Polygenic Risk Score Predicts Earlier-Onset Adult Systemic Lupus Erythematosus and First-Year Renal Diseases in a Taiwanese Cohort.

OBJECTIVES: This study aimed to develop a predictive model using polygenic risk score (PRS) to forecast renal outcomes for adult systemic lupus erythematosus (SLE) in a Taiwanese population. METHODS: Patients with SLE (n=2782) and matched non-SLE controls (n=11 128) were genotyped using Genome-Wide TWB 2.0 single-nucleotide polymorphism (SNP) array. PRS models (C+T, LDpred2, Lassosum, PRSice-2, PRS-continuous shrinkage (CS)) were constructed for predicting SLE susceptibility. Logistic regression was assessed for C+T-based PRS association with renal involvement in patients with SLE. RESULTS: In the training set, C+T-based SLE-PRS, only incorporating 27 SNPs, outperformed other models with area under the curve (AUC) values of 0.629, surpassing Lassosum (AUC=0.621), PRSice-2 (AUC=0.615), LDpred2 (AUC=0.609) and PRS-CS (AUC=0.602). Additionally, C+T-based SLE-PRS demonstrated consistent predictive capacity in the testing set (AUC=0.620). Individuals in the highest quartile exhibited earlier SLE onset (39.06 vs 44.22 years, p<0.01), higher Systemic Lupus Erythematosus Disease Activity Index scores (3.00 vs 2.37, p=0.04), elevated risks of renal involvement within the first year of SLE diagnosis, including WHO class III-IV lupus nephritis (OR 2.36, 95% CI 1.47 to 3.80, p<0.01), estimated glomerular filtration rate <60 mL/min/1.73m2 (OR 1.49, 95% CI 1.18 to 1.89, p<0.01) and urine protein-to-creatinine ratio >150 mg/day (OR 2.07, 95% CI 1.49 to 2.89, p<0.01), along with increased seropositivity risks, compared with those in the lowest quartile. Furthermore, among patients with SLE with onset before 50 years, the highest PRS quartile was significantly associated with more serious renal diseases within the first year of SLE diagnosis. CONCLUSIONS: PRS of SLE is associated with earlier onset, renal involvement within the first year of SLE diagnosis and seropositivity in Taiwanese patients. Integrating PRS with clinical decision-making may enhance lupus nephritis screening and early treatment to improve renal outcomes in patients with SLE.

AGR2 expression as a predictive biomarker for therapy response in esophageal squamous cell carcinoma.

Despite multidisciplinary therapy, the prognosis is poor for esophageal squamous cell carcinoma (ESCC). In the locally advanced stage, neoadjuvant chemoradiotherapy (nCRT) followed by surgery could provide survival benefits to some patients. Here, we aimed to identify for tumor therapy response a biomarker based on RNA sequencing. We collected endoscopic biopsies of 32 ESCC patients, who were divided according to nCRT response, into two groups: the complete response group (n = 13) and the non-complete response group (n = 19). RNA-sequencing data showed that 464 genes were differentially expressed. Increased in non-complete response group, 4 genes increased expressions were AGR2 (anterior gradient 2), GADD45B (growth arrest and DNA damage inducible beta), PPP1R15A (protein phosphatase 1 regulatory subunit 15A) and LRG1 (leucine rich alpha-2-glycoprotein 1). The areas under the curve (AUC) of the AGR2 gene was 0.671 according to read counts of RNA-seq and therapy response of nCRT. In vitro study showed that apoptosis cell was significantly increased in the AGR2-knockdown TE-2 cell line treated with cisplatin and 5-Fluorouracil (5-FU), when compared with si-control. Results suggest that in ESCC, the AGR2 gene is a promising and predictive gene marker for the response to anti-tumor therapy.

A Novel Quality-Control Procedure to Improve the Accuracy of Rare Variant Calling in SNP Arrays.

Background: Single-nucleotide polymorphism (SNP) arrays are an ideal technology for genotyping genetic variants in mass screening. However, using SNP arrays to detect rare variants [with a minor allele frequency (MAF) of <1%] is still a challenge because of noise signals and batch effects. An approach that improves the genotyping quality is needed for clinical applications. Methods: We developed a quality-control procedure for rare variants which integrates different algorithms, filters, and experiments to increase the accuracy of variant calling. Using data from the TWB 2.0 custom Axiom array, we adopted an advanced normalization adjustment to prevent false calls caused by splitting the cluster and a rare het adjustment which decreases false calls in rare variants. The concordance of allelic frequencies from array data was compared to those from sequencing datasets of Taiwanese. Finally, genotyping results were used to detect familial hypercholesterolemia (FH), thrombophilia (TH), and maturity-onset diabetes of the young (MODY) to assess the performance in disease screening. All heterozygous calls were verified by Sanger sequencing or qPCR. The positive predictive value (PPV) of each step was estimated to evaluate the performance of our procedure. Results: We analyzed SNP array data from 43,433 individuals, which interrogated 267,247 rare variants. The advanced normalization and rare het adjustment methods adjusted genotyping calling of 168,134 variants (96.49%). We further removed 3916 probesets which were discordant in MAFs between the SNP array and sequencing data. The PPV for detecting pathogenic variants with 0.01%10,000 are available. The results demonstrated our procedure could perform correct genotype calling of rare variants. It provides a solution of pathogenic variant detection through SNP array. The approach brings tremendous promise for implementing precision medicine in medical practice.

Molecular profiling of thymoma with myasthenia gravis: Risk factors of developing myasthenia gravis in thymoma patients.

OBJECTIVE: Thymoma is a rare epithelial tumor arising from the thymus in the anterior mediastinum. Nearly 50% of patients with thymoma develop myasthenia gravis, which is an indication of a poor long-term prognosis. Here, we identified specific and effective molecular markers for predicting in the development of myasthenia gravis patients with thymoma. MATERIAL AND METHODS: We investigated molecular profiling based on RNA-sequencing (RNA-seq) for myasthenia gravis development in patients with thymoma. RNA was extracted from 34 patients with thymoma, 16 of whom had myasthenic and 18 of whom did not, and transcriptome profiles were analyzed through next-generation sequencing. RESULTS: We discovered 140 differential expressed genes associated with myasthenia gravis in thymoma patients. The four genes, hypoxia-inducible factor 3 alpha (HIF3A), insulin-like growth factor-binding protein 1, pyruvate dehydrogenase kinase, and Krüppel-like factor 15 were differentially expressed in patients with thymoma who has myasthenia gravis and were validated by quantitative polymerase chain reaction. HIF3A expression was significantly higher in patients with myasthenia gravis than in those without. CONCLUSION: HIF3A is aberrantly expressed in patient with thymoma who has myasthenia gravis and may be involved in the development of myasthenia gravis in thymoma patient.

Association between secreted phosphoprotein-1 (SPP1) polymorphisms and low bone mineral density in women.

BACKGROUND: A recent meta-analysis found that secreted phosphoprotein-1 (SPP1) can predict the risk of both osteoporosis and fracture. No study has explored the association of SPP1 haplotype-tagging single nucleotide polymorphisms (htSNPs) and haplotypes with bone mineral density (BMD). METHODS: This is a cross-sectional study. A total of 1,313 healthy Taiwanese women aged 40 to 55 years were recruited from MJ Health Management Institute from 2009 to 2010. BMD was dichotomized into high and low BMD groups. Three common (allele frequency ≥5%) htSNPs were selected to examine the association between sequence variants of SPP1 and BMD. RESULTS: Homozygosity for the T allele of rs4754 were protective from low BMD [TT vs. CC: adjusted OR (AOR)  = 0.58, 95% confidence interval (CI)  = 0.83-0.89]. A protective effect was also found for women carrying 2 copies of Hap3 TCT (AOR  = 0.57, 95% CI  = 0.34-0.95). Menopausal status marginally interacted with SPP1 rs6839524 on BMD (p = 0.049). Postmenopausal women carrying variant rs6839524 (GG+GC vs. CC: AOR  = 2.35, 95% CI  = 1.06-5.20) or Hap1 TGC (AOR  = 2.36, 95% CI  = 1.06-5.24) were associated with 2.4-fold risk of low BMD. For women with low BMI (<18.5 kg/m2), variant rs6839524 (AOR  = 7.64) and Hap1 (AOR  = 6.42) were associated with increased risk of low BMD. These findings did not reach statistical significance after correction for multiple tests. CONCLUSIONS: SPP1 htSNP protected against low BMD in middle-aged women. SPP1 genetic markers may be important for the prediction of osteoporosis at an early age.