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Secreted modular calcium-binding protein 2 haplotypes are associated with pulmonary function.

ABSTRACT: Previously reported linkage to FEV(1) (LOD score = 5.0) on 6q27 in the Framingham Heart Study (FHS) led us to explore a candidate gene, SMOC2, at 168.6 Mb.We tested association between SMOC2 polymorphisms and FEV(1) and FVC in unrelated FHS participants.Twenty single-nucleotide polymorphisms (SNPs) around SMOC2 were genotyped in 1,734 subjects.SNP data were analyzed using multiple linear regression models incorporating sex, age, body mass index, height, and smoking history as covariates, and analyses were repeated within strata of ever- and never-smokers. The minor allele of SNP rs1402 was associated with higher mean FEV(1) (p = 0.003) and FVC (p = 0.02) measures. In never-smoking subjects, association with higher measures was observed with the minor allele of rs747995 (FEV(1), p = 0.0006; FVC, p = 0.0008). These two SNPs lie in different haplotype blocks and reside in intron 4 of SMOC2. Haplotype analysis revealed a common G-T haplotype (rs747995-rs1402) with 77% frequency in never-smoking FHS subjects. The G-T haplotype was associated with reduction of 126 ml for FEV(1) (p = 0.0002) and 157 ml for FVC (p = 0.0002). The G-T haplotype was similarly associated in a set of never-smoking subjects from the Family Heart Study (FEV(1), p = 0.03; FVC, p = 0.03).The replication of the association in two populations supports the possibility that SMOC2 might play an important role in the determination of FEV(1) and FVC.

SUBMITTER: Wilk JB

PROVIDER: S-EPMC1899283 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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Secreted modular calcium-binding protein 2 haplotypes are associated with pulmonary function.

Wilk Jemma B JB Herbert Alan A Shoemaker Christina M CM Gottlieb Daniel J DJ Karamohamed Samer S

American journal of respiratory and critical care medicine 20070104 6

<h4>Rationale</h4>Previously reported linkage to FEV(1) (LOD score = 5.0) on 6q27 in the Framingham Heart Study (FHS) led us to explore a candidate gene, SMOC2, at 168.6 Mb.<h4>Objectives</h4>We tested association between SMOC2 polymorphisms and FEV(1) and FVC in unrelated FHS participants.<h4>Methods</h4>Twenty single-nucleotide polymorphisms (SNPs) around SMOC2 were genotyped in 1,734 subjects.<h4>Measurements and main results</h4>SNP data were analyzed using multiple linear regression models ...[more]

PMID: 17204727

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Project description:Background: Secreted modular calcium-binding protein 1 (SMOC1) belongs to a family of matricellular proteins; it was involved in embryo development, endothelial cell proliferation, angiogenesis, integrin-matrix interactions, cell adhesion, and regulation of glucose metabolism. Previous studies showed that the expression of SMOC1 was increased in some tumors. However, the prognostic value and the biological function of SMOC1 in tumor remain unclear. Methods: In this study, we explored the expression profile and prognostic value of SMOC1 in pan-cancers, especially glioma, via multiple databases, including Oncomine, Gene Expression Profiling Interactive 2, PrognoScan, Kaplan-Meier plotter, and the Chinese Glioma Genome Atlas database. Furthermore, LinkedOmics was used to identify the genes coexpressed with SMOC1 and to perform Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology analysis in low-grade glioma (LGG). Also, the Cancer Single-Cell State Atlas database was used to evaluate the correlation between SMOC1 expression and functional state activities in glioma cells. In addition, the Tumor Immune Estimation Resource and TISIDB databases were used to evaluate the correlations between SMOC1 expression and tumor-infiltrating immune cells in the tumor microenvironment. Results: Compared with normal brain tissues, the expression of SMOC1 was increased in LGG tissues. The higher expression of SMOC1 was significantly correlated with better survival of LGG patients. Additionally, functional analyses showed that the SMOC1 coexpressed genes were inhibited in processes such as response to type I interferon and interferon-gamma, lymphocyte-mediated immunity, leukocyte migration, adaptive immune response, neutrophil-mediated immunity, T cell activation, and pathways including EMC-receptor interaction, Th17 cell differentiation, and leukocyte trans-endothelial migration in LGG. Moreover, the expression of SMOC1 was correlated with stemness, hypoxia, EMT, and metastasis of glioma cells. Additionally, the expression of SMOC1 expression was negatively correlated with levels of infiltrating B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells, and gene markers of most immune cells in LGG. Conclusion: Our results suggest that SMOC1 could be a potential biomarker to determine prognosis and might play a specific role in the tumor microenvironment of glioma, thereby influencing the development and progression of glioma. These findings provide some new insights for further investigation.

Project description:Background & aimsHistological assessment of liver biopsies is the gold standard for diagnosis of non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD), despite its well-established limitations. Therefore, non-invasive biomarkers that can offer an integrated view of the liver are needed to improve diagnosis and reduce sampling bias. Hepatic stellate cells (HSCs) are central in the development of hepatic fibrosis, a hallmark of NASH. Secreted HSC-specific proteins may, therefore, reflect disease state in the NASH liver and serve as non-invasive diagnostic biomarkers.MethodsWe performed RNA-sequencing on liver biopsies from a histologically characterised cohort of obese patients (n = 30, BMI >35 kg/m2) to identify and evaluate HSC-specific genes encoding secreted proteins. Bioinformatics was used to identify potential biomarkers and their expression at single-cell resolution. We validated our findings using single-molecule fluorescence in situ hybridisation (smFISH) and ELISA to detect mRNA in liver tissue and protein levels in plasma, respectively.ResultsHepatic expression of SPARC-related modular calcium-binding protein 2 (SMOC2) was increased in NASH compared to no-NAFLD (p.adj <0.001). Single-cell RNA-sequencing data indicated that SMOC2 was primarily expressed by HSCs, which was validated using smFISH. Finally, plasma SMOC2 was elevated in NASH compared to no-NAFLD (p <0.001), with a predictive accuracy of AUROC 0.88.ConclusionsIncreased SMOC2 in plasma appears to reflect HSC activation, a key cellular event associated with NASH progression, and may serve as a non-invasive biomarker of NASH.Impact and implicationsNon-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), are the most common forms of chronic liver diseases. Currently, liver biopsies are the gold standard for diagnosing NAFLD. Blood-based biomarkers to complement liver biopsies for diagnosis of NAFLD are required. We found that activated hepatic stellate cells, a cell type central to NAFLD pathogenesis, upregulate expression of the secreted protein SPARC-related modular calcium-binding protein 2 (SMOC2). SMOC2 was elevated in blood samples from patients with NASH and may hold promise as a blood-based biomarker for the diagnosis of NAFLD.

Project description:BACKGROUND: The monocyte chemoattractant protein 1 (MCP-1) is involved in the recruitment of lymphocytes and monocytes and their migration to sites of injury and cellular immune reactions. In a Ghanaian tuberculosis (TB) case-control study group, associations of the MCP1 -362C and the MCP1 -2581G alleles with resistance to TB were recently described. The latter association was in contrast to genetic effects previously described in study groups originating from Mexico, Korea, Peru and Zambia. This inconsistency prompted us to further investigate the MCP1 gene in order to determine causal variants or haplotypes genetically and functionally. RESULTS: A 14 base-pair deletion in the first MCP1 intron, int1del554-567, was strongly associated with protection against pulmonary TB (OR=0.84, CI 0.77-0.92, Pcorrected=0.00098). Compared to the wildtype combination, a haplotype comprising the -2581G and -362C promoter variants and the intronic deletion conferred an even stronger protection than did the -362C variant alone (OR=0.78, CI 0.69-0.87, Pnominal=0.00002; adjusted Pglobal=0.0028). In a luciferase reporter gene assay, a significant reduction of luciferase gene expression was observed in the two constructs carrying the MCP1 mutations -2581 A or G plus the combination -362C and int1del554-567 compared to the wildtype haplotype (P=0.02 and P=0.006). The associated variants, in particular the haplotypes composed of these latter variants, result in decreased MCP-1 expression and a decreased risk of pulmonary TB. CONCLUSIONS: In addition to the results of the previous study of the Ghanaian TB case-control sample, we have now identified the haplotype combination -2581G/-362C/int1del554-567 that mediates considerably stronger protection than does the MCP1 -362C allele alone (OR=0.78, CI 0.69-0.87 vs OR=0.83, CI 0.76-0.91). Our findings in both the genetic analysis and the reporter gene study further indicate a largely negligible role of the variant at position -2581 in the Ghanaian population studied.

Dataset Information

Secreted modular calcium-binding protein 2 haplotypes are associated with pulmonary function.

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Secreted modular calcium-binding protein 2 haplotypes are associated with pulmonary function.

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