Biomarkers Predicting Isocyanate-Induced Asthma

Palikhe, Nami Shrestha,Kim, Joo-Hee,Park, Hae-Sim The Korean Academy of Asthma, Allergy and Clinical 2011 Allergy, Asthma & Immunology Research Vol.3 No.1

<P>Three diisocyanates can cause occupational asthma (OA): toluene diisocyanate (TDI), 4,4 diphenylmethane diisocyanate (MDI), and 1,6-hexamethylene diisocyanate (HDI). We analyzed potential biomarkers of isocyanate-induced OA, based on investigated immunologic, genetic, neurogenic, and protein markers, because there is no serological testing method. The prevalence of serum IgG to cytokeratin (CK)18 and CK19 in TDI-OA was significantly higher than in controls, although the prevalence of these antibodies was too low for them to be used as biomarkers. Another candidate biomarker was serum IgG to tissue transglutaminase (tTG), because the prevalence of serum specific IgG to tTG was significantly higher in patients with TDI-OA than in controls. The human leukocyte antigen (HLA) DRB1*1501-DQB1*0602-DPB1*0501 haplotype may be used as a genetic marker for TDI-OA in Koreans via enhanced specific IgE sensitization in exposed subjects. The genetic polymorphisms of catenin alpha 3, alpha-T catenin (CTNNA3) were significantly associated with TDI-OA. Additionally, examining the neurokinin 2 receptor (NK2R) 7853G>A and 11424 G>A polymorphisms, the NK2R 7853GG genotype had higher serum vascular endothelial growth factor (VEGF) levels than the GA or AA genotypes among Korean workers exposed to TDI. To identify new serologic markers using a proteomic approach, differentially expressed proteins between subjects with MDI-OA and asymptomatic exposed controls in a Korean population showed that the optimal serum cutoff levels were 69.8 ng/mL for ferritin and 2.5 µg/mL for transferrin. When these two parameters were combined, the sensitivity was 71.4% and the specificity was 85.7%. The serum cytokine matrix metalloproteinase-9 (MMP-9) level is a useful biomarker for identifying cases of TDI-OA among exposed workers. Despite these possible biomarkers, more effort should be focused on developing early diagnostic biomarkers using a comprehensive approach based on the pathogenic mechanisms of isocyanate-induced OA.</P>

Genetic variability of prostaglandin E2 receptor subtype EP4 gene in aspirin-intolerant chronic urticaria.

Palikhe, Nami Shrestha,Sin, Hye Jung,Kim, Seung Hyun,Sin, Hyun Jung,Hwang, Eui Kyung,Ye, Young Min,Park, Hae-Sim Springer-Verlag 2012 Journal of human genetics Vol.57 No.8

<P>Prostaglandin E2 receptor subtype EP4 (PTGER4) is one of the four subtypes of receptors for prostaglandin E2 (PGE2). Overproduction of cysteinyl leukotriene in mast cells may be related with suppression of PGE2 in patients with aspirin hypersensitivity. Considering the association of PTGER4 in mast cells, urticaria- and aspirin-related disease, we hypothesized the genetic variability of PTGER4 may be associated with aspirin-intolerant chronic urticaria (AICU). The case-control study was performed in 141 with AICU, 153 with aspirin-tolerant chronic urticaria (ATCU) and 174 with normal controls (NCs). PTGER4 promoter single-nucleotide polymorphism was genotyped using a primer extension method with the SNAPshot ddNTP primer extension kit. The functional variability of PTGER4 promoter polymorphism was carried out by dual-luciferase system and electrophoretic mobility shift assay (EMSA) in human mast cells (HMC-1). Furthermore, the effect of aspirin was performed for PTGER4 mRNA expression using real-time PCR, and PGE2 production was checked in HMC-1 cells using ELISA. AICU patients carrying GG genotype at -1254?G>A showed significantly higher frequency compared with NC (P=0.032). Similarly, the minor allele frequency, G allele was significantly higher in AICU compared with NC (P=0.031). In vitro functional study demonstrated that the -1254?G allele had lower luciferase activity (P<0.001) in HMC-1 cells. EMSA finding showed that PTGER4 -1254?G produced a specific band. Significantly decreased PTGER4 expression (P=0.008) and PGE2 production by aspirin exposure was confirmed in in vitro HMC cell line model (P=0.001). The PTGER4 -1254?G allele demonstrated a higher frequency in AICU patients and lower promoter activity with decreased expression of PTGER4 and contributes to the development of AICU.</P>

Association of CRTH2 gene polymorphisms with the required dose of antihistamines in patients with chronic urticaria.

Palikhe, Nami Shrestha,Kim, Seung-Hyun,Ye, Young-Min,Hur, Gyu-Young,Cho, Bo-Young,Park, Hae-Sim Ashley Publications 2009 Pharmacogenomics Vol.10 No.3

<P>INTRODUCTION: Chronic urticaria (CU), defined as the recurring incidence of wheals with or without angioedema for more than 6 weeks, is a common disorder associated with mast cell activation, degranulation, and histamine release. Considering the association between the CRTH2 gene and mast cells, we investigated the association of this gene polymorphism with the CU phenotype and antihistamine drug requirement in patients with CU. MATERIALS & METHODS: Two groups consisting of 384 patients with CU and 231 patients as normal controls (NCs) were enrolled from the Department of Allergy and Rheumatology, Ajou University Hospital, Suwon, Korea. Two polymorphisms of the CRTH2 gene, -466T>C and -129C>A were genotyped using primer extension methods. RESULTS: No significant differences were detected in the genotype and allele frequencies of the two CRTH2 polymorphisms between the CU and NC groups, and no significant associations were observed with clinical parameters, such as atopy status, serum total IgE, prevalence of autoantibodies and duration of CU. However, CU patients with homozygous TT genotypes had significantly higher dose requirements of antihistamines to control the CU symptoms (164.56 +/- 115.62 vs 137.38 +/- 90.15 loratadine equivalents, mg/week) than those with the CT and CC genotypes (p = 0.025). The luciferase activity was significantly enhanced in the construct containing CRTH2 466C compared with the -466T-containing construct (p < 0.001). Co-transfection experiments with GATA-3 (300 ng) and the -466T and -466C CRTH2 alleles revealed that the CRTH2 -466T allele produced a greater increase in induction of luciferase activity than the -466C allele (p < 0.001). CONCLUSION: The CRTH2 -466T>C gene polymorphism may not affect on the phenotype of CU, but contributes to the required dose of antihistamines in patients with CU.</P>

Association of thromboxane A2 receptor (<i>TBXA2R</i>) gene polymorphism in patients with aspirin‐intolerant acute urticaria

Palikhe, N. S.,Kim, S.‐,H.,Lee, H.‐,Y.,Kim, J.‐,H.,Ye, Y.‐,M.,Park, H.‐,S. Blackwell Publishing Ltd 2011 Clinical and experimental allergy Vol.41 No.2

<P>Cite this as: N. S. Palikhe, S.‐H. Kim,H.‐Y. Lee, J.‐H. Kim, Y.‐M. Ye and H.‐S. Park, Clinical & Experimental Allergy, 2011 (41) 179–185.</P><P><B>Summary</B></P><P><B>Background </B> The thromboxane A2 receptor (<I>TBXA2R</I>) is a potent broncho‐ and vaso‐constrictor and is associated with leukotriene synthesis. Polymorphisms in the <I>TBXA2R</I> gene have been linked to atopy, asthma, and atopic dermatitis. This study evaluated the association between genetic <I>TBXA2R</I> variants and the development of acetyl salicylic acid (ASA)‐intolerant acute urticaria (AIAU).</P><P><B>Methods </B> AIAU patients (<I>n</I>=167), ASA‐intolerant chronic urticaria (AICU) patients (<I>n</I>=149), and healthy controls (NC) (<I>n</I>=265) were included. All patients were enrolled at Ajou University Hospital in Suwon, Korea. Two <I>TBXA2R</I> polymorphisms (−4684T>C and 795T>C) were genotyped by primer extension using a SNAPshot ddNTP primer extension kit. Luciferase activity was measured using a dual‐luciferase reporter assay kit. An electrophoretic mobility shift assay (EMSA) was performed using a nuclear extract from a human mast cell line (HMC‐1).</P><P><B>Results </B> Genetic association data demonstrated that compared with NC subjects, AIAU patients had a significantly higher frequency of the homozygous TT genotype of <I>TBXA2R</I>−4684T>C (<I>P=</I>0.005, <I>P</I><SUB>corr</SUB>=0.03). No differences were identified between the AICU and the NC groups. Luciferase activity, reflecting promoter activity, was significantly lower with the <I>TBXA2R</I>−4684T‐containing construct than with the −4684C‐containing construct (<I>P</I><0.001); the activity decreased further upon co‐transfection with ETS‐like gene transcription factor‐1 (ELK‐1) (<I>P=</I>0.012). EMSA revealed that the −4684T allele produced a specific shifted band, with a greater affinity than that produced by the −4684C allele.</P><P><B>Conclusion and clinical relevance </B> These results suggest that the <I>TBXA2R</I>−4684T allele may be associated with lower TBXA2R expression, which may contribute to the development of the AIAU phenotype.</P>

Genetic variability in<i>CRTH2</i>polymorphism increases eotaxin-2 levels in patients with aspirin exacerbated respiratory disease

Palikhe, N. S.,Kim, S.-H.,Cho, B.-Y.,Ye, Y.-M.,Choi, G.-S.,Park, H.-S. Wiley (Blackwell Publishing) 2010 Allergy Vol.65 No.3

A Role of the ABCC4 Gene Polymorphism in Airway Inflammation of Asthmatics

Palikhe, Sailesh,Uuganbayar, Udval,Trinh, Hoang Kim Tu,Ban, Ga-Young,Yang, Eun-Mi,Park, Hae-Sim,Kim, Seung-Hyun Carfax 2017 MEDIATORS OF INFLAMMATION Vol.2017 No.3

Systematic Analysis of Production Errors and Accuracy when using Pin-Bed Mold of Free-form Concrete Panels

Palikhe, Shraddha,Kim, Joseph J.,Lim, Jeeyoung,Kim, Sunkuk Springer-Verlag 2018 KSCE Journal of Civil Engineering Vol.22 No.9

A Role of the ABCC4 Gene Polymorphism in Airway Inflammation of Asthmatics

Palikhe, Sailesh,Uuganbayar, Udval,Trinh, Hoang Kim Tu,Ban, Ga-Young,Yang, Eun-Mi,Park, Hae-Sim,Kim, Seung-Hyun Carfax 2017 MEDIATORS OF INFLAMMATION Vol.2017 No.-

<P>The ATP-binding cassette subfamily C member 4 gene encodes a transmembrane protein involved in the export of proinflammatory molecules, including leukotriene, prostaglandin, and sphingosine-1-phosphate across the plasma membrane. Those metabolites play important roles in asthma. We investigated the potential associations between <I>ABCC4</I> gene polymorphisms and asthma phenotype. In total, 270 asthma patients and 120 normal healthy controls were enrolled for a genetic association study. Two polymorphisms (−1508A>G and −642C>G) in the <I>ABCC4</I> promoter were genotyped. The functional variability of the promoter polymorphisms was analyzed by luciferase reporter assay. Inflammatory cytokine levels were measured by enzyme-linked immunosorbent assay. Serum and urinary eicosanoid metabolites, sphingosine-1-phosphate, were evaluated by quadrupole time-of-flight mass spectrometry. Asthma patients carrying the G allele at −1508A>G had significantly higher serum levels of periostin, myeloperoxidase, and urinary levels of 15-hydroxyeicosatetraenoic acid and sphingosine-1-phosphate (<I>P</I> = 0.016, <I>P</I> = 0.027, <I>P</I> = 0.032, and <I>P</I> = 0.010, resp.) compared with noncarrier asthma patients. Luciferase activity was significantly enhanced in human epithelial A549 cells harboring a construct containing the −1508G allele (<I>P</I> < 0.01 for each) compared with a construct containing the −1508A allele. A functional polymorphism in the <I>ABCC4</I> promoter, −1508A>G, may increase extracellular 15-hydroxyeicosatetraenoic acid, sphingosine-1-phosphate, and periostin levels, contributing to airway inflammation in asthmatics.</P>

Association Between PTPN22 Polymorphisms and IgE Responses to Staphylococcal Superantigens in Chronic Urticaria

Sailesh Palikhe,김승현,Le Duy Pham,예영민,박해심 대한천식알레르기학회 2015 Allergy, Asthma & Immunology Research Vol.7 No.3

Protein tyrosine phosphatase-22 (PTPN22) gene encodes lymphoid-specific tyrosine phosphatase (Lyp), an inhibitor of T cell activation. A polymorphism of the PTPN22 gene has been found to be associated with chronic urticaria (CU). We investigated the associations between PTPN22 gene polymorphisms and CU characteristics, including serum specific IgE antibodies response to toxic shock syndrome toxin-1 (TSST-1) and staphylococcal enterotoxin A (SEA). CU patients (n=409) and normal healthy controls (n=388) were enrolled in the present study. Serum specific IgE to TSST-1 and SEA were measured by ImmunoCAP®. Five PTPN22 single nucleotide polymorphisms, -1123G>C, 1858C>T, 13145A>G, 14943C>T, and 20628A>G, were genotyped. There were no significant differences in genotype or haplotype frequencies of these polymorphisms between the 2 groups. CU patients carrying the GG genotype at 20628A>G (P=0.035) or haplotype 3 [GGG] (P=0.047) had a significantly higher prevalence of serum specific IgE to TSST-1 compared to non-carriers. Similarly, CT/TT genotype at 14943C>T had a significantly higher prevalence of serum specific IgE to SEA (P=0.045). The findings suggest that the PTPN22 gene polymorphisms at 20628A>G and 14943C>T may enhance serum specific IgE responses to TSST-1 and SEA, which may contribute to CU pathogenesis.

Update on Recent Advances in the Management of Aspirin Exacerbated Respiratory Disease

Nami Shrestha Palikhe,Joo-Hee Kim,Hae-Sim Park 연세대학교의과대학 2009 Yonsei medical journal Vol.50 No.6

Aspirin intolerant asthma (AIA) is frequently characterized as an aspirin (ASA)-exacerbated respiratory disease (AERD). It is a clinical syndrome associated with chronic severe inflammation in the upper and lower airways resulting in chronic rhinitis, sinusitis, recurrent polyposis, and asthma. AERD generally develops secondary to abnormalities in inflammatory mediators and arachidonic acid biosynthesis expression. Upper and lower airway eosinophil infiltration is a key feature of AERD; however, the exact mechanisms of such chronic eosinophilic inflammation are not fully understood. Cysteinyl leukotriene over-production may be a key factor in the induction of eosinophilic activation. Genetic studies have suggested a role for variability of genes in disease susceptibility and response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLADPB1* 301, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10 -1082A > G, ACE -262A > T, and CRTH2 -466T > C; the four-locus SNP set was composed of B2ADR 46A > G, CCR3 -520T > G, CysLTR1 -634C > T, and FCER1B -109T > C. Management of AERD is an important issue. Aspirin ingestion may result in significant morbidity and mortality, and patients must be advised regarding aspirin risk. Leukotriene receptor antagonists (LTRA) that inhibit leukotriene pathways have an established role in long-term AERD management and rhinosinusitis. Aspirin desensitization may be required for the relief of upper and lower airway symptoms in AERD patients. Future research should focus on identification of biomarkers for a comprehensive diagnostic approach. Aspirin intolerant asthma (AIA) is frequently characterized as an aspirin (ASA)-exacerbated respiratory disease (AERD). It is a clinical syndrome associated with chronic severe inflammation in the upper and lower airways resulting in chronic rhinitis, sinusitis, recurrent polyposis, and asthma. AERD generally develops secondary to abnormalities in inflammatory mediators and arachidonic acid biosynthesis expression. Upper and lower airway eosinophil infiltration is a key feature of AERD; however, the exact mechanisms of such chronic eosinophilic inflammation are not fully understood. Cysteinyl leukotriene over-production may be a key factor in the induction of eosinophilic activation. Genetic studies have suggested a role for variability of genes in disease susceptibility and response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLADPB1* 301, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10 -1082A > G, ACE -262A > T, and CRTH2 -466T > C; the four-locus SNP set was composed of B2ADR 46A > G, CCR3 -520T > G, CysLTR1 -634C > T, and FCER1B -109T > C. Management of AERD is an important issue. Aspirin ingestion may result in significant morbidity and mortality, and patients must be advised regarding aspirin risk. Leukotriene receptor antagonists (LTRA) that inhibit leukotriene pathways have an established role in long-term AERD management and rhinosinusitis. Aspirin desensitization may be required for the relief of upper and lower airway symptoms in AERD patients. Future research should focus on identification of biomarkers for a comprehensive diagnostic approach.