The expression of keratan sulfate in malignant melanoma enhances the adhesion and invasion activity of melanoma cells.

Mammals express a wide variety of glycans that include N-glycans, O-glycans, proteoglycans, glycolipids, etc. Glycan expression can modulate the cellular functions, and hence is strongly involved in the onset and progression of numerous diseases. Here, we report the relevance of the ectopic expression of keratan sulfate (KS) glycan chains in human malignant melanomas. Using a human melanoma cell line, we found that the KS enhanced the invasiveness of the cells but caused no change in the growth rate of the cells. The phosphorylation of paxillin, a focal adhesion-associated adaptor protein, was strong at the region where KS was expressed in the melanoma tissues, indicating that KS stimulated the phosphorylation of paxillin. We also observed that KS enhanced the adhesion of melanoma cells and this was accompanied by a greatly increased level of phosphorylation of paxillin. These data suggest that the expression of KS contributes to the development of malignant phenotypes such as strong cell adhesion and the invasiveness of melanoma cells.

Urinary proteomics links keratan sulfate degradation and lysosomal enzymes to early type 1 diabetes.

Diabetes is the leading cause of end-stage renal disease worldwide. Our understanding of the early kidney response to chronic hyperglycemia remains incomplete. To address this, we first investigated the urinary proteomes of otherwise healthy youths with and without type 1 diabetes and subsequently examined the enriched pathways that might be dysregulated in early disease using systems biology approaches. This cross-sectional study included two separate cohorts for the discovery (N = 30) and internal validation (N = 30) of differentially excreted proteins. Discovery proteomics was performed on a Q Exactive Plus hybrid quadrupole-orbitrap mass spectrometer. We then searched the pathDIP, KEGG, and Reactome databases to identify enriched pathways in early diabetes; the Integrated Interactions Database to retrieve protein-protein interaction data; and the PubMed database to compare fold changes of our signature proteins with those published in similarly designed studies. Proteins were selected for internal validation based on pathway enrichment and availability of commercial enzyme-linked immunosorbent assay kits. Of the 2451 proteins identified, 576 were quantified in all samples from the discovery cohort; 34 comprised the urinary signature for early diabetes after Benjamini-Hochberg adjustment (Q < 0.05). The top pathways associated with this signature included lysosome, glycosaminoglycan degradation, and innate immune system (Q < 0.01). Notably, all enzymes involved in keratan sulfate degradation were significantly elevated in urines from youths with diabetes (|fold change| > 1.6). Increased urinary excretion of monocyte differentiation antigen CD14, hexosaminidase A, and lumican was also observed in the validation cohort (P < 0.05). Twenty-one proteins from our signature have been reported elsewhere as potential mediators of early diabetes. In this study, we identified a urinary proteomic signature for early type 1 diabetes, of which lysosomal enzymes were major constituents. Our findings highlight novel pathways such as keratan sulfate degradation in the early kidney response to hyperglycemia.

Microenvironment of ruptured cerebral aneurysms discovered using data driven analysis of gene expression.

BACKGROUND: It is well known that ruptured intracranial aneurysms are associated with substantial morbidity and mortality, yet our understanding of the genetic mechanisms of rupture remains poor. We hypothesize that applying novel techniques to the genetic analysis of aneurysmal tissue will yield key rupture-associated mechanisms and novel drug candidates for the prevention of rupture. METHODS: We applied weighted gene co-expression networks (WGCNA) and population-specific gene expression analysis (PSEA) to transcriptomic data from 33 ruptured and unruptured aneurysm domes. Mechanisms were annotated using Gene Ontology, and gene network/population-specific expression levels correlated with rupture state. We then used computational drug repurposing to identify plausible drug candidates for the prevention of aneurysm rupture. RESULTS: Network analysis of bulk tissue identified multiple immune mechanisms to be associated with aneurysm rupture. Targeting these processes with computational drug repurposing revealed multiple candidates for preventing rupture including Btk inhibitors and modulators of hypoxia inducible factor. In the macrophage-specific analysis, we identify rupture-associated mechanisms MHCII antigen processing, cholesterol efflux, and keratan sulfate catabolism. These processes map well onto several of highly ranked drug candidates, providing further validation. CONCLUSIONS: Our results are the first to demonstrate population-specific expression levels and intracranial aneurysm rupture, and propose novel drug candidates based on network-based transcriptomics.

Genetic testing of Mucopolysaccharidoses disease using multiplex PCR- based panels of STR markers: in silico analysis of novel mutations.

The Mucopolysaccharidoses (MPS) are group of inherited metabolic diseases caused by the deficiency of enzymes required to degrade glycosaminoglycans (GAGs) in the lysosomes. GAGs are sulfated polysaccharides involving repeating disaccharides, uronic acid and hexosamines including chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS) and keratan sulfate (KS). Hyaluronan is excluded in terms of being non-sulfated in the GAG family. Different types of mutations have been identified as the causative agent in all types of MPS. Herein, we planned to investigate the pathogenic mutations in different types of MPS including type I (IDUA gene), IIIA (SGSH) and IIIB (NAGLU) in the eight Iranian patients. Autozygosity mapping was performed to identify the potential pathogenic variants in these 8 patients indirectly with the clinical diagnosis of MPSs. so three panels of STR (Short Tandem Repeat) markres flanking IDUA, SGSH and NAGLU genes were selected for multiplex PCR amplification. Then in each family candidate gene was sequenced to identify the pathogenic mutation. Our study showed two novel mutations c.469 T > C and c.903C > G in the IDUA gene, four recurrent mutations: c.1A > C in IDUA, c.220C > T, c.1298G > A in SGSH gene and c.457G > A in the NAGLU gene. The c.1A > C in IDUA was the most common mutation in our study. In silico analysis were performed as well to predict the pathogenicity of the novel variants.

Novel data on growth phenotype and causative genotypes in 29 patients with Morquio (Morquio-Brailsford) syndrome from Central-Eastern Europe.

Mucopolysaccharidosis type IVA, also known as Morquio (Morquio-Brailsford) syndrome results from accumulation of keratan sulfate (KS) and chondroitin-6-sulfate (C6S), whereas the primary cause is mutations in the gene encoding galactosamine (N-acetyl)-6-sulfatase (GALNS). Phenotypically it seems to be a well-defined condition, with two main clinical forms: mild (attenuated) and severe, which are determined based on a combination of symptoms, i.e., enzymatic activity of GALNS, age of onset, and symptom severity. Nevertheless, the natural history of MPSIVA in relation to specific anthropometric parameters (growth, head circumference, body proportions, and face phenotype) is not precisely characterized. The aim of our work was to analyze the aforementioned anthropometric parameters, including correlation to molecular data (causative GALNS mutations).

Asporin-deficient mice have tougher skin and altered skin glycosaminoglycan content and structure.

The main structural component of connective tissues is fibrillar, cross-linked collagen whose fibrillogenesis can be modulated by Small Leucine-Rich Proteins/Proteoglycans (SLRPs). Not all SLRPs' effects on collagen and extracellular matrix in vivo have been elucidated; one of the less investigated SLRPs is asporin. Here we describe the successful generation of an Aspn-/- mouse model and the investigation of the Aspn-/- skin phenotype. Functionally, Aspn-/- mice had an increased skin mechanical toughness, although there were no structural changes present on histology or immunohistochemistry. Electron microscopy analyses showed 7% thinner collagen fibrils in Aspn-/- mice (not statistically significant). Several matrix genes were upregulated, including collagens (Col1a1, Col1a2, Col3a1), matrix metalloproteinases (Mmp2, Mmp3) and lysyl oxidases (Lox, Loxl2), while lysyl hydroxylase (Plod2) was downregulated. Intriguingly no differences were observed in collagen protein content or in collagen cross-linking-related lysine oxidation or hydroxylation. The glycosaminoglycan content and structure in Aspn-/- skin was profoundly altered: chondroitin/dermatan sulfate was more than doubled and had an altered composition, while heparan sulfate was halved and had a decreased sulfation. Also, decorin and biglycan were doubled in Aspn-/- skin. Overall, asporin deficiency changes skin glycosaminoglycan composition, and decorin and biglycan content, which may explain the changes in skin mechanical properties.

[Characteristics of refractive status of mutant Lumican transgenic mice].

OBJECTIVE: To investigate the change of refractive status in transgenic mice with mutant Lumican (bright proteoglycan) gene at different ages. METHODS: Experimental Study. Fifty-four 3-week-old with mutant Lumican gene (cDNA 596T > C) mice (27 male and 27 female) were randomly divided into 9 groups (n = 6, half male and half female) by random number table. One group (3-week-old) was randomly chosen and measured the refractive status by retinoscopy after mydriasis. Measurement of other groups were repeated the method above respectively in the fourth, fifth, sixth, eighth, tenth, twelfth, sixteenth, and twentieth week. Differences of diopter between right and left eye and between male and female were compared within each group by paired t test. The differences of mice's diopters in different age were compared by Kruskal-Wallis H test. Pairwise comparisons were acquired by Mann-Whitney U test. RESULTS: There were no statistic difference of diopters between binoculus: The mice's diopters of right and left eyes were respective measured in the twentieth week (1.50 ± 0.45) D and (1.25 ± 0.42) D (t = -0.889, P > 0.05), The mice's diopters of right and left eyes were respective measured in the third week (-2.50 ± 2.59) D and (-2.50 ± 4.32) D (t = 0.000, P > 0.05); There were no statistic difference of diopters between different genders: The mice's diopters of female and male were respective measured in the third week (-0.5 ± 3.83) D and (-4.17 ± 1.94) D, (t = 2.079, P > 0.05), The mice's diopters of female and male were respective measured in the twelfth week (1.50 ± 0.84) D and (1.50 ± 1.87) D (t = 0.000, P > 0.05); Analysis of binocular diopters revealed significant differences among nine groups (H = 20.910, P < 0.05). Diopters measured in the third week (-2.50 ± 3.40D) and the sixth week (+3.25 ± 2.67) D had statistical difference (Z = -3.259, P < 0.001). There were no statistical significance between other groups (P > 0.001). CONCLUSIONS: Characteristics of diopters gathered from mice with Lumican gene mutation at different weeks are summarized as follows: Myopia could be observed in the third week. And this situation of myopia was gradually transformed into hyperopia with aging. The maximum hyperopic diopter was observed at 6th-week-old mice. From the eighth to twentieth week, the degree of hyperopic diopter gradually decreased and stabilized.

Effect of interleukin-1beta and dehydroepiandrosterone on the expression of lumican and fibromodulin in fibroblast-like synovial cells of the human temporomandibular joint.

Several epidemiological studies have reported that temporomandibular disorders (TMDs) are more prevalent in women than in men. It has recently been proposed that sex hormones such as estrogen, testosterone and dehydroepiandrosterone (DHEA) are involved with the pathogenesis of TMDs. Although studies have investigated the relationship between estrogen and testosterone and the restoration of TMDs, the relationship between DHEA and TMDs is unknown. The synovial tissue of the temporomandibular joint (TMJ) is made up of connective tissue with an extracellular matrix (ECM) composed of collagen and proteoglycan. One proteoglycan family, comprised of small leucine-rich repeat proteoglycans (SLRPs), was found to be involved in collagen fibril formation and interaction. In recent years, the participation of SLRPs such as lumican and fibromodulin in the internal derangement of TMJ has been suggested. Although these SLRPs may contribute to the restoration of the synovium, their effect is still unclear. The purpose of this study was to investigate the effect of DHEA, a sex hormone, on the expression of lumican and fibromodulin in human temporomandibular specimens and in cultured human TMJ fibroblast-like synovial cells in the presence or absence of the pro-inflammatory cytokine interleukin-1beta (IL-1beta). In the in vivo study, both normal and osteoarthritic (OA) human temporomandibular synovial tissues were immunohistochemically examined. In the in vitro study, five fibroblast-like synoviocyte (FLS) cell lines were established from human TMJ synovial tissue of patients with osteoarthritis. The subcultured cells were then incubated for 3, 6, 12 or 24 h with/without IL-1beta (1 ng/mL) in the presence or absence of DHEA (10 µM). The gene expression of lumican and fibromodulin was examined using the real-time polymerase chain reaction (PCR) and their protein expression was examined using immunofluorescent staining. We demonstrated that the expression of lumican significantly differs from that of fibromodulin in synovial tissue in OA and furthermore, that IL-1beta induced a significant increase in lumican mRNA and immunofluorescent staining in FLS compared to cells without IL-1beta. DHEA plus IL-1beta induced a significant increase in fibromodulin, but not in lumican mRNA, compared to DHEA alone, IL-1beta alone and in the absence of DHEA and IL-1beta. In immunofluorescent staining, weaker fibromodulin staining of FLS cells was observed in cells cultured in the absence of both DHEA and IL-1beta compared to fibromodulin staining of cells cultured with DHEA alone, with DHEA plus IL-1beta, or with IL-1beta alone. These results indicate that DHEA may have a protective effect on synovial tissue in TMJ by enhancing fibromodulin formation after IL-1beta induced inflammation. DHEA enhancement of fibromodulin expression may also exert a protective effect against the hyperplasia of fibrous tissue that TGF-beta1 induces. In addition lumican and fibromodulin are differentially expressed under different cell stimulation conditions and lumican and fibromodulin may promote regeneration of the TMJ after degeneration and deformation induced by IL-1beta.

Analysis of disease-associated protein expression using quantitative proteomics­fibulin-5 is expressed in association with hepatic fibrosis.

Hepatic fibrosis and cirrhosis are major health problems worldwide. Until now, highly invasive biopsy remains the diagnostic gold standard despite many disadvantages. To develop noninvasive diagnostic assays for the assessment of liver fibrosis, it is urgently necessary to identify molecules that are robustly expressed in association with the disease. We analyzed biopsied tissue samples from 95 patients with HBV/HCV-associated hepatic fibrosis using three different quantification methods. We performed a label-free proteomics discovery study to identify novel disease-associated proteins using a subset of the cohort (n = 27). Subsequently, gene expression data from all available clinical samples were analyzed (n = 77). Finally, we performed a targeted proteomics approach, multiple reaction monitoring (MRM), to verify the disease-associated expression in samples independent from the discovery approach (n = 68). We identified fibulin-5 (FBLN5) as a novel protein expressed in relation to hepatic fibrosis. Furthermore, we confirmed the altered expression of microfibril-associated glycoprotein 4 (MFAP4), lumican (LUM), and collagen alpha-1(XIV) chain (COL14A1) in association to hepatic fibrosis. To our knowledge, no tissue-based quantitative proteomics study for hepatic fibrosis has been performed using a cohort of comparable size. By this means, we add substantial evidence for the disease-related expression of the proteins examined in this study.

Gene expression profiling of giant cell tumor of bone reveals downregulation of extracellular matrix components decorin and lumican associated with lung metastasis.

Giant cell tumor of bone (GCTB) displays worrisome clinical features such as local recurrence and occasionally metastatic disease which are unpredictable by morphology. Additional routinely usable biomarkers do not exist. Gene expression profiles of six clinically defined groups of GCTB and one group of aneurysmal bone cyst (ABC) were determined by microarray (n = 33). The most promising differentially expressed genes were validated by Q-PCR as potential biomarkers in a larger patient group (n = 41). Corresponding protein expression was confirmed by immunohistochemistry. Unsupervised hierarchical clustering reveals a metastatic GCTB cluster, a heterogeneous, non-metastatic GCTB cluster, and a primary ABC cluster. Balanced score testing indicates that lumican (LUM) and decorin (DCN) are the most promising biomarkers as they have lower level of expression in the metastatic group. Expression of dermatopontin (DPT) was significantly lower in recurrent tumors. Validation of the results was performed by paired and unpaired t test in primary GCTB and corresponding metastases, which proved that the differential expression of LUM and DCN is tumor specific rather than location specific. Our findings show that several genes related to extracellular matrix integrity (LUM, DCN, and DPT) are differentially expressed and may serve as biomarkers for metastatic and recurrent GCTB.

Extracellular lumican inhibits pancreatic cancer cell growth and is associated with prolonged survival after surgery.

PURPOSE: To evaluate the relevance between lumican expression patterns and the clinical course of patients with pancreatic ductal adenocarcinoma (PDAC), and to investigate the role of lumican in PDAC progression. EXPERIMENTAL DESIGN: One hundred thirty-one patient tumors were chosen for tissue microarray staining, and Cox regression analysis was used to test the associations between lumican expression and clinical, pathologic, and oncologic outcomes in all patients. Primary PDAC cells and recombinant human lumican protein were used to establish a working model to mimic the in vivo interactions between stromal lumican and PDAC cells. Using this model, we tested the effects of lumican on EGFR signaling via Akt and hypoxia-inducible factor-1α (HIF1α) and its subsequent influence on glucose consumption, lactate production, intracellular ATP, and apoptotic cell death. RESULTS: Lumican was present in the stroma surrounding PDAC cells in roughly one-half of primary tumors and the direct xenografts. Patients with stromal lumican were associated with a profound reduction in metastatic recurrence after surgery and 3-fold longer survival than patients without stromal lumican. In PDAC cells, extracellular lumican reduced EGFR expression and phosphorylation through enhanced dimerization and internalization of EGFR and the resultant inhibition of Akt kinase activity. Lumican also reduced HIF1α expression and activity via Akt. PDAC cells with enhanced HIF1α activity were resistant to lumican-induced inhibition of glucose consumption, lactate production, intracellular ATP, and apoptosis. CONCLUSIONS: There is a positive association between stromal lumican in primary PDAC tumors and prolonged survival after tumor resection. Lumican plays a restrictive role in EGFR-expressing pancreatic cancer progression.

Altered protein expression profiles in umbilical veins: insights into vascular dysfunctions of the children born after in vitro fertilization.

Cardiovascular dysfunction and remodeling have been found in some children conceived by in vitro fertilization (IVF). However, the underlying mechanisms remain unclear. In this study, the retrospective investigation showed that the blood pressure of IVF-conceived Chinese children was higher than that of naturally conceived (NC) children at ages 3-13 yr. We analyzed the expression profile of proteins in the umbilical veins of IVF and NC newborns by proteomic techniques. Using iTRAQ (isobaric tags for relative and absolute quantitation), 47 differentially expressed proteins (DEPs) were identified by feature selection in IVF umbilical veins compared with NC. Ingenuity Pathway Analysis, which is used to explore the signaling pathways of DEPs, revealed that these DEPs played important roles in vascular system development and carbon metabolism, implying that these DEPs might be potential candidates for further exploration of the mechanism(s) of vascular dysfunction in IVF children. We found that the serum estradiol (E2) level in the cord blood of IVF newborns was significantly higher than that of NC newborns. High concentrations of E2 induced alteration of lumican and vimentin expression in human umbilical vein endothelial cells, which was consistent with the proteomic results. These findings suggested that abnormal expression of proteins in umbilical veins might be related to the cardiovascular dysfunction and remodeling in IVF offspring. In conclusion, our data for the first time reveal the protein expression profile in blood vessels of IVF offspring and provide information for further mechanism study and evaluation of risks of cardiovascular abnormality in IVF children.

Lack of association between LUM rs3759223 polymorphism and high myopia.

PURPOSE: Previous evidence has indicated that the lumican (LUM) gene is a candidate susceptibility gene of high myopia; however, the association between LUM promoter regions rs3759223 polymorphism and high myopia remains controversial and ambiguous. This study performed a meta-analysis to clarify the association between the rs3759223 polymorphism and high myopia risk. METHODS: Eligible studies were identified by comprehensive search of PubMed, EMBASE, Web of Science, and Chinese Biomedical Literature database. The crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the rs3759223 polymorphism and high myopia susceptibility. Meta-regression and subgroup analyses were performed to identify the source of heterogeneity. RESULTS: Finally, six studies including 1238 cases and 1059 healthy controls were included. Meta-analyses showed no association between rs3759223 polymorphism and high myopia susceptibility in all genetic models (CC vs. TT, OR = 1.089; 95% CI, 0.690 to 1.718; CT vs. TT, OR = 0.865; 95% CI, 0.646 to 1.157; CC + CT vs. TT, OR = 1.202; 95% CI, 0.730 to 1.980; CC vs. CT + TT, OR = 0.914; 95% CI, 0.771 to 1.083) and no significance in subgroup analyses according to the definition of high myopia (based on more myopic than -6.00 diopters vs. not based on more myopic than -6.00 diopters). Publication bias was not evident in this study. CONCLUSIONS: This meta-analysis has suggested that there is a lack of association of the rs3759223 polymorphism with high myopia risk. However, further large and well-designed studies with the consideration of LUM gene locus interactions and gene-gene and gene-environment interactions are still required to further evaluate high myopia risk.

Meta-analysis of the association between lumican gene polymorphisms and susceptibility to high Myopia.

BACKGROUNDS: Many studies have evaluated the association between lumican (LUM) gene polymorphisms and high myopia. However, the results remain controversial. This meta-analysis aims to comprehensively evaluate the relationship between two common LUM polymorphisms (rs3759223 and rs3759222) and the risk of high myopia. METHODS: A comprehensive literature search for studies published up until September of 2013 was performed. Data were extracted independently by two investigators, and the weighted Odds Ratios (ORs) and 95% Confidence Intervals (CIs) for the associations were obtained by using a random-effects model. RESULTS: Eight studies (1425cases and 1271 controls) were identified for the analysis of the association between rs3759223 polymorphism and high myopia. The results indicated that rs3759223 polymorphism was associated with high myopia under a recessive model (OR = 1.71, 95%CI 1.04-2.81). Further subgroup analysis indicated that this polymorphism was associated with high myopia among Chinese people in the additive model (OR = 1.17, 95%CI 1.06-1.29) and a recessive model (OR = 1.75, 95%CI 1.00-3.06) with control group coming from hospital based population. Four studies (1024 cases and 1163 controls) were identified for the analysis of the association between rs3759222 polymorphism and high myopia. The results indicated that rs3759222 polymorphism was not associated with high myopia in all genetic models, even the subgroup analysis couldn't provide relative proof to assure the outcome. CONCLUSION: This meta-analysis suggests that LUM polymorphisms are associated with the risk of high myopia. However, well-designed studies with larger sample sizes and more ethnic groups are required to further validate this association.

[Establishment of a mutant Lumican transgenic mouse model].

OBJECTIVE: Pathological myopia (PM) is a hereditary ocular disease leading to severe loss of visual acuity and blindness. Lumican gene (LUM) is one of those candidate genes of PM. The purpose of this study was to establish a mutant Lumican transgenic mouse model, and to prepare for the further study of the pathogenesis of PM. METHODS: Experimental study. Mutation of LUM gene was created by site-directed mutagenesis. Recombinant DNA techniques were used for the construction of the pRP. EX3d-EF1A>LUM/flag>IRES/hrGFP transgene. The gene fragments were microinjected into the zygote male pronuclei of BDF1 mice, and then the zygote cells alive were transplanted into the oviduct of acceptor pregnant female ICR mice. The F0 generation transgenic mice obtained were named C57-TgN (LUM)CCMU. Genome DNA from mice tail was detected by PCR and Western blotting. RESULTS: Six of 31 F0 generation mice were positive transgenic mice. The western blotting study showed that the flag-tag was expressed in the mouse tail tissue. Sixty-eight of 128 mice (F1 to F3 generation) were positive transgenic mice, the positive rate is 53.13%. CONCLUSIONS: The mutant Lumican (cDNA 596T>C) transgenic mouse model has been established. This model will provide fundamental conditions for studies of the pathogenesis of PM. Also it will be the basis of further studies about the effect of Lumican mutation on the development of PM and structure and function of the extra cellular matrix.

Posterior amorphous corneal dystrophy is associated with a deletion of small leucine-rich proteoglycans on chromosome 12.

Posterior amorphous corneal dystrophy (PACD) is a rare, autosomal dominant disorder affecting the cornea and iris. Next-generation sequencing of the previously identified PACD linkage interval on chromosome 12q21.33 failed to yield a pathogenic mutation. However, array-based copy number analysis and qPCR were used to detect a hemizygous deletion in the PACD linkage interval containing 4 genes encoding small leucine-rich proteoglycans (SLRPs): KERA, LUM, DCN, and EPYC. Two other unrelated families with PACD also demonstrated deletion of these SLRPs, which play important roles in collagen fibrillogenesis and matrix assembly. Given that these genes are essential to the maintenance of corneal clarity and the observation that knockout murine models display corneal phenotypic similarities to PACD, we provide convincing evidence that PACD is associated with haploinsufficiency of these SLRPs.

Association between a lumican promoter polymorphism and high myopia in the Chinese population: a meta-analysis of case-control studies.

PURPOSE: To evaluate the relationship between lumican polymorphisms and high myopia in Chinese populations. METHODS: An electronic search was conducted in Pubmed, Embase, Cochrane Library and the China Biological Medicine Database for articles published prior to September 30, 2012. A meta-analysis was performed to assess heterogeneity, combine results and determine publication bias. RESULTS: This meta-analysis, including 1,545 subjects from 5 studies, indicated that Chinese lumican rs3759223 C allele carriers had a decreased risk of high myopia in comparison to T allele carriers (odds ratio: 0.531; 95% confidence interval, CI: 0.304-0.925; p = 0.025). There was some heterogeneity between studies. A metaregression showed that the mean axial length of controls weakens the effect of rs3759223 on high myopia (slope: -0.914; 95% CI: -1.490 to 0.337; p = 0.002). Sensitivity analysis confirmed the reliability and stability of this meta-analysis. CONCLUSION: Chinese lumican rs3759223 C allele carriers may be at reduced risk of high myopia.

Genes encoding proteoglycans are associated with the risk of anterior cruciate ligament ruptures.

BACKGROUND: Genetic variants within genes involved in fibrillogenesis have previously been implicated in anterior cruciate ligament (ACL) injury susceptibility. Proteoglycans also have important functions in fibrillogenesis and maintaining the structural integrity of ligaments. Genes encoding proteoglycans are plausible candidates to be investigated for associations with ACL injury susceptibility; polymorphisms within genes encoding the proteoglycans aggrecan (ACAN), biglycan (BGN), decorin (DCN), fibromodulin (FMOD) and lumican (LUM) were examined. METHODS: A case-control genetic association study was conducted. 227 participants with surgically diagnosed ACL ruptures (ACL group) and 234 controls without any history of ACL injury were genotyped for 10 polymorphisms in 5 proteoglycan genes. Inferred haplotypes were constructed for specific regions. RESULTS: The G allele of ACAN rs1516797 was significantly under-represented in the controls (p=0.024; OR=0.72; 95% CI 0.55 to 0.96) compared with the ACL group. For DCN rs516115, the GG genotype was significantly over-represented in female controls (p=0.015; OR=9.231; 95%CI 1.16 to 73.01) compared with the ACL group and the AA genotype was significantly under-represented in controls (p=0.013; OR=0.33; 95% CI 0.14 to 0.78) compared with the female non-contact ACL injury subgroup. Haplotype analyses implicated regions overlapping ACAN (rs2351491 C>T-rs1042631 T>C-rs1516797 T>G), BGN (rs1126499 C>T-rs1042103 G>A) and LUM-DCN (rs2268578 T>C-rs13312816 A>T-rs516115 A>G) in ACL injury susceptibility. CONCLUSIONS: These independent associations and haplotype analyses suggest that regions within ACAN, BGN, DCN and a region spanning LUM-DCN are associated with ACL injury susceptibility. Taking into account the functions of these genes, it is reasonable to propose that genetic sequence variability within the genes encoding proteoglycans may potentially modulate the ligament fibril properties.