Transporter associated with antigen processing (TAP) 1 gene polymorphisms in patients with hypersensitivity pneumonitis

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Experimental and Molecular Pathology 84 (2008) 173 – 177 www.elsevier.com/locate/yexmp

Transporter associated with antigen processing (TAP) 1 gene polymorphisms in patients with hypersensitivity pneumonitis Arnoldo Aquino-Galvez a , Ángel Camarena a , Martha Montaño a , Armida Juarez a , Ana C. Zamora a , Georgina González-Avila a , Marco Checa a , Gabriel Sandoval-López a , Gilberto Vargas-Alarcon c , Julio Granados b , Annie Pardo d , Joaquín Zúñiga a,1 , Moisés Selman a,⁎,1 b

a Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, Col. Sección XVI, 14080, Mexico City, Mexico Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Vasco de Quiroga 15, Col. Sección XVI, 14050, Mexico City, Mexico c Instituto Nacional de Cardiología “Ignacio Chávez.”, Juan Badiano 1, Col Sección XVI, Mexico City, Mexico d Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico

Received 21 January 2008 Available online 14 February 2008

Abstract Hypersensitivity pneumonitis (HP) is a lung inflammatory disease caused by the inhalation of a variety of antigens. Previous studies support the role of the major histocompatibility complex (MHC) class II genes in the susceptibility to develop HP. However, the putative role of other MHC loci has not been elucidated. Transporters associated with antigen processing (TAP) genes are located within the MHC class II region and play an important role transporting peptides across the endoplasmic reticulum membrane for MHC class I molecules assembly. The distribution of single nucleotide polymorphisms (SNPs) in TAP1 genes was analyzed in 73 hypersensitivity pneumonitis (HP) patients and 58 normal subjects. We found a significant association of the allele Gly-637 (GGC) ( p = 0.00004, OR = 27.30, CI = 3.87–548.04) and the genotypes Asp-637/Gly-637 ( p = 0.01, OR = 16.0, CI = 2.19–631.21), Pro-661/Pro-661 ( p = 0.006, OR = 11.30, CI = 2.28–75.77) with HP. A significant decrease in the frequency of the allele Pro-661 (CCA) ( p = 0.008, OR = 0.06, CI = 0–0.45), the genotype Asp-637/Asp-637 ( p = 0.01, OR = 0.17, 95% CI = 0.05– 0.58) and the haplotype [Val-333 (GTC), Val-458 (GTG), Gly-637 (GGC), Pro-661 (CCA)] was detected in HP patients compared with controls ( p = 0.002, OR = 0.07, CI = 0.0–0.57). These findings suggest that TAP1 gene polymorphisms are related to HP risk, and highlight the importance of the MHC in the development of this disease. © 2008 Elsevier Inc. All rights reserved. Keywords: Genetic susceptibility; Hypersensitivity pneumonitis; Major histocompatibility complex (MHC); Transporter associated with antigen processing genes; TAP1

Introduction Hypersensitivity pneumonitis (HP) is an immunologicallymediated lung disease caused by repeated inhalation of dispersed antigens in susceptible individuals (Lacasse et al., 2003). Pigeon breeder's disease is one of the most common clinical forms of HP, caused by exposure to various avian-derived ⁎ Corresponding author. Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502; CP 14080, Mexico City, Mexico. Fax: +52 55 5665 4623. E-mail address: [email protected] (M. Selman). 1 These authors contributed equally. 0014-4800/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.yexmp.2008.01.002

antigens. The clinical presentation is heterogeneous and the individuals exposed to low levels of avian antigens, can develop a sub-acute or chronic disease and some of them may evolve to pulmonary fibrosis (Selman et, 2004; Ramírez-Venegas et al., 1998). Importantly, only a small proportion of individuals exposed to potential HP causing antigens develop the disease. In this context, HP is considered a multifactorial disease involving complex interactions between antigen exposure and perhaps other environmental factors and alleles of many genes (Selman, 2004; Ramírez-Venegas et al., 1998; Fink et al., 2005). MHC genes have been involved with the susceptibility to HP in

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different ethnic groups. In previous studies, we have described a significant association of the MHC class II haplotype: HLADRB1⁎1305-DQB1⁎0301 with the susceptibility to HP in Mexicans. Furthermore, our results suggested the existence of additional susceptibility loci within the MHC which might contribute to the disease susceptibility (Camarena et al., 2001). The transporters associated with antigen processing (TAP) genes are mapped within the MHC class II region and are critical for antigen processing and presentation by MHC class I molecules (Walsh et al., 2003; Powis et al., 1993). TAP translocates antigenic peptides from the cytosol into the endoplasmic reticulum (ER) lumen, where peptides are loaded onto MHC class I molecules (Koch et al., 2004). The functional TAP complex is a heterodimer composed by TAP1 and TAP2 and their function is dependent on adenosine triphosphate (ATP) hydrolysis (Koch et al., 2004; McCluskey et al., 2004). Because of their role in endogenous antigen processing, their location within MHC, and their polymorphisms, the TAP genes have been reported to be important candidates for disease association (Lajoie et al., 2003). The aim of this study was to investigate the distribution of four single nucleotide polymorphisms (SNPs) located in the coding region of TAP1 gene in Mexican Mestizos and analyze their potential role in the susceptibility to HP. Materials and methods Subjects Seventy three Mexican patients with diagnosis of HP were included in this study. Patients were recruited from the Interstitial Lung Diseases Clinic of the National Institute of Respiratory Diseases. Diagnosis of HP was established according to the following criteria: a) bird exposure preceding the disease and positive serum antibodies against avian antigens as determined by ELISA; b) shortness of breath with partial improvement after avoidance of avian antigen exposure; c) clinical and functional features of an interstitial lung disease; d) high-resolution computed tomography scan of the chest showing diffuse centrilobular poorly defined micronodules, ground glass attenuation, focal air trapping and mild/moderate fibrotic changes and e) N40% lymphocytes in bronchoalveolar lavage fluid (Ramírez-Venegas et al., 1998; Selman et al., 2006). Forty-five percent of the patients were biopsied and in all of them lung histology was compatible with the diagnosis of HP. Fifty eight healthy Mexican individuals, without history of connective tissue disorders or pulmonary disease, were included in the study as controls. For this study we enrolled only those individuals whose last two generations were born in Mexico, and thus considered to be Mexican Mestizo. Our control group has been genetically characterized and admixture estimation studies have revealed a proportion of 56% Indian genes, 40% Caucasian genes and 4% black genes (Lisker et al., 1998; Lisker et al., 1990). The protocol was approved by the Institutional Review Board and only those patients who signed informed consent letter were included in the study.

DNA extraction Genomic DNA from whole blood containing EDTA was isolated by a salting-out procedure.

TAP polymorphism typing Variations in the TAP1 gene were identified by polymerase chain reaction and hybridization with sequence-specific oligonucleotide probes (PCR-SSOP) as previously described (Perry et al., 1998). PCR was performed in a 25 μl final volume containing 100 ng of genomic DNA, 1.5 mM MgCl2, 0.2 mM dNTPs,

1× Taq DNA polymerase buffer, 0.5 μM of each oligonucleotide primer and 2.5 U of recombinant Taq DNA polymerase (Invitrogen, Carlsbad, CA). PCR conditions were initial denaturation at 94 °C during 5 min followed by 35 cycles of 94 °C during 30 s, 54 °C or 68 °C during 30 s, and 72 °C during 5 min. Cycling was carried out in a GeneAmp PCR System 9700 (Applied Biosystems, Foster City CA). PCR products were heat-denatured during 10 min at 94 °C and 5 μl of the sample was spotted onto positively charged nylon membranes (Amersham Biosciences, Bucks UK) previously soaked in SSC 10× (10 min) and then they were UV-cross linked. Blots were pre-hybridized with DIG Easy Hyb solution (Roche Diagnostics GmbH, Mannheim Germany) during 30 min at the calculated melting temperature for each oligonucleotide and then hybridized with mix Dig Easy Hyb/digoxigenin-labeled SSO probes (25 ng/ml) overnight at the calculated melting temperature for each SSO probe. Blots were washed twice with 2× SSC, 0.1% SDS, twice with 0.5× SSC, 0.1% SDS and washing buffer (0.1 M maleic acid, 0.15 M NaCl, pH 7.5, 0.3% [v/v] Tween 20) at room temperature. Membranes were incubated with 10% blocking solution during 30 min (Roche Diagnostics GmbH, Mannheim Germany) and treated with antidigoxigenin-Ab-alkaline phosphatase conjugate (Roche Diagnostics GmbH, Mannheim Germany) in blocking solution during 30 min at room temperature and then washed two times during 15 min in washing buffer. Membranes were incubated with detection buffer during 5 min, and washed with sterile double distilled water. Results were documented by Electrophoresis Documentation and Analysis System 290 (Kodak, Rochester NY).

Statistical analysis Comparison of TAP1 allele, genotypic and haplotypic frequencies of TAP1 gene SNPs (corresponding to amino acid positions 333, 458, 637 and 661) were evaluated by the Mantel–Haenszel, Chi-square test that combined the 2 × 2 contingency tables in HP patients and control group using the EPIINFO statistical program (Version 6.04b). P values were corrected by the Bonferroni method multiplying the p value for the number of comparisons. Relative risks (RR) with 95% confidence interval (95% CI) were estimated as the odds ratios. Hardy–Weinberg equilibrium was also tested for all genotypic combinations of each TAP variant.

Results The gene and genotype frequencies of the TAP1 polymorphisms in the positions 333, 458, 637 and 661 are presented in Table 1. The most common alleles for these positions were: Ile333 (ATC) for position 333 (g.f. = 0.808 in HP patients and 0.853 in healthy controls); Val-458 (GTG) for position 458 (g.f. = 0.993 in HP patients and 0.965 in controls); Asp-637 (GAC) for position 637 (g.f. = 0.801 in HP patients and 0.931 in controls) and Pro-661 (CCG) for position 661 (g.f. = 0.979 in HP patients compared with 0.948 in controls). The most frequent genotypes were homozygous Ile-333/Ile-333 (ATC/ATC) for position 333; homozygous Val-458/Val-458 (GTG/GTG) for position 458; homozygous Asp-637/Asp-637 (GAC/GAC) for position 637 and homozygous Pro-661/Pro-661 (CCG/CCG) for position 661 (Table 1). Significant deviations from the Hardy–Weinberg equilibrium in the distribution of TAP1 SNP genotypes in HP patients and healthy controls were not detected. We found a significant increase in the frequency of the allele Gly-637 (GGC) in HP patients compared with controls ( p = 0.00004, OR = 27.30, 95% CI = 3.87–548.04), Table 1. We also observed a significant decrease in the frequency of the allele Pro-661 (CCA) in HP patients ( p = 0.008, OR = 0.06, 95% CI = 0–0.45). In regard to the genotype analysis we found a significant increase in the frequency of Asp-637/Gly-637 ( p = 0.01,

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Table 1 Gene and genotype frequencies of TAP1 polymorphisms in patients with hypersensitivity pneumonitis (HP) and healthy controls TAP 1

Position 333 Alleles Genotypes

Position 458 Alleles Genotypes

Position 637 Alleles Genotypes

Position 661 Alleles Genotypes

HP patients (N=73)

Controls (N = 58)

n

g.f.

n

Ile-333 (ATC) Val-333 (GTC) Ile-333/Ile-333 Ile-333/Val-333 Val-333/Val-333

118 28 47 24 2

0.808 0.191 0.643 0.328 0.027

99 17 41 17 0

0.853 0.146 0.706 0.293 –

NS NS NS NS NS

Leu-458 (TTG) Val-458 (GTG) Leu-458/Leu-458 Leu-458/Val-458 Val-458/Val-458

2 145 0 2 71

0.013 0.993 – 0.027 0.972

4 112 0 4 54

0.034 0.965 – 0.068 0.931

NS NS NS NS NS

Asp-637 (GAC) Gly-637 (GGC) Asp-637/Asp-637 Asp-637/Gly-637 Gly-637/Gly-637

117 27 51 15 6

0.801 0.184 0.698 0.205 0.082

108 0 54 0 0

0.931 – 0.931 – –

0.004 0.00004 0.01 0.01 NS

Pro-661 (CCA) Pro-661 (CCG) Pro-661/Pro-661 Pro-661/Pro-661 Pro-661/Pro-661

1 143 0 1 71

0.006 0.979 – 0.013 0.972

12 110 0 12 44

0.103 0.948 – 0.206 0.758

0.008 NS NS NS 0.006

OR = 16.0, 95% CI = 2.19–631.21) and Pro-661/Pro-661 ( p = 0.006, OR = 11.30, 95% CI = 2.28–75.77) in the patients group. Interestingly, the frequency of the genotype Asp-637/ Asp-637 was considerably lower in HP ( p = 0.01, OR = 0.17, 95% CI = 0.05–0.58). The haplotype frequencies of the polymorphisms at positions 333, 458, 637 and 661 are shown in Table 2. As expected, the haplotypic combination of SNPs that define the TAP1⁎0101 allele was the most frequent in both groups. Besides, a significant decrease in the frequency of the haplotype [Val-333 (GTC), Val-458 (GTG), Gly-637 (GGC), Pro-661 (CCA)] was detected in the group of patients compared to controls (h.f. = 0.006 in HP patients vs. h.f. = 0.077 in controls, p = 0.002, OR = 0.07, 95% CI = 0.0–0.57). This combination of poly-

pC

OR

95% CI

0.30 27.30 0.17 16.0

0.12–0.72 3.87–548.04 0.05–0.58 2.10–631.21

0.06

0–0.45

g.f.

11.30

2.28–75.77

morphisms at positions 333, 458, 637 and 661 identify the allele TAP1⁎02012. Contrasting this finding, we observed a trend of association of the haplotype [Val-333 (GTC), Val-458 (GTG), Gly-637 (GGC), Pro (CCG)] with the susceptibility to HP, however the p value was not significant after Bonferroni correction ( p = 0.09, OR = 4.19). Discussion Hypersensitivity pneumonitis is a complex syndrome characterized by an immunologically-induced lung inflammation in response to a large variety of inhaled antigens. Previous studies have shown that genetic susceptibility to develop HP is related, at least in part, to the MHC class II genes, as well as with tumor

Table 2 Haplotypic frequencies of polymorphic residues of TAP1 alleles in hypersensitivity pneumonitis (HP) patients and healthy controls TAP 1 allele

0101 02011 02012 0301 0401 X

Position

HP patients (N = 73)

Healthy Controls (N=58)

333

458

637

661

n

h.f.

n

h.f.

Ile (ATC) Val (GTC) Val (GTC) Val (GTC) Val (GTC)

Val (GTG) Val (GTG) Val (GTG) Val (GTG) Leu (TTG)

Asp (GAC) Gly (GGC) Gly (GGC) Asp (GAC) Gly (GGC)

Pro (CCG) Pro (CCG) Pro (CCA) Pro (CCG) Pro (CCG)

110 10 1 10 2 13

0.753 0.068 0.006 0.068 0.013 0.089

91 2 9 9 0 5

0.784 0.017 0.077 0.077 – 0.043

pC

OR

95% CI

NS NS 0.03 0.08 0.00–0.65 NS NS

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necrosis factor alpha (TNF-α) promoter polymorphisms (Camarena et al., 2001). In this study, we have investigated the distribution of four biallelic polymorphisms in the TAP1 gene corresponding to amino acid positions 333, 458, 637 and 661 in a group of 73 HP patients and 58 control Mexican Mestizo subjects. The single nucleotide polymorphisms (SNP) producing Ile→Val substitution at codon 333, Val→Leu substitution at codon 458, Asp→Gly substitution at codon 637 and synonymous substitution Pro→Pro at codon 661 were determined by molecular methods. We found a significant association of the allele Gly637 (GGC) and the genotypes Asp-637/Gly-637, and Pro-661/ Pro-661 with HP. In addition, we also observed a significant decrease in the frequency of the allele Pro-661 (CCA), the genotype Asp-637/Asp-637 and the haplotype Val-333 (GTC), Val-458 (GTG), Gly-637 (GGC), Pro-661 (CCA) in HP patients compared with controls. Several reports have described genetic associations of TAP1 polymorphisms with inflammatory and infectious diseases (Camarena et al., 2001; Vejbaesca et al., 2000; Rajalingam et al., 1997; Foley et al., 1999; Pyo et al., 2003; WitkowskaTobola et al., 2004; Hang et al., 2003). Interestingly, TAP1 polymorphism in position 333 in combination with HLA-A3 has also been correlated with rapid human immunodeficiency virus (HIV) disease progression (Keet et al., 1997; Kaslow et al., 1996. Further studies are necessary to elucidate the molecular mechanism (s) by which TAP1 may mediate the susceptibility to HP; however, the so far identified mechanisms involved in the pathogenesis of HP suggests that TAP1 polymorphisms might be directly associated with the susceptibility to the disease. In this context, it is currently accepted that an exaggerated cell-mediated immune response contributes to the development of HP (Barrera et al., 2008). Activation of cytotoxic T-cells which play a relevant role in HP requires presentation of endogenous antigenic peptides by MHC class I molecules. For this purpose, antigens are cleaved into smaller peptides by the proteasome and then transported into the endoplasmatic reticulum by TAP proteins, where they can bind to MHC molecules. Moreover, even though the involvement of TAP proteins in the MHC class I antigen-presenting pathway is well known (McCluskey et al., 2004), there is also evidence supporting their role in the loading of peptides onto MHC class II molecules (Tewari et al., 2005; Dissanayake et al., 2005; Dani et al., 2004). In this context, it is possible that polymorphisms in the TAP genes sequence resulting in amino acid substitutions increase the affinity of certain intracytoplasmic antigens to the peptide binding region of MHC class II molecules, inducing exacerbated immune activation. In the case of pre-endosomal peptide loading onto MHC class II molecules, TAP1 polymorphisms may lead the display of self or intracellular pathogen derived antigens with the subsequent interruption of self-tolerance or exaggerated immune activation, respectively with pathologic consequences. Interestingly, our results suggest that the presence of Gly (non-polar residue) instead of Asp (polar residue) in the position 637 located within the putative TAP1 ATP-binding domain contributes to the HP susceptibility. It is important to mention

that TAP mediated peptide translocation requires binding and hydrolysis of ATP by the nucleotide-binding domains of TAP1 and TAP2 proteins (Lankat-Buttgereit and Tampe, 2002). Highlighting the relevance of the polymorphisms in the TAP1 ATP-binding domain, some studies have described that TAP1 binds ATP much more efficiently than does TAP2 (Lajoie et al., 2003; Alberts et al., 2001). The frequencies of TAP1 polymorphisms in Mexican Mestizos show some differences in the distribution of TAP1⁎0201, TAP1⁎0301 and TAP1⁎0401 alleles in relation with previous published studies in Mexican Amerindians and Mestizos (Balladares et al., 2002). Such discrepancies could be related to the differences in the sample size and with the methodological approach. Thus, the hybridization with sequence specific oligonucleotides (SSO) used in this study may be more reliable than the amplification refractory mutation system (ARMS), a very common and easy method used to analyze TAP polymorphisms (Jordan et al., 1995). Moreover, the method used in our study allow us the differentiation between TAP1⁎02011 and TAP1⁎02012 alleles. Some population genetic studies support the notion that distribution of TAP alleles in people living in developing countries may differ from that seen in people living in developed countries due to pathogen driving selection pressures (Lajoie et al., 2003; Faucz et al., 2000). In this context, phylogenetic analyses have demonstrated that TAP1⁎0101 is the most recent allele of TAP1 polymorphisms and alleles ⁎02012 and ⁎02011 are the ancestral alleles in humans (Tang et al., 2001). The predominance of TAP1⁎0101 allele frequency contrasting with the low frequency of ⁎02012 and ⁎02011 alleles might be due to functional advantages of the allele ⁎0101 over other alleles. In conclusion, the frequencies of the alleles Gly-637 (GGC) and the genotypes Asp-637/Gly-637 and Pro-661/Pro-661 are increased in Mexican HP patients. These findings suggest that SNP at position 637 of TAP1 gene could be implicated in the susceptibility to the disease in Mexican population. Additional studies in a large number of patients may help to establish the true significance and the deleterious effect of these variations located in the coding region of TAP1 gene in the susceptibility to HP. Acknowledgments This study was supported by Universidad Nacional Autónoma de México Grant SDI.PTID.05.6. The authors are grateful to the study participants. References Alberts, P., Daimke, O., Deverson, E.V., Howard, J.C., Knittler, M.R., 2001. Distinct functional properties of the TAP subunits coordinate the nucleotidedependent transport cycle. Curr. Biol. 11, 242–251. Balladares, S., Alaez, C., Pujol, J., Duran, C., Navarro, J.L., Gorodezky, C., 2002. Distribution of TAP gene polymorphisms and extended MHC haplotypes in Mexican Mestizos and Seri Indians from northwest Mexico. Genes Immun. 3, 78–85. Barrera, L., Mendoza, F., Zuniga, J., Estrada, A., Zamora, A., Melendro, E.I., Ramirez, R., Pardo, A., Selman, M., 2008. Functional diversity of T cell subpopulations in subacute and chronic hypersensitivity pneumonitis. Am. J. Respir. Crit. Care Med. 177, 44–55.

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