Hsing Fang Lu

Interaction between HLA-B60 and HLA-B27 as a Better Predictor of Ankylosing Spondylitis in a Taiwanese Population

Objective Ankylosing spondylitis (AS) is a form of chronic inflammatory spondyloarthritis (SpA) that causes pain and stiffness in spines or joints. Human leukocyte antigen B27 (HLA-B27) and B60 (HLA-B60) have been reported as major genetic risk factors of AS. In addition, rs13202464, located on major histocompatibility complex (MHC) region, showed high sensitivity (98.7%) and specificity (98.0%) for HLA-B27. Design The aim of our study is to test whether the interaction between HLA-B60 and HLA-B27 (rs13202464) can serve as a better predictor of AS. We have genotyped HLA-B60 and rs13202464 among 471 patients with AS and 557 healthy subjects. Combined risk factors were investigated to test the biological interaction. Results Our results indicated that the relative risk (RR) for HLA-B27+/HLA-B60− was 152 (95% CI 91 to 255) and it increased to 201 (95% CI 85 to 475) in HLA-B27+/HLA-B60+ patients (with HLA-B27−/HLA-B60− as reference). Combinational analysis of two risk factors (HLA-B27+/HLA-B60+) showed a relative excess risk due to interaction (RERI) of 46.79 (95% CI: -117.58 to 211.16), attributable proportion (AP) of 0.23 (95% CI: -0.41 to 0.88) and a synergy index (S) of 1.31 (95% CI: 0.56 to 3.04). Conclusion In conclusion, genetic interaction analysis revealed that the interaction between HLA-B60 and HLA-B27 is a better marker for the risk of AS susceptibility in a Taiwanese population.

Study of the association between ITPKC genetic polymorphisms and calcium Nephrolithiasis

Nephrolithiasis is a multifactorial disease caused by environmental, hormonal, and genetic factors. Genetic polymorphisms of ORAI1, which codes for the main subunit of the store-operated calcium (SOC) channel, were reported to be associated with the risk and recurrence of calcium nephrolithiasis. Inositol 1,4,5-trisphosphate (IP3) 3-kinase C (ITPKC) is a negative regulator of the SOC channel-mediated signaling pathway. We investigated the association between calcium containing nephrolithiasis and genetic variants of ITPKC gene in Taiwanese patients. 365 patients were recruited in this study. Eight tagging single nucleotide polymorphisms of ITPKC were selected for genotyping. ITPKC genotypes were determined by TaqMan assay. ITPKC plasmids were transfected into cells to evaluate the intracellular calcium mobilization. Our results indicated that rs2607420 CC genotype in the intron region of the ITPKC gene is associated with a lower eGFR by both Modification of Diet in Renal Diseases (P = 0.0405) and Cockcroft-Gault (P = 0.0215) equations in patients with calcium nephrolithiasis. Our results identify a novel polymorphism for renal function and highlight the importance of ITPKC as a key molecule to regulate calcium signaling.

Identification of genes and pathways related to lymphovascular invasion in breast cancer patients: A bioinformatics analysis of gene expression profiles:

Surgery is the most effective treatment for breast cancer patients. However, some patients developed recurrence and distant metastasis after surgery. Adjuvant therapy is considered for high-risk patients depending on several prognostic markers, and lymphovascular invasion has become one of such prognostic markers that help physicians to identify the risk for distant metastasis and recurrence. However, the mechanism of lymphovascular invasion in breast cancer remains unknown. This study aims to unveil the genes and pathways that may involve in lymphovascular invasion in breast cancer. In total, 108 breast cancer samples were collected during surgery and microarray analysis was performed. Significance analysis of the microarrays and limma package for R were used to examine differentially expressed genes between lymphovascular invasion–positive and lymphovascular invasion–negative cases. Network and pathway analyses were mapped using the Ingenuity Pathway Analysis and the Database for Annotation, Visualization and Integrated Discovery. In total, 86 differentially expressed genes, including 37 downregulated genes and 49 upregulated genes were identified in lymphovascular invasion–positive patients. Among these genes, TNFSF11, IL6ST, and EPAS1 play important roles in cytokine–receptor interaction, which is the most enriched pathway related to lymphovascular invasion. Moreover, the results also suggested that an imbalance between extracellular matrix components and tumor micro-environment could induce lymphovascular invasion. Our study evaluated the underlying mechanisms of lymphovascular invasion, which may further help to assess the risk of breast cancer progression and identify potential targets of adjuvant treatment.

rs2841277 ( PLD4 ) is associated with susceptibility and rs4672495 is associated with disease activity in rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, can lead to long-term joint damage, chronic pain, and loss of motor function in the hands, and may share some common genetic factors with other autoimmune disorders, such as ankylosing spondylitis (AS). Many single-nucleotide polymorphisms (SNPs) were reported by genome-wide association studies (GWASs) of RA, but some of them have not been examined in the Taiwanese population. In this study, for 15 SNPs reported in previous RA and AS GWASs, we investigated their association with RA in a Taiwanese population. Based on 334 RA patients recruited from the Taichung Veterans General Hospital and 16,036 healthy subjects from the Taiwan Biobank (TWB) project, we observed that subjects having minor allele C at rs2841277 (phospholipase D family, member 4 (PLD4)) have lower susceptibility of RA, compare to those having genotype TT (Odds ratio (OR) = 0.6, p = 3.0 × 10−6). Among the RA patients, we observed that subjects having GG at rs4672495 have a lower proportion of severe RA, compare to other subjects (OR = 0.09, p = 5.6 × 10−3). Results of a bioinformatics approach showed that rs2841277 is able to influence expression of LINC00638 and AHNAK2 and rs4672495 is able to influence the expression of B3GNT2. In summary, this study replicated an association of rs2841277 with RA susceptibility and showed an AS-associated SNP, rs4672495, is associated with RA activity in the Taiwanese population.Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, can lead to long-term joint damage, chronic pain, and loss of motor function in the hands, and may share some common genetic factors with other autoimmune disorders, such as ankylosing spondylitis (AS). Many single-nucleotide polymorphisms (SNPs) were reported by genome-wide association studies (GWASs) of RA, but some of them have not been examined in the Taiwanese population. In this study, for 15 SNPs reported in previous RA and AS GWASs, we investigated their association with RA in a Taiwanese population. Based on 334 RA patients recruited from the Taichung Veterans General Hospital and 16,036 healthy subjects from the Taiwan Biobank (TWB) project, we observed that subjects having minor allele C at rs2841277 (phospholipase D family, member 4 (PLD4)) have lower susceptibility of RA, compare to those having genotype TT (Odds ratio (OR) = 0.6, p = 3.0 x 10-6). Among the RA patients, we observed that subjects having GG at rs4672495 have a lower proportion of severe RA, compare to other subjects (OR = 0.09, p = 5.6 x 10-3). Results of a bioinformatics approach showed that rs2841277 is able to influence expression of LINC00638 and AHNAK2 and rs4672495 is able to influence the expression of B3GNT2. In summary, this study replicated an association of rs2841277 with RA susceptibility and showed an AS-associated SNP, rs4672495, is associated with RA activity in the Taiwanese population.

Correlation of HAMP gene polymorphisms and expression with the susceptibility and length of hospital stays in Taiwanese children with Kawasaki disease

Kawasaki disease (KD) is a form of systemic vasculitis. Regarding its pathogenesis, HAMP gene encoding hepcidin, which is significant for iron metabolism, has a vital function. In this study, we recruited a total of 381 KD patients for genotyping. Data from 997 subjects (500 subjects from cohort 1; 497 subjects from cohort 2) were used for analysis. Using TaqMan allelic discrimination, we determined five tag SNPs (rs916145, rs10421768, rs3817623, rs7251432, and rs2293689). Treatment outcome data related to such clinical phenotypes as coronary artery lesions (CAL), coronary artery aneurysms (CAA), and intravenous immunoglobulin (IVIG) effects were also collected. Furthermore, we measured plasma hepcidin levels with an enzyme-linked immunosorbent assay. We found that HAMP gene polymorphism (rs7251432, and rs2293689) was significantly correlated with KD risk and that plasma hepcidin levels both before and after IVIG treatment had a significantly positive correlation with length of hospital stays (R = 0.217, p = 0.046 and R = 0.381, p < 0.0001, respectively). In contrast, plasma hepcidin levels has a negative correlation with KD patients’ albumin levels (R = −0.27, p < 0.001) prior to IVIG treatment. This studys findings indicate that HAMP might have a role in the disease susceptibility, as well as its expressions correlated length of hospital stays, and albumin levels in Taiwanese children with KD.

Scoliosis and the Subsequent Risk of Depression: A Nationwide Population-based Cohort Study in Taiwan.

Study Design. A retrospective cohort study by using the Taiwanese National Health Insurance Research Database (NHIRD). Objective. The purpose of this study is to conduct a large-scale cohort study to investigate the relationship between scoliosis and depression. Summary of Background Data. The association between scoliosis and depression has rarely been studied in Asian populations. Methods. The study cohort consisted of patients with diagnosis of scoliosis between 2003 and 2005 (N = 1409). A comparison cohort was constructed from five age- and gender-matched control subjects selected via random sampling (N = 7045). Data on adjusted hazard ratios (AHRs) of depression, 5-year freedom from depression rates, and risk factors for depression for the two cohorts were compared. All subjects were tracked for 5 years from the date of cohort entry to identify the development of depression. Cox proportional hazard regressions were performed to evaluate the 5-year freedom from depression rates. This study is supported by the University research grant without any study-specific conflicts. Results. During the 5-year follow-up period, 116 and 307 depression patients belonged to the scoliosis cohort and the comparison cohort, respectively. The AHRs of depression in patients with scoliosis was higher [AHR 1.95; 95% confidence interval (95% CI) 1.58–2.42; P < 0.001] than that of the controls during the 5-year follow-up. The risk of depression also demonstrated to be age-dependent for scoliosis patients. The middle-age (41–65 years old) and young adults (18–40 years old) scoliosis patients had higher AHRs (middle-age: AHR 2.45; 95% CI 1.67–3.59; P < 0.05; young adult: AHR 1.99; 95% CI 1.41–2.82; P < 0.05). Conclusion. The population-based study indicated that patients with scoliosis may have an increased risk of depression. Health care professionals should consider designing and planning effective psychological prevention and treatment for scoliosis patients. Level of Evidence: 4

rs657075 (CSF2) Is Associated with the Disease Phenotype (BAS-G) of Ankylosing Spondylitis

Ankylosing spondylitis (AS) is a systemic autoimmune disease mainly affecting the lumbar spine and sacroiliac joints, and exhibits peripheral inflammatory arthropathy. More than 25 loci have been identified as associated with AS. Because both AS and rheumatoid arthritis (RA) are autoimmune diseases that may share some common genetic factors, we therefore examined if the newly identified RA genetic polymorphisms were associated with AS in a Taiwanese population. In this study, we enrolled 475 AS patients and 11,301 healthy subjects from a Taiwanese biobank as controls. Although none of single-nucleotide polymorphisms (SNPs) were associated with the susceptibility to AS, the AS disease index Bath AS Global (BAS-G) clinical phenotype was observed as significantly correlated to the AA genotype of rs657075 (CSF2). The significance remains after gender/age/disease duration adjustment and after group categorization by human leukocyte antigen-B 27 (HLA-B27) genotype. We further investigated the possible functions of rs657075 through bioinformatics approaches. Results revealed that polymorphism of rs657075 is able to influence the expression of acyl-CoA synthetase long-chain family member 6 (ACSL6). In conclusion, our study indicated that rs657075 (CSF2) is strongly associated with the AS disease index Bath AS Global (BAS-G) clinical phenotype.

Association Study between the FTCDNL1 ( FONG) and Susceptibility to Osteoporosis

Osteoporosis is a systemic skeletal disease characterized by a decreased bone mineral density that results in an increased risk of fragility fractures. Previous studies indicated that genetic factors are involved in the pathogenesis of osteoporosis. Polymorphisms of the FONG (FTCDNL1) gene (rs7605378) were reported to be associated with the risk of osteoporosis in a Japanese population. To assess whether polymorphisms of the FTCDNL1 gene contribute to the susceptibility and severity of osteoporosis in a Taiwanese population, 326 osteoporosis patients and 595 controls of a Taiwanese population were included in this study. Our results indicated that rs10203122 was significantly associated with osteoporosis susceptibility among female. Our findings provide evidence that rs10203122 in FTCDNL1 is associated with a susceptibility to osteoporosis.