We demonstrate that this mutation co-segregated with the disease phenotype within a Chinese family affected with psoriasis vulgaris and is predicted to have an impact on the normal function of MGST2 protein. However, the mutation was absent in 551 additional cases and 384 healthy Chinese controls. While requiring independent confirmation, our results suggest that this rare mutation could play a causal role in a small subset of psoriasis individuals.

[Refinement of DSAP1 locus and mutation detection for candidate genes].

Disseminated superficial actinic porokeratosis (DSAP) is an uncommon autosomal dominant chronic keratinization disorder,characterized by multiple superficial keratotic lesions surrounded by a slightly raised keratotic border. In previous studies,the disease gene was mapped to 12q23. 2-24.1 (DSAP1), and 15q25. 1-26.1 (DSAP2). In this study,genome-wide scan was performed in two unrelated six-generation DSAP pedigrees to localize and identify the candidate gene(s) of disease. Linkage analysis showed that the cumulative maximum two-point lod score of 8.28 was obtained with the marker D12S84 at a recombination fraction theta of 0.00. Haplotype analysis defined an 8.0 cM critical region for DSAP gene(s) between markers D12S330 and D12S354 on 12q24. 1-q24. 2, which partially overlapped with the region identified for DSAP1. DNA sequencing of the coding exons of six candidate genes (CRY1, PWP1, ASCL4, PRDM4, KIAA0789 and CMKLR1) on the basis of their location in the critical overlap interval, failed to detect any mutation in DSAP patients. Thus, it is likely that these genes are not involved in DSAP.

Two closely linked variations in actin cytoskeleton pathway in a Chinese pedigree with disseminated superficial actinic porokeratosis.

BACKGROUND: Disseminated superficial actinic porokeratosis (DSAP) is an uncommon autosomal dominant chronic keratinization disorder, characterized by multiple superficial keratotic lesions surrounded by a slightly raised keratotic border. Recently, SSH1 was identified as the DSAP candidate gene. OBJECTIVE: Our purpose was to determine the locus of DSAP and identify the candidate gene(s) of the disease. METHODS: Genome-wide scanning and linkage analysis were performed in a 6-generation Chinese family with DSAP. The coding exons and promoter region of the candidate genes were screened for the nucleotide variations. RESULTS: A missense mutation (p.Ser63Asn) in SSH1 and a variation (dbSNP3759383: G>A) in the promoter region of ARPC3 were closely linked with DSAP in the pedigree. CONCLUSION: Both SSH1 and ARPC3 are involved in the actin cytoskeleton pathway and interacted with adherent junctions in the epidermal cells. We suggested that cytoskeleton disorganization in epidermal cells was likely associated with the pathogenesis of DSAP.