Putative association of <i>SMAPIL</i> polymorphisms with risk of aspirin intolerance in asthmatics

Yongha Kim, Jason,Kim, Jeong-Hyun,Park, Byng-Lae,Sub Cheong, Hyun,Sook Park, Jong,Soo Jang, An,Uh, Soo-Taek,Choi, Jae-Sung,Kim, Yong-Hoon,Kim, Mi-Kyeong,Choi, Inseon S.,Heon Cho, Sang,Whui Choi, Byoun Informa Healthcare 2010 The Journal of asthma Vol.47 No.9

<P><I>Background.</I> Aspirin-intolerant asthma (AIA), as a clinical syndrome caused by aspirin, is characterized by lung inflammation and reversible bronchoconstriction. Recently, the altered trafficking and diminished airway reactivity have been implicated in allergic airway remodeling. The stromal membrane-associated protein 1-like (SMAP1L) exerts common and distinct functions in vesicle trafficking including endocytosis. The disturbance of pulmonary surfactant synthesis has been elucidated to be associated with asthma experimentally. Moreover, in alveolar type II (ATII) cells that synthesize pulmonary surfactant, alterations of clathrin-dependent endocytosis cause disturbance at the surfactant function, suggesting that SMAP1L, which directly interacts with clathrin, could be associated with asthma and related phenotypes. <I>Objective.</I> To verify our hypothesis that <I>SMAP1L</I> could play a role in the development of AIA, this study investigated associations between single-nucleotide polymorphisms (SNPs) of the <I>SMAP1L</I> gene and AIA. <I>Methods.</I> We conducted an association study between 19 SNPs of the <I>SMAP1L</I> gene and AIA in a total of 592 Korean subjects including 163 AIA and 429 aspirin-tolerant asthma (ATA) patients. Associations between polymorphisms of <I>SMAP1L</I> and AIA were analyzed with sex, smoking status, atopy, and body mass index as covariates. <I>Results.</I> Logistic analyses revealed that three common polymorphisms, <I>rs2982510</I>, <I>rs2294752</I>, and <I>rs446738</I>, were putatively associated with the increased susceptibility to AIA (<I>p</I> = .003, <I>p</I><SUP>corr</SUP> = .004, OR = 0.24, 95% CI = 0.09-0.62 for <I>rs2982510</I> and <I>rs2294752</I>; <I>p</I> = .008, <I>p</I><SUP>corr</SUP> = .03, OR = 0.44, 95% CI = 0.24-0.80 for <I>rs446738</I>, in the recessive model). In addition, <I>rs2982510</I> and <I>rs2294752</I> were significantly associated with the fall of forced expiratory volume in 1 s (FEV<SUB>1</SUB>) by aspirin provocation (<I>p</I> = .001, <I>p</I><SUP>corr</SUP> = .04 in the recessive model for both SNPs). <I>Conclusions.</I> Our findings suggest that <I>SMAP1L</I> might be a susceptible gene to AIA, providing a new strategy for the control of aspirin intolerance.</P>

Potential Association of <i>DDR1</i> Genetic Variant with FEV₁ Decline by Aspirin Provocation in Asthmatics

Kim, Jason Yongha,Kim, Jeong-Hyun,Park, Byung-Lae,Pasaje, Charisse Flerida A.,Bae, Joon Seol,Uh, Soo-Taek,Kim, Yong-Hoon,Kim, Mi-Kyeong,Choi, Inseon S.,Cho, Sang Heon,Choi, Byoung Whui,Park, Jong Sook Informa Healthcare 2012 The Journal of asthma Vol.49 No.3

<P><I>Background.</I> The <I>discoidin domain receptor tyrosine kinase 1</I> (<I>DDR1</I>) is positioned within the major histocompatibility complex (MHC) region which plays an important role in the immune system. In addition, DDR1 has been elucidated to be downregulated during the epithelial-mesenchymal transition of bronchial epithelium. <I>Objective.</I> To investigate the potential genetic associations between <I>DDR1</I> and aspirin-exacerbated respiratory disease (AERD), this study conducted association studies of <I>DDR1</I> single nucleotide polymorphisms (SNPs) with AERD and the obstructive symptom of forced expiratory volume in 1 s (FEV<SUB>1</SUB>) decline after aspirin provocation. <I>Methods.</I> Nine common SNPs were genotyped in 93 AERD patients and 96 aspirin-tolerant asthma (ATA) controls. The genotype distributions of all loci were in Hardy-Weinberg equilibrium (HWE; <I>p</I> > .05). <I>Results.</I> In the results of logistic analyses using age, sex, smoking status, and atopy as covariates, <I>DDR1 rs1264320</I> in the intronic region showed a potent association signal with FEV<SUB>1</SUB> decline by aspirin provocation in asthmatics of this study even after corrections for multiple testing (<I>p</I> == .003 and corrected <I>p</I> == .01). However, the variants of <I>DDR1</I> were not significantly associated with the AERD development (corrected <I>p</I> > .05). On further comparison of FEV<SUB>1</SUB> decline by aspirin provocation between AERD and ATA, the variant <I>rs1264320</I> was found to be associated with the FEV<SUB>1</SUB> decline of ATA rather than AERD. <I>Conclusion.</I> Despite the need for further functional evaluations and replications, we conclude that <I>DDR1</I> polymorphisms are not likely to contribute to predispositions of AERD, but may be potentially associated with FEV<SUB>1</SUB> decline by aspirin provocation in asthmatics.</P>

Lack of association between IRAK2 genetic variants and aspirin exacerbated respiratory disease

Jason Yongha Kim,김정현,박병래,정현섭,배준설,박종숙,김용훈,김미경,최인선,조상헌,최병휘,박춘식,신형두 한국유전학회 2013 Genes & Genomics Vol.35 No.4

Asthma is a global health problem which threatens approximately 300 million patients worldwide. Among them, up to 20 % of the asthma patients are classified as aspirin exacerbated respiratory disease (AERD). Interleukin-1receptor associated kinase (IRAK2) is associated with necrosis factor kappa B (NF-rB) pathway via interleukin-1(IL-1) signaling. NF-rB pathway is known to be involved in asthmadevelopment, and several interleukin and IRAKfamily membershavealsobeen reported tobeassociatedwithasthma or AERD. Since IRAK2 plays an important role in the asthma etiology, we hypothesized that the genetic variants of IRAK2may be associatedwithAERD. This study genotyped a total of 25 common single nucleotide polymorphisms (SNPs) in 163AERD cases and 429 aspirin-tolerant asthma (ATA) controls. As a result, no significant association was found between the genetic variants of IRAK2 and AERD (P[0.05). In further regression analysis for the forced expiratory volume in 1 s (FEV1) decline, an important phenotype for diagnosing AERD, although one haplotype (BL1_ht3) showed a nominal association with FEV1 decline (P = 0.04), the significance disappeared after correction for multiple testing (P[0.05). Despite limitations in our study and need for replications, our results suggest that the genetic variants of IRAK2 might not be associated with AERD and the obstructive symptoms in asthma.

Lack of association between CD226 genetic variants and inflammatory demyelinating diseases in Korean population.

Kim, Jason Yongha,Kim, Ho Jin,Cheong, Hyun Sub,Bae, Joon Seol,Kim, Jeong-Hyun,Park, Byung Lae,Shin, Hyoung Doo Edition Medizin 2013 Neuro endocrinology letters Vol.34 No.5

<P>This study was conducted to find the possible association between CD226 polymorphisms and inflammatory demyelinating diseases in Korean population.</P>

Association Analysis Between FILIP1 Polymorphisms and Aspirin Hypersensitivity in Korean Asthmatics

Jason Yongha Kim,장안수,김정현,박병래,Charisse Flerida A. Pasaje,배준설,박종숙,김용훈,김미경,최인선,어수택,조상헌,최병휘,박춘식,신형두 대한천식알레르기학회 2013 Allergy, Asthma & Immunology Research Vol.5 No.1

Purpose: Aspirin exacerbated respiratory disease (AERD) results in a severe asthma attack after aspirin ingestion in asthmatics. The filamin A interactingprotein 1 (FILIP1) may play a crucial role in AERD pathogenesis by mediating T cell activation and membrane rearrangement. We investigatedthe association of FILIP1 variations with AERD and the fall rate of forced expiratory volume in one second (FEV1). Methods: A total of 34common FILIP1 single nucleotide polymorphisms (SNPs) were genotyped in 592 Korean asthmatic subjects that included 163 AERD patients and 429aspirin-tolerant asthma (ATA) controls. Results: This study found that 5 SNPs (P=0.006-0.01) and 2 haplotypes (P=0.01-0.03) of FILIP1 showednominal signals; however, corrections for the multiple testing revealed no significant associations with the development of AERD (Pcorr>0.05). In addition,association analysis of the genetic variants with the fall rate of FEV1, an important diagnostic marker of AERD, revealed no significant evidence(Pcorr>0.05). Conclusions: Although further replications and functional evaluations are needed, our preliminary findings suggest that geneticvariants of FILIP1 might be not associated with the onset of AERD.

Investigating the potential genetic association between RANBP9 polymorphisms and the risk of schizophrenia.

Bae, Joon Seol,Kim, Jason Yongha,Park, Byung-Lae,Cheong, Hyun Sub,Kim, Jeong-Hyun,Namgoong, Suhg,Kim, Ji-On,Park, Chul Soo,Kim, Bong-Jo,Lee, Cheol-Soon,Lee, Migyung,Choi, Woo Hyuk,Shin, Tae-Min,Hwang, D. A. Spandidos 2015 MOLECULAR MEDICINE REPORTS Vol.11 No.4

<P>Schizophrenia is a serious mental disorder that is affected by genetic and environmental factors. As the disease has a high heritability rate, genetic studies identifying candidate genes for schizophrenia have been conducted in various populations. The gene for human Ran???binding protein 9 (RANBP9) is a newly discovered candidate gene for schizophrenia. As RANBP9 is a small guanosine???5'???triphosphate???binding protein that interacts with the disrupted in schizophrenia 1 protein, it is considered to be an important molecule in the pathogenesis of schizophrenia. However, to date, no study has examined the possible association between the genetic variations of RANBP9 and the risk of schizophrenia. In the present study, it was hypothesized that RANBP9 variations may influence the risk of schizophrenia. In order to investigate the association between RANBP9 polymorphisms and the risk of schizophrenia and smooth pursuit eye movement (SPEM) abnormalities, a case???control association analysis was performed. Using a TaqMan assay, five single???nucleotide polymorphisms and an insertion/deletion variation within the start codon region of RANBP9 were genotyped. Five major haplotypes were identified in 449 patients with schizophrenia and 393 unrelated healthy individuals as controls (total, n=842). However, the association analyses revealed no associations between all genetic variants and schizophrenia and SPEM abnormality. To the best of our knowledge, this is the first study to investigate an association between RANBP9 polymorphisms and schizophrenia and SPEM abnormality. The findings of allele frequencies and association results in this study may aid in further genetic etiological studies in schizophrenia in various populations.</P>

Association Analysis of TEC Polymorphisms with Aspirin-Exacerbated Respiratory Disease in a Korean Population

이진솔,배준설,박병래,정현섭,김정현,Jason Yongha Kim,남궁석,김지온,박춘식,신형두 한국유전체학회 2014 Genomics & informatics Vol.12 No.2

The tyrosine-protein kinase Tec (TEC) is a member of non-receptor tyrosine kinases and has critical roles in cell signalingtransmission, calcium mobilization, gene expression, and transformation. TEC is also involved in various immune responses,such as mast cell activation. Therefore, we hypothesized that TEC polymorphisms might be involved in aspirin-exacerbatedrespiratory disease (AERD) pathogenesis. We genotyped 38 TEC single nucleotide polymorphisms in a total of 592 subjects,which comprised 163 AERD cases and 429 aspirin-tolerant asthma controls. Logistic regression analysis was performed toexamine the associations between TEC polymorphisms and the risk of AERD in a Korean population. The results revealed thatTEC polymorphisms and major haplotypes were not associated with the risk of AERD. In another regression analysis for thefall rate of forced expiratory volume in 1 second (FEV1) by aspirin provocation, two variations (rs7664091 and rs12500534)and one haplotype (TEC_BL2_ht4) showed nominal associations with FEV1 decline (p = 0.03-0.04). However, theassociation signals were not retained after performing corrections for multiple testing. Despite TEC playing an important rolein immune responses, the results from the present study suggest that TEC polymorphisms do not affect AERD susceptibility. Findings from the present study might contribute to the genetic etiology of AERD pathogenesis.

Association study between TRIM26 polymorphisms and risk of aspirin-exacerbated respiratory disease.

Lee, Jin Sol,Bae, Joon Seol,Kim, Jeong-Hyun,Kim, Jason Yongha,Park, Tae Joon,Pasaje, Charisse Flerida,Park, Byung-Lae,Cheong, Hyun Sub,Jang, An-Soo,Uh, Soo-Taek,Park, Choon-Sik,Shin, Hyoung Doo D.A. Spandidos 2012 International journal of molecular medicine Vol.29 No.5

<P>Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome that is characterized by nasal polyposis, general symptoms of asthma and sensitive response to non-steroidal anti-inflammatory drugs (NSAIDs). Although the exact function of tripartite motif-containing 26 (TRIM26) still remains unknown, the gene functions in the immune response. Thus, we hypothesized that TRIM26 polymorphisms may affect aspirin-induced bronchospasm and explored whether the gene can be a marker for diagnosis of AERD. To investigate our hypothesis that TRIM26 may serve as a genetic marker for diagnosis of AERD, this study focused on demonstrating the associations between single nucleotide polymorphisms (SNPs) of the TRIM26 gene and AERD. We genotyped 18 polymorphisms of TRIM26 in a total of 189 asthmatics and examined their associations with the risk of AERD. We performed logistic analysis for obtaining P-values and regression analysis for demonstrating an association between the phenotype with FEV1 and the genotype. We observed no associations between polymorphisms in TRIM26 and the risk of AERD in both logistic and regression analyses. Although our results reveal a lack of association, the suggested functional role of TRIM26 makes it a putative candidate gene for AERD. Thus, replications in other populations using larger samples may provide valuable information for AERD etiology.</P>

CD55 polymorphisms and risk of aspirin-exacerbated respiratory disease

LEE, JIN SOL,BAE, JOON SEOL,KIM, JEONG-HYUN,KIM, JASON YONGHA,PARK, TAE JOON,PASAJE, CHARISSE FLERIDA,PARK, BYUNG-LAE,CHEONG, HYUN SUB,UH, SOO-TAEK,JANG, AN-SOO,CHOI, INSEON S.,PARK, CHOON-SIK,SHIN, H Spandidos Publications 2012 MOLECULAR MEDICINE REPORTS Vol.6 No.5

<P>Aspirin-exacerbated respiratory disease (AERD) is a respiratory disease characterized by acute bronchial responses upon the administration of non-steroidal anti?inflammatory drugs (NSAIDs) and the immune response by mast cells is regarded as one of the noteworthy causes of AERD pathogenesis. The complement cascade is regarded as a key mechanism for clearing pathogens from the host. CD55 is one of the proteins involved in self-recognition, a central component of the complement system and autoimmunity. To investigate the associations between CD55 single nucleotide polymorphisms (SNPs) and the risk of AERD, we carried out logistic analyses with three genetic models and further regression analysis was performed with the fall rate of forced expiratory volume in 1?sec (FEV1) by aspirin provocation. However, our results demonstrate that no CD55 polymorphisms are associated with the risk of AERD and the fall rate of FEV1 (P>0.05). Therefore, our results suggest that CD55 polymorphisms are not genetic markers of aspirin?induced bronchospasm, including FEV1, in the population studied. Although the genetic role of CD55 has been found to be integral to human immunity, our results indicate that genetic variations of CD55 do not influence the risk of AERD and the fall rate of FEV1 in the population studied.</P>

Association Analysis of TEC Polymorphisms with Aspirin-Exacerbated Respiratory Disease in a Korean Population

Lee, Jin Sol,Bae, Joon Seol,Park, Byung-Lae,Cheong, Hyun Sub,Kim, Jeong-Hyun,Kim, Jason Yongha,Namgoong, Suhg,Kim, Ji-On,Park, Choon-Sik,Shin, Hyoung Doo Korea Genome Organization 2014 Genomics & informatics Vol.12 No.2

The tyrosine-protein kinase Tec (TEC) is a member of non-receptor tyrosine kinases and has critical roles in cell signaling transmission, calcium mobilization, gene expression, and transformation. TEC is also involved in various immune responses, such as mast cell activation. Therefore, we hypothesized that TEC polymorphisms might be involved in aspirin-exacerbated respiratory disease (AERD) pathogenesis. We genotyped 38 TEC single nucleotide polymorphisms in a total of 592 subjects, which comprised 163 AERD cases and 429 aspirin-tolerant asthma controls. Logistic regression analysis was performed to examine the associations between TEC polymorphisms and the risk of AERD in a Korean population. The results revealed that TEC polymorphisms and major haplotypes were not associated with the risk of AERD. In another regression analysis for the fall rate of forced expiratory volume in 1 second ($FEV_1$) by aspirin provocation, two variations (rs7664091 and rs12500534) and one haplotype (TEC_BL2_ht4) showed nominal associations with $FEV_1$ decline (p=0.03-0.04). However, the association signals were not retained after performing corrections for multiple testing. Despite TEC playing an important role in immune responses, the results from the present study suggest that TEC polymorphisms do not affect AERD susceptibility. Findings from the present study might contribute to the genetic etiology of AERD pathogenesis.