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Genetic Association Analysis of TAP1 and TAP2 Polymorphisms with Aspirin Exacerbated Respiratory Disease and Its FEV1 Decline

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Genetic Association Analysis of TAP1 and TAP2 Polymorphisms with Aspirin Exacerbated Respiratory Disease and Its FEV1 Decline Journal of Human Genetics (2011) 56, 652–659 & 2011 The Japan Society of Human Genetics All rights reserved 1434-5161/11 $32.00 www.nature.com/jhg ORIGINAL ARTICLE Genetic association analysis of TAP1 and TAP2 polymorphisms with aspirin exacerbated respiratory disease and its FEV1 decline Jeong-Hyun Kim1, Byung-Lae Park2, Charisse Flerida A Pasaje1, Joon Seol Bae1, Jong Sook Park3, Sung Woo Park3, Soo-Taek Uh3, Mi-Kyeong Kim4, Inseon S Choi5, Sang Heon Cho6, Byoung Whui Choi7, Choon-Sik Park3 and Hyoung Doo Shin1,2 Aspirin exacerbated respiratory disease (AERD) induces bronchoconstriction in asthmatic patients characterized with a clinical condition of severe decline in forced expiratory volume in one second (FEV1) after ingestion of aspirin. Two genes consisting a heterodimer, transporter 1 and 2, ATP-binding cassette, sub-family B (MDR/TAP) (TAP1 and TAP2) within the major histocompatibility complex (MHC) region, have been implicated in immunodeficiency and bronchiectasis development. To investigate the associations of TAP1 and TAP2 genetic polymorphisms with AERD and phenotypic FEV1 decline, a total of 43 common single-nucleotide polymorphisms (SNPs) including 12 SNPs of TAP1 and 31 SNPs of TAP2 were genotyped in 93 AERD patients and 96 aspirin-tolerant asthma controls. Interestingly, regression analysis revealed that polymorphisms and haplotypes of TAP2 were associated with FEV1 decline by aspirin provocation (P¼0.002–0.04), with about twofold decline rate of FEV1 in most of minor homozygotes compared with major homozygotes. In addition, nominal evidences of association between TAP2 and AERD development were observed (P¼0.02–0.04). However, TAP1 polymorphisms showed no relations to both AERD and FEV1 decline after aspirin challenge (P40.05). Although further functional evaluations and replications are required, our preliminary findings provide supporting information that variants of TAP2 might be predisposing factors for FEV1 decline-related symptoms. Journal of Human Genetics (2011) 56, 652–659; doi:10.1038/jhg.2011.75; published online 28 July 2011 Keywords: aspirin exacerbated respiratory disease (AERD); haplotype; single-nucleotide polymorphism; TAP1; TAP2 INTRODUCTION also reported that genes on other pathways, such as the structural gene Aspirin exacerbated respiratory disease (AERD) is characterized by protocadherin-1 (PCDH1) and the transporter gene solute carrier distinct clinical symptoms associated with severe bronchoconstriction family 6 (neurotransmitter transporter, betaine/GABA) member 12 after ingestion of non-steroidal anti-inflammatory drugs including (SLC6A12), could be involved in the development of aspirin hyper- aspirin. Estimates of AERD prevalence are about 0.6–2.5% in the sensitivity in asthmatics.5,6 general population and 10–20% in asthmatic patients.1,2 The disease Both transporter 1 and 2, ATP-binding cassette, sub-family B (MDR/ often accompanies by other symptoms referred to aspirin triad, such TAP) (TAP1 and TAP2), also referred as transporter associated with as bronchial asthma and chronic rhinosinusitis with nasal polyps.2,3 antigen processing, are located within the major histocompatibility Forced expiratory volume in one second (FEV1), as one of criteria for complex (MHC) class II region of the leukocyte antigen (HLA) locus total lung capacity, can determine severe decline of lung function. on human chromosome 6. TAP complex is a heterodimer consisted of Although comprehensive mechanisms have not been known, changes two subunits encoded by TAP1 and TAP2. Mutations in either TAP1 in the structure and function of the airways cause bronchospasms. or TAP2 have been found to impair the translocation of peptides from Although pathophysiology of AERD has been closely linked to the the cytosol into the endoplasmic reticulum.7 The TAP deficiency overproduction of cysteinyl-leukotrienes (CysLTs),4 recent studies have syndrome characterized by immunodeficiency usually shows recurrent 1Department of Life Science, Sogang University, Seoul, Republic of Korea; 2Department of Genetic Epidemiology, SNP Genetics, Inc, Seoul, Republic of Korea; 3Division of Allergy and Respiratory Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea; 4Division of Internal Medicine, Chungbuk National University, Cheongju, Republic of Korea; 5Department of Allergy, Chonnam National University, Gwangju, Republic of Korea; 6Department of Internal Medicine and Institute of Allergy and Clinical Immunology, Seoul National University, Seoul, Republic of Korea and 7Department of Internal Medicine, Chung-Ang University Yongsan Hospital, Seoul, Republic of Korea Correspondence: Dr C-S Park, Genome Research Center for Allergy and Respiratory Diseases, Division of Allergy and Respiratory Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 140-743, Republic of Korea. E-mail: [email protected] or Professor HD Shin, Department of Life Science, Sogang University, 1 Shinsu-dong, Mapo-gu, Seoul 121-742, Republic of Korea. E-mail: [email protected] Received 14 April 2011; revised 6 June 2011; accepted 8 June 2011; published online 28 July 2011 TAP1/TAP2 variants and AERD J-H Kim et al 653 Table 1 Clinical profiles of study subjects Clinical profiles AERD (n¼93) ATA (n¼96) P-value Age year, mean (range) 44.4 (17–73) 45.8 (15–77) 0.497 Sex (male/female) 32/61 24/72 0.156 Ex-smoker/Current smoker (%) 15.63/9.38 6.45/12.90 0.219 Blood eosinophil (%) 6.29±5.80 4.88±4.19 0.060 PC20, methacholine (mg mlÀ1)4.23±7.18 3.04±4.27 0.193 Total IgE (IU mlÀ1)321.65±623.31 309.54±426.04 0.878 Decline of FEV1 by aspirin provocation (%) 23.61±14.48 0.94±2.76 0.001 Positive rate of skin test (%) 61.46 56.99 0.532 Abbreviations: AERD, aspirin exacerbated respiratory disease; ATA, aspirin-tolerant asthma; FEV1, forced expiratory volume in one second. Value significant at Po0.05 is shown in bold. Table 2 Polymorphisms of TAP1 and TAP2 investigated in this study Gene SNP ID Polymorphism Position Amino-acid change Genotype (n) MAF HWE* TAP1 rs2071481 A/G Intron AA (109) AG (60) GG (10) 0.223 0.648 rs2284190 T/C Intron TT (132) TC (50) CC (3) 0.151 0.479 rs4148880 A/G Exon Ile393Val AA (124) AG (55) GG (8) 0.190 0.549 rs2395269 T/G Intron TT (125) TG (52) GG (8) 0.184 0.391 rs12529313 A/G Intron AA (124) AG (55) GG (8) 0.190 0.549 rs2071482 G/T Intron GG (125) GT (53) TT (7) 0.181 0.643 rs735883 C/T Intron CC (78) CT (85) TT (22) 0.349 0.875 rs1800453 A/G Exon Asp697Gly AA (130) AG (48) GG (7) 0.168 0.341 rs4711312 A/G Intron AA (130) AG (48) GG (7) 0.168 0.341 rs1057373 G/T 3¢UTR GG (132) GT (46) TT (7) 0.162 0.248 rs2071540 G/A 3¢near GG (61) GA (94) AA (30) 0.416 0.535 rs2071541 T/C 3¢near TT (127) TC (50) CC (8) 0.178 0.289 TAP2 rs3763366 C/G 5¢near CC (51) CG (94) GG (44) 0.481 0.957 rs4148870 G/A Intron GG (55) GA (89) AA (43) 0.468 0.546 rs2071544 G/A Intron GG (50) GA (95) AA (44) 0.484 0.931 rs2071465 G/C Intron GG (89) GC (78) CC (19) 0.312 0.755 rs2239701 A/G Intron AA (44) GA (101) GG (42) 0.495 0.272 rs241424 C/T Intron CC (49) CT (94) TT (44) 0.487 0.934 rs3819721 G/A Intron GG (101) GA (72) AA (14) 0.267 0.814 rs241426 T/A Intron TT (74) TA (91) AA (22) 0.361 0.453 rs3819714 G/A Intron GG (63) GA (98) AA (26) 0.401 0.214 rs241429 C/T Intron CC (74) CT (86) TT (27) 0.374 0.804 rs4148871 C/T Intron CC (122) CT (62) TT (3) 0.182 0.118 rs241430 G/A Intron GG (68) GA (95) AA (25) 0.386 0.362 rs241432 A/C Intron AA (66) AC (95) CC (28) 0.399 0.512 rs4148873 G/A Exon Val379Ile GG (141) GA (43) AA (3) 0.131 0.893 rs2228397 G/T Exon Synonymous GG (90) GT (78) TT (19) 0.310 0.730 (Gly386Gly) rs241433 T/G Intron TT (63) TG (96) GG (28) 0.406 0.381 rs1015166 C/T Intron CC (99) CT (75) TT (13) 0.270 0.813 rs4576294 G/A Exon Synonymous GG (177) GA (10) AA (0) 0.027 0.707 (Asn436Asn) rs241436 C/T Intron CC (57) CT (82) TT (48) 0.476 0.098 rs241437 C/T Intron CC (52) CT (92) TT (43) 0.476 0.851 rs241438 G/A Intron GG (49) GA (91) AA (48) 0.497 0.662 rs241439 C/A Intron CC (52) CA (91) AA (44) 0.479 0.733 rs4148876 C/T Exon/intron Arg651Cys CC (132) CT (52) TT (3) 0.155 0.403 rs241454 T/C 3¢UTR/intron TT (71) TC (92) CC (24) 0.374 0.492 rs10484565 G/A 3¢UTR/intron GG (146) GA (38) AA (3) 0.118 0.772 rs2857101 A/G 3¢UTR/intron AA (71) AG (94) GG (24) 0.376 0.407 rs13501 G/A 3¢UTR/intron GG (56) GA (96) AA (35) 0.444 0.586 rs1894411 A/G 3¢near/intron AA (141) AG (42) GG (5) 0.138 0.390 rs2856993 C/G 3¢near/intron CC (89) CG (83) GG (15) 0.302 0.473 rs2857103 G/T 3¢near/intron GG (56) GT (96) TT (35) 0.444 0.586 rs2621321 T/C 3¢near TT (81) TC (88) CC (18) 0.332 0.399 Abbreviations: HWE, Hardy–Weinberg equilibrium; MAF, minor allele frequency; SNP, single-nucleotide polymorphism; UTR, untranslated region. *P-value of deviation from HWE.
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