Prediction of transformation in the histopathological growth pattern of colorectal liver metastases after chemotherapy using CT-based radiomics.

Chemotherapy alters the prognostic biomarker histopathological growth pattern (HGP) phenotype in colorectal liver metastases (CRLMs) patients. We aimed to develop a CT-based radiomics model to predict the transformation of the HGP phenotype after chemotherapy. This study included 181 patients with 298 CRLMs who underwent preoperative contrast-enhanced CT followed by partial hepatectomy between January 2007 and July 2022 at two institutions. HGPs were categorized as pure desmoplastic HGP (pdHGP) or non-pdHGP. The samples were allocated to training, internal validation, and external validation cohorts comprising 153, 65, and 29 CRLMs, respectively. Radiomics analysis was performed on pre-enhanced, arterial phase, portal venous phase (PVP), and fused images. The model was used to predict prechemotherapy HGPs in 112 CRLMs, and HGP transformation was analysed by comparing these findings with postchemotherapy HGPs determined pathologically. The prevalence of pdHGP was 19.8% (23/116) and 45.8% (70/153) in chemonaïve and postchemotherapy patients, respectively (P < 0.001). The PVP radiomics signature showed good performance in distinguishing pdHGP from non-pdHGPs (AUCs of 0.906, 0.877, and 0.805 in the training, internal validation, and external validation cohorts, respectively). The prevalence of prechemotherapy pdHGP predicted by the radiomics model was 33.0% (37/112), and the prevalence of postchemotherapy pdHGP according to the pathological analysis was 47.3% (53/112; P = 0.029). The transformation of HGP was bidirectional, with 15.2% (17/112) of CRLMs transforming from prechemotherapy pdHGP to postchemotherapy non-pdHGP and 30.4% (34/112) transforming from prechemotherapy non-pdHGP to postchemotherapy pdHGP (P = 0.005). CT-based radiomics method can be used to effectively predict the HGP transformation in chemotherapy-treated CRLM patients, thereby providing a basis for treatment decisions.

Risk stratification for 1- to 2-cm gastric gastrointestinal stromal tumors: visual assessment of CT and EUS high-risk features versus CT radiomics analysis.

OBJECTIVES: To investigate the ability of CT and endoscopic sonography (EUS) in predicting the malignant risk of 1-2-cm gastric gastrointestinal stromal tumors (gGISTs) and to clarify whether radiomics could be applied for risk stratification. METHODS: A total of 151 pathologically confirmed 1-2-cm gGISTs from seven institutions were identified by contrast-enhanced CT scans between January 2010 and March 2021. A detailed description of EUS morphological features was available for 73 gGISTs. The association between EUS or CT high-risk features and pathological malignant potential was evaluated. gGISTs were randomly divided into three groups to build the radiomics model, including 74 in the training cohort, 37 in validation cohort, and 40 in testing cohort. The ROIs covering the whole tumor volume were delineated on the CT images of the portal venous phase. The Pearson test and least absolute shrinkage and selection operator (LASSO) algorithm were used for feature selection, and the ROC curves were used to evaluate the model performance. RESULTS: The presence of EUS- and CT-based morphological high-risk features, including calcification, necrosis, intratumoral heterogeneity, irregular border, or surface ulceration, did not differ between very-low and intermediate risk 1-2-cm gGISTs (p > 0.05). The radiomics model consisting of five radiomics features showed favorable performance in discrimination of malignant 1-2-cm gGISTs, with the AUC of the training, validation, and testing cohort as 0.866, 0.812, and 0.766, respectively. CONCLUSIONS: Instead of CT- and EUS-based morphological high-risk features, the CT radiomics model could potentially be applied for preoperative risk stratification of 1-2-cm gGISTs. KEY POINTS: • The presence of EUS- and CT-based morphological high-risk factors, including calcification, necrosis, intratumoral heterogeneity, irregular border, or surface ulceration, did not correlate with the pathological malignant potential of 1-2-cm gGISTs. • The CT radiomics model could potentially be applied for preoperative risk stratification of 1-2-cm gGISTs.

Detecting and monitoring tumors in orthotopic colorectal liver metastatic animal models with high-resolution ultrasound.

The ability to noninvasively detect and monitor the growth of orthotopic liver transplantation tumors is critical for replicating advanced colorectal cancer liver metastases (CRLMs) in animal models. We assessed the use of high-resolution ultrasound (HRU) to monitor CRLMs transplanted using various cell concentrations. Sixty BALB/c female mice were randomly divided into 3 groups, and murine colonic CT26 cells were injected into the left liver lobe at concentrations of 1 × 102 (group 1), 1 × 103 (group 2), or 1 × 104 (group 3). Tumor presentation, location, number, size, shape, and echogenicity were assessed daily with 24-MHz center frequency HRU starting 6 days after injection. Animals were sacrificed when the largest tumor was ≥ 1 cm in diameter. Sensitivity, specificity, and area under curve (AUC) of CRLMs diagnosed with HRU were calculated using receiver operating characteristic curve analysis. In group 1, 94% of mice formed < 5 tumors, and 41% formed a single tumor. Tumors were first detected with HRU on day 12 in group 1, day 10 in group 2, and day 7 in group 3; tumor volume doubling times were 14-15 days, 11-12 days, and 7-8 days, respectively. With a long diameter threshold of 2.4 mm, diagnostic sensitivity and specificity of HRU were 94.1% and 88.7%, respectively, and the AUC was 0.962. These findings suggest that HRU can be used to accurately detect and monitor the growth of CRLMs in an orthotopic transplantation mouse model, especially when a lower concentration of cells is used.

MG53 suppresses tumor progression and stress granule formation by modulating G3BP2 activity in non-small cell lung cancer.

BACKGROUND: Cancer cells develop resistance to chemotherapeutic intervention by excessive formation of stress granules (SGs), which are modulated by an oncogenic protein G3BP2. Selective control of G3BP2/SG signaling is a potential means to treat non-small cell lung cancer (NSCLC). METHODS: Co-immunoprecipitation was conducted to identify the interaction of MG53 and G3BP2. Immunohistochemistry and live cell imaging were performed to visualize the subcellular expression or co-localization. We used shRNA to knock-down the expression MG53 or G3BP2 to test the cell migration and colony formation. The expression level of MG53 and G3BP2 in human NSCLC tissues was tested by western blot analysis. The ATO-induced oxidative stress model was used to examine the effect of rhMG53 on SG formation. Moue NSCLC allograft experiments were performed on wild type and transgenic mice with either knockout of MG53, or overexpression of MG53. Human NSCLC xenograft model in mice was used to evaluate the effect of MG53 overexpression on tumorigenesis. RESULTS: We show that MG53, a member of the TRIM protein family (TRIM72), modulates G3BP2 activity to control lung cancer progression. Loss of MG53 results in the progressive development of lung cancer in mg53-/- mice. Transgenic mice with sustained elevation of MG53 in the bloodstream demonstrate reduced tumor growth following allograft transplantation of mouse NSCLC cells. Biochemical assay reveals physical interaction between G3BP2 and MG53 through the TRIM domain of MG53. Knockdown of MG53 enhances proliferation and migration of NSCLC cells, whereas reduced tumorigenicity is seen in NSCLC cells with knockdown of G3BP2 expression. The recombinant human MG53 (rhMG53) protein can enter the NSCLC cells to induce nuclear translation of G3BP2 and block arsenic trioxide-induced SG formation. The anti-proliferative effect of rhMG53 on NSCLC cells was abolished with knockout of G3BP2. rhMG53 can enhance sensitivity of NSCLC cells to undergo cell death upon treatment with cisplatin. Tailored induction of MG53 expression in NSCLC cells suppresses lung cancer growth via reduced SG formation in a xenograft model. CONCLUSION: Overall, these findings support the notion that MG53 functions as a tumor suppressor by targeting G3BP2/SG activity in NSCLCs.

CT-detected extramural venous invasion-related gene signature for the overall survival prediction in patients with gastric cancer.

BACKGROUND: Computed tomography (CT)-detected extramural venous invasion (EMVI) has been identified as an independent factor that can be used for risk stratification and prediction of prognosis in patients with gastric cancer (GC). Overall survival (OS) is identified as the most important prognostic indicator for GC patients. However, the molecular mechanism of EMVI development and its potential relationship with OS in GC are not fully understood. In this radiogenomics-based study, we sought to investigate the molecular mechanism underlying CT-detected EMVI in patients with GC, and aimed to construct a genomic signature based on EMVI-related genes with the goal of using this signature to predict the OS. MATERIALS AND METHODS: Whole mRNA genome sequencing of frozen tumor samples from 13 locally advanced GC patients was performed to identify EMVI-related genes. EMVI-prognostic hub genes were selected based on overlapping EMVI-related differentially expressed genes and OS-related genes, using a training cohort of 176 GC patients who were included in The Cancer Genome Atlas database. Another 174 GC patients from this database comprised the external validation cohort. A risk stratification model using a seven-gene signature was constructed through the use of a least absolute shrinkage and selection operator Cox regression model. RESULTS: Patients with high risk score showed significantly reduced OS (training cohort, p = 1.143e-04; validation cohort, p = 2.429e-02). Risk score was an independent predictor of OS in multivariate Cox regression analyses (training cohort, HR = 2.758; 95% CI: 1.825-4.169; validation cohort, HR = 2.173; 95% CI: 1.347-3.505; p < 0.001 for both). Gene functions/pathways of the seven-gene signature mainly included cell proliferation, cell adhesion, regulation of metal ion transport, and epithelial to mesenchymal transition. CONCLUSIONS: A CT-detected EMVI-related gene model could be used to predict the prognosis in GC patients, potentially providing clinicians with additional information regarding appropriate therapeutic strategy and medical decision-making.

Radiomics diagnosed histopathological growth pattern in prediction of response and 1-year progression free survival for colorectal liver metastases patients treated with bevacizumab containing chemotherapy.

OBJECTIVE: To investigate the capability of a radiomics model, which was designed to identify histopathologic growth pattern (HGP) of colorectal liver metastases (CRLMs) based on contrast-enhanced multidetector computed tomography (ceMDCT), to predict early response and 1-year progression free survival (PFS) in patients treated with bevacizumab-containing chemotherapy. METHODS: Patients with unresectable CRLMs who were treated with bevacizumab-containing chemotherapy were included in this multicenter retrospective study. For each target lesion, the radiomics-diagnosed HGP (RAD_HGP) of desmoplastic (D) pattern or replacement (R) pattern was determined. Logistic regression and receiver operating characteristic (ROC) curves were used to assess lesion- and patient-based responses according to morphologic response criteria. One-year PFS was calculated using Kaplan-Meier curves. Hazard ratios for 1-year PFS were obtained through Cox proportional hazard regression analysis. RESULTS: Among 119 study patients, 206 D pattern and 140 R pattern lesions were identified. In patients with multiple lesions, 52 had D pattern, 31 had R pattern, and 36 had mixed (D + R) pattern. The area under the curve value for RAD_HGP in predicting early response was 0.707 for lesion-based analysis and 0.720 for patient-based analysis. Patients with D pattern had a significantly longer PFS than patients with R pattern or mixed pattern (P < 0.001). RAD_HGP was the only independent predictor of 1-year PFS. CONCLUSIONS: HGP diagnosed using a radiomics model could be used as an effective predictor of PFS for patients with CRLMs treated with bevacizumab-containing chemotherapy.

Risk stratification in GIST: shape quantification with CT is a predictive factor.

BACKGROUND: Tumor shape is strongly associated with some tumor's genomic subtypes and patient outcomes. Our purpose is to find the relationship between risk stratification and the shape of GISTs. METHODS: A total of 101 patients with primary GISTs were confirmed by pathology and immunohistochemistry and underwent enhanced CT examination. All lesions' pathologic sizes were 1 to 10 cm. Points A and B were the extremities of the longest diameter (LD) of the tumor and points C and D the extremities of the small axis, which was the longest diameter perpendicular to AB. The four angles of the quadrangle ABCD were measured and each angle named by its summit (A, B, C, D). For regular lesions, we took angles A and B as big angle (BiA) and small angle (SmA). For irregular lesions, we compared A/B ratio and D/C ratio and selected the larger ratio for analysis. The chi-square test, t test, ROC analysis, and hierarchical or binary logistic regression analysis were used to analyze the data. RESULTS: The BiA/SmA ratio was an independent predictor for risk level of GISTs (p = 0.019). With threshold of BiA at 90.5°, BiA/SmA ratio at 1.35 and LD at 6.15 cm, the sensitivities for high-risk GISTs were 82.4%, 85.3%, and 83.8%, respectively; the specificities were 87.1%, 71%, and 77.4%, respectively; and the AUCs were 0.852, 0.818, and 0.844, respectively. LD could not effectively distinguish between intermediate-risk and high-risk GISTs, but BiA could (p < 0.05). Shape and Ki-67 were independent predictors of the mitotic value (p = 0.036 and p < 0.001, respectively), and the accuracy was 87.8%. CONCLUSIONS: Quantifying tumor shape has better predictive efficacy than LD in predicting the risk level and mitotic value of GISTs, especially for high-risk grading and mitotic value > 5/50HPF. KEY POINTS: • The BiA/SmA ratio was an independent predictor affecting the risk level of GISTs. LD could not effectively distinguish between intermediate-risk and high-risk GISTs, but BiA could. • Shape and Ki-67 were independent predictors of the mitotic value. • The method for quantifying the tumor shape has better predictive efficacy than LD in predicting the risk level and mitotic value of GISTs.

USP7-mediated deubiquitination differentially regulates CSB but not UVSSA upon UV radiation-induced DNA damage.

Cockayne syndrome group B (CSB) protein participates in transcription-coupled nucleotide excision repair. The stability of CSB is known to be regulated by ubiquitin-specific protease 7 (USP7). Yet, whether USP7 acts as a deubiquitinating enzyme for CSB is not clear. Here, we demonstrate that USP7 deubiquitinates CSB to maintain its levels after ultraviolet (UV)-induced DNA damage. While both CSB and UV-stimulated scaffold protein A (UVSSA) exhibit a biphasic decrease and recovery upon UV irradiation, only CSB recovery depends on USP7, which physically interacts with and deubiquitinates CSB. Meanwhile, CSB overexpression stabilizes UVSSA, but decrease UVSSA's presence in nuclease-releasable/soluble chromatin, and increase the presence of ubiquitinated UVSSA in insoluble chromatin alongside CSB-ubiquitin conjugates. Remarkably, CSB overexpression also decreases CSB association with USP7 and UVSSA in soluble chromatin. UVSSA exists in several ubiquitinated forms, of which mono-ubiquitinated form and other ubiquitinated UVSSA forms are detectable upon 6xHistidine tag-based purification. The ubiquitinated UVSSA forms, however, are not cleavable by USP7 in vitro. Furthermore, USP7 disruption does not affect RNA synthesis but decreases the recovery of RNA synthesis following UV exposure. These results reveal a role of USP7 as a CSB deubiquitinating enzyme for fine-tuning the process of TC-NER in human cells.

Malignant jejunal gastrointestinal stromal tumor with history of prostate cancer: A case report.

RATIONALE: The problem of the coexistence of gastrointestinal stromal tumor (GIST) with other neoplasms is complex, and carcinomas of prostate is one of the common types of GIST-associated cancers. Doubling time of GIST is about 3.9 months for high-risk GIST, and the treatment paradigm for GIST has required the integration of surgery and molecular therapy. PATIENT CONCERNS: A 70-year-old man with postoperative history of prostate cancer experienced fast-growing malignant jejunal GIST with multiple peritoneal metastases within 1 year. DIAGNOSES: Enhanced computed tomography (CT) detected a neoplasm of small intestine with multiple peritoneal nodules and postoperative pathology confirmed GIST. INTERVENTIONS: Oral imatinib after surgery, at 400 mg per day, was used for 4 years. OUTCOMES: The patient remains well, and the peritoneal nodules located in front of the rectum disappeared gradually. LESSONS: Physicians should be aware of possibility of GIST in patients with prostate cancer and can perform abdominal examination in these patients. For postoperative patients with prostate cancer, an yearly or half-yearly abdominal and pelvic cavity examination can be performed. Suspicion and timely work-up is necessary in these postoperative prostate cancer patients, especially when they have abdominopelvic pain.

Sonic Hedgehog Signaling Regulates Hematopoietic Stem/Progenitor Cell Activation during the Granulopoietic Response to Systemic Bacterial Infection.

Activation and reprogramming of hematopoietic stem/progenitor cells play a critical role in the granulopoietic response to bacterial infection. Our current study determined the significance of Sonic hedgehog (SHH) signaling in the regulation of hematopoietic precursor cell activity during the host defense response to systemic bacterial infection. Bacteremia was induced in male Balb/c mice via intravenous injection (i.v.) of Escherichia coli (5 × 107 CFUs/mouse). Control mice received i.v. saline. SHH protein level in bone marrow cell (BMC) lysates was markedly increased at both 24 and 48 h of bacteremia. By contrast, the amount of soluble SHH ligand in marrow elutes was significantly reduced. These contrasting alterations suggested that SHH ligand release from BMCs was reduced and/or binding of soluble SHH ligand to BMCs was enhanced. At both 12 and 24 h of bacteremia, SHH mRNA expression by BMCs was significantly upregulated. This upregulation of SHH mRNA expression was followed by a marked increase in SHH protein expression in BMCs. Activation of the ERK1/2-SP1 pathway was involved in mediating the upregulation of SHH gene expression. The major cell type showing the enhancement of SHH expression in the bone marrow was lineage positive cells. Gli1 positioned downstream of the SHH receptor activation serves as a key component of the hedgehog (HH) pathway. Primitive hematopoietic precursor cells exhibited the highest level of baseline Gli1 expression, suggesting that they were active cells responding to SHH ligand stimulation. Along with the increased expression of SHH in the bone marrow, expression of Gli1 by marrow cells was significantly upregulated at both mRNA and protein levels following bacteremia. This enhancement of Gli1 expression was correlated with activation of hematopoietic stem/progenitor cell proliferation. Mice with Gli1 gene deletion showed attenuation in activation of marrow hematopoietic stem/progenitor cell proliferation and inhibition of increase in blood granulocytes following bacteremia. Our results indicate that SHH signaling is critically important in the regulation of hematopoietic stem/progenitor cell activation and reprogramming during the granulopoietic response to serious bacterial infection.

Human CRL4DDB2 ubiquitin ligase preferentially regulates post-repair chromatin restoration of H3K56Ac through recruitment of histone chaperon CAF-1.

Acetylated histone H3 lysine 56 (H3K56Ac) diminishes in response to DNA damage but is restored following DNA repair. Here, we report that CRL4DDB2 ubiquitin ligase preferentially regulates post-repair chromatin restoration of H3K56Ac through recruitment of histone chaperon CAF-1. We show that H3K56Ac accumulates at DNA damage sites. The restoration of H3K56Ac but not H3K27Ac, H3K18Ac and H3K14Ac depends on CAF-1 function, whereas all these acetylations are mediated by CBP/p300. The CRL4DDB2 components, DDB1, DDB2 and CUL4A, are also required for maintaining the H3K56Ac and H3K9Ac level in chromatin, and for restoring H3K56Ac following induction of DNA photolesions and strand breaks. Depletion of CUL4A decreases the recruitment of CAF-1 p60 and p150 to ultraviolet radiation- and phleomycin-induced DNA damage. Neddylation inhibition renders CRL4DDB2 inactive, decreases H3K56Ac level, diminishes CAF-1 recruitment and prevents H3K56Ac restoration. Mutation in the PIP box of DDB2 compromises its capability to elevate the H3K56Ac level but does not affect XPC ubiquitination. These results demonstrated a function of CRL4DDB2 in differential regulation of histone acetylation in response to DNA damage, suggesting a novel role of CRL4DDB2 in repair-driven chromatin assembly.

Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis.

Disseminated superficial actinic porokeratosis (DSAP) is an autosomal dominantly inherited epidermal keratinization disorder whose etiology remains unclear. We performed exome sequencing in one unaffected and two affected individuals from a DSAP family. The mevalonate kinase gene (MVK) emerged as the only candidate gene located in previously defined linkage regions after filtering against existing SNP databases, eight HapMap exomes and 1000 Genomes Project data and taking into consideration the functional implications of the mutations. Sanger sequencing in 57 individuals with familial DSAP and 25 individuals with sporadic DSAP identified MVK mutations in 33% and 16% of these individuals (cases), respectively. All 14 MVK mutations identified in our study were absent in 676 individuals without DSAP. Our functional studies in cultured primary keratinocytes suggest that MVK has a role in regulating calcium-induced keratinocyte differentiation and could protect keratinocytes from apoptosis induced by type A ultraviolet radiation. Our results should help advance the understanding of DSAP pathogenesis.

Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models.

Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer's disease (AD). Amyloid beta-protein (Abeta), the central component of neuritic plaques, is derived from beta-amyloid precursor protein (APP) after beta- and gamma-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epilepsy and bipolar disorder. We found that VPA decreased Abeta production by inhibiting GSK-3beta-mediated gamma-secretase cleavage of APP both in vitro and in vivo. VPA treatment significantly reduced neuritic plaque formation and improved memory deficits in transgenic AD model mice. We also found that early application of VPA was important for alleviating memory deficits of AD model mice. Our study suggests that VPA may be beneficial in the prevention and treatment of AD.

A novel locus for disseminated superficial porokeratosis maps to chromosome 18p11.3.

Disseminated superficial porokeratosis (DSP) is a rare autosomal dominant epidermal keratinization disorder of lesions characterized by cornoid lamella with parakeratosis, hyperkeratosis, and loss of granular layers. The genetic basis for this disease is unknown. Through a proband with a diagnosis of DSP, we identified a large four-generation Chinese family with multiple DSP-affected members from Anhui province in China. After excluding the linkage of the disease phenotype to two known loci for disseminated superficial actinic porokeratosis in this family, we performed a genome-wide linkage analysis using 387 microsatellite markers and identified a novel disease locus for DSP at 18p11.3. Our subsequent fine mapping and haplotype analyses further narrowed down the disease locus into an 18.7 cM region between the telomere and D18S391 with a maximum two-point LOD (logarithm of the odds) score of 4.82 (theta =0.00) at D18S1138. Therefore, this study provides strong linkage evidence for a DSP locus at 18p11.3.

Association between alcohol, smoking and HLA-DQA1*0201 genotype in psoriasis.

Psoriasis is a chronic skin disease triggered by genetic, environment or other risk factors such as infection, drugs, stress, moisture, alcohol, and smoking. A major psoriasis susceptibility locus at 6p21.3 has been identified. Further studies found that HLA-DQA1*0201 allele was associated with psoriasis. However, there were few data exploring an association between the environmental factors and susceptibility genes. In this study, the samples of 189 patients with psoriasis and 333 healthy controls were collected with their consent and were carried on analysis through polymerase chain reaction sequence-specific primer (PCR-SSP) method. The proportion of male psoriasis patients engaging in the smoking and alcohol was much higher than that of the control group (P<0.005). The HLA-DQA1*0201 allele was present at significantly higher frequency in the patients with psoriasis (OR=4.25, P<1.0 x 10(-6)). Association was found between smoking, alcohol and HLA-DQA1*0201 in male patients with psoriasis (OR>6.91, P<1.0 x 10(-4)).

Identification of a locus for punctate palmoplantar keratodermas at chromosome 8q24.13-8q24.21.

Punctate palmoplantar keratodermas (PPK) is a rare autosomal dominant cutaneous disorder characterized by numerous hyperkeratotic papules that are irregularly distributed on the palms and soles. The genetic basis for this disease is unknown. We performed a genome-wide search in two Chinese families with punctate PPK to map the chromosome location of the responsible gene. We identified a locus at chromosome 8q24.13-8q24.21 with a cumulative maximum two-point LOD score of 5.41 at markers D8S1793 and D8S1774 (at recombination fraction theta=0.00). Haplotype analysis indicated that the disease gene is located within 9.20 cM region between markers D8S1804 and D8S1720. It is the first locus identified for the punctate PPK. This study provides a map location for isolation of a disease gene-causing punctate PPK.

HLA-DQA1 and DQB1 alleles are associated with genetic susceptibility to psoriasis vulgaris in Chinese Han.

BACKGROUND: Psoriasis vulgaris is a chronic skin disorder characterized by infiltration of inflammatory elements, keratinocyte hyperproliferation and altered differentiation. Although the pathogenesis of psoriasis is not fully understood, there is solid evidence of a susceptibility locus in the human leukocyte antigen (HLA) region. OBJECTIVES: To investigate whether HLA-DQA1 and DQB1 alleles are associated with genetic susceptibility to psoriasis vulgaris in Chinese Han. PATIENTS AND METHODS: The polymerase chain reaction-sequence-specific primer (PCR-SSP) method was used to analyse the distribution of HLA-DQA1 and DQB1 alleles in 189 patients with psoriasis and 273 healthy controls. RESULTS: The HLA-DQA1*0104 (OR = 2.33, P = 0.0001154, Pc = 2.0 x 10-3), DQA1*0201 (OR = 3.36, P < 1.0 x 10-7, Pc < 1.0 x 10-6), DQB1*0201 (OR = 1.64, P = 0.0192, Pc > 0.05) and DQB1*0303 (OR = 1.55, P = 0.0377, Pc > 0.05) alleles were more prevalent in patients with psoriasis vulgaris than in controls, and HLA-DQA1*0501 (OR = 0.30, P = 0.0000039, Pc < 4.0 x 10-5) alleles were less prevalent. The HLA-DQA1*0104 (OR = 2.42, P = 0.0001159, Pc < 2.0 x 10-3), DQA1*0201 (OR = 3.74, P < 1.0 x 10-7, Pc < 1.0 x 10-6) and DQA1*0501 (OR = 0.30, P = 0.0000374, Pc < 4.0 x 10-4) alleles were only associated with type I psoriasis. HLA-DQA1*0104 and DQA1*0201 were more prevalent in patients with or without a family history of psoriasis. However, the DQA1*0501 allele was only more prevalent in patients without a family history of psoriasis. CONCLUSION: HLA-DQA1*0104 and DQA1*0201 alleles may be psoriasis susceptibility genes or may be in close linkage with the susceptibility genes. The HLA-DQA1*0501 allele seems to have a protective effect against the development of psoriasis vulgaris in Chinese Han. There may be a difference in genetic background between psoriasis patients with and without a family history of psoriasis.

Association of HLA class I alleles with psoriasis vulgaris in southeastern Chinese Hans.

BACKGROUND: Predisposing genetic factors in psoriasis include associations with human leukocyte antigen (HLA). Accumulative evidence has shown that certain HLA at class I locus, especially HLA-Cw6, are associated closely with psoriasis. OBJECTIVE: To evaluate the association of HLA class I alleles with susceptibility to psoriasis in the southeastern Chinese Han population. METHODS: We performed genotype for HLA-A, -B and -C loci in 166 patients with psoriasis vulgaris by means of polymerase chain reaction with sequence-specific primers technique. The distribution of HLA allelic frequencies was further analyzed according to age of onset, i.e. under 35-y and beyond 35-y groups. These data were compared with the healthy controls of 204 unrelated Hans. RESULTS: The frequencies of HLA-A*26 (24.7% vs. 13.1%, OR=2.36, Pc<0.01), -B*13 (27.2% vs. 14.8%, OR=2.34, Pc<0.01), -B*27 (12.2% vs. 4.0%, OR=3.49, Pc<0.01) and -Cw*0602 (17.9% vs. 5.3%, OR=4.20, Pc<0.001) were significantly increased in psoriasis patients, whereas HLA-Cw*0304 frequency (4.9% vs. 13.4%, OR=0.32, Pc<0.01) was highly decreased, when compared to the controls. HLA-A*26-B*27-Cw*0602 was identified as a high-risk haplotype of HLA class I in developing psoriasis in the test. HLA-Cw*0602 was found to be strongly associated with the early-onset psoriasis (age of onset <35 y). CONCLUSION: This study demonstrated the positive associations of HLA class I markers with psoriasis vulgaris, of which HLA-Cw*0602 was the strongest susceptibility determinant for development of early-onset psoriasis, in the southeastern Chinese Han population.

Linkage analysis suggests a locus of ichthyosis vulgaris on 1q22.

Ichthyosis vulgaris (IV) is an inherited scaling skin disorder with a prevalence estimated at 2.29% in China. The gene responsible for this disorder has not been elucidated. To find the disease gene, we ascertained two Chinese IV families. Linkage analysis identified an IV locus on chromosome 1q22 with a maximum two-point Lod score of 2.47 at D1S1653 (theta=0.00). Haplotype analysis placed the critical region in a 7-cM interval defined by D1S1653 and D1S2675. These results provide the basis for further identifying the gene responsible for IV disorder.

Evidence for a major psoriasis susceptibility locus at 6p21(PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese hans.

Psoriasis is a heterogeneous disease with seven major psoriasis susceptibility loci reported so far on chromosomes 1p, 1q, 3q, 4q, 6p, 17q, and 19p, respectively. To investigate the psoriasis susceptibility loci in Chinese Hans, a genome-wide scan was performed with two-point and multipoint parametric and nonparametric linkage analyses in 61 multiplex families. These families were Chinese Hans residing in east and south-east China, comprising 189 affected and 166 unaffected individuals. We detected evidence for linkage at 6p21 (PSORS1) with nonparametric linkage scores > 3 in the range of 39.9-62.3 cM and a maximum multipoint nonparametric linkage score of 4.58 (p=0.000032). Parametric analysis revealed a maximum two-point heterogeneity lod score of 4.30 with 58% as the proportion of linked families (alpha) and a maximum multipoint heterogeneity lod score of 4.25 (alpha=53%) under the assumption of a dominant model. We could not confirm a previous reported locus (PSORS3) on distal chromosome 4q; however, a region of highly suggestive linkage was identified proximal to this proposed locus. Multipoint nonparametric analysis demonstrated nonparametric linkage scores > 3 throughout a region between 152.5 cM and 165.1 cM (from pter) with a maximum peak of 3.69 (p=0.00033) at 157.9 cM, which locates D4S413. A maximum multipoint heterogeneity lod score of 2.31 (alpha=46%) was reached at 163.1 cM. With two-point parametric linkage analysis, we observed the highest lod score of 2.43 and heterogeneity lod score of 3.94 (alpha=77%) at marker D4S1597. Our results showed that chromosomes 6p and 4q may contain genes involved in the susceptibility to psoriasis vulgaris in a Chinese Han population. Other regions with weaker evidence for linkage could also hide minor susceptibility genes.