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(Chest. 2005;128:94-101.)
© 2005 American College of Chest Physicians

NRAMP1 Gene Polymorphism and Susceptibility to Nontuberculous Mycobacterial Lung Diseases*

Won-Jung Koh, MD; O. Jung Kwon, MD; Eun Joo Kim, PhD; Kyung Soo Lee, MD; Chang-Seok Ki, MD and Jong Won Kim, MD

* From the Division of Pulmonary and Critical Care Medicine, Departments of Medicine (Drs. Koh, Kwon, and E.J. Kim), Radiology (Dr. Lee), and Laboratory Medicine (Drs. Ki, and J.W. Kim), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

Correspondence to: O. Jung Kwon, MD, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Gangnam-gu, Seoul 135–710, South Korea; e-mail: ojkwon{at}smc.samsung.co.kr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objectives: Pulmonary disease caused by nontuberculous mycobacteria (NTM) may occur in patients with no underlying lung disease and no known immunodeficiency. The purpose of this study was to evaluate a potential role for natural-resistance-associated macrophage protein 1 (NRAMP1) gene polymorphisms for human susceptibility to the NTM lung disease.

Design: A case-control study.

Setting: Tertiary university medical center.

Participants: Forty-one adult patients with NTM lung disease (Mycobacterium avium complex infection, 18 patients; Mycobacterium abscessus infection, 23 patients) were included in the study population. The diagnosis of NTM lung disease was made when the patients fulfilled the diagnostic criteria published by the American Thoracic Society. All patients had findings on high-resolution CT scans, such as bilateral bronchiectasis combined with multiple small nodules and branching linear structures, that were characteristic of the nodular bronchiectatic form of NTM lung disease. Fifty healthy individuals were selected as control subjects.

Results: Heterozygotes at intron 4 (469 + 14G/C) [INT4], codon 543 in exon 15 (D543N), and 3' untranslated region (3'UTR) were observed at significantly higher frequencies in patients with NTM lung disease than in control subjects. The odds ratios (ORs) were 2.78 (95% confidence interval [CI], 1.12 to 6.89; p = 0.026) for INT4 G/C, 5.74 (95% CI, 1.48 to 22.30; p = 0.006) for D543 G/A, and 9.54 (95% CI, 2.49 to 36.53; p < 0.001) for 3'UTR TGTG+/del. Subjects who were heterozygous for two NRAMP1 polymorphisms in INT4 and D543N were particularly overrepresented among those with NTM lung disease, compared with those with the most common NRAMP1 genotype (OR, 10.88, 95% CI, 1.18 to 100.45; p = 0.035). There were no significant differences in the frequencies of INT4, D543N, and 3'UTR polymorphisms between the patients with M avium complex infection and those with M abscessus infection.

Conclusions: These findings suggest that the NRAMP1 genetic polymorphisms are associated with human susceptibility to NTM lung disease.

Key Words: atypical mycobacteria • cation transport proteins • genetic predisposition to disease • lung diseases • polymorphism


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
The incidence of pulmonary disease caused by nontuberculous mycobacteria (NTMs) in HIV-negative patients has been increasing, and a substantial proportion of these patients have no preexisting lung disease and no demonstrable immunodeficiency.12 These patients are predominantly elderly women with no history of smoking.1234567 High-resolution CT scans revealed the characteristic findings of multifocal bronchiectasis combined with multiple small nodules (nodular bronchiectasis), which were usually confined to or were most severe in the right middle lobe and lingular segment of the left upper lobe.891011

NTMs are ubiquitous environmental organisms. Because exposure to these organisms is universal and the occurrence of disease is rare, normal host defense mechanisms must be effective enough to prevent the infection.12 So, otherwise healthy individuals who develop NTM lung disease are likely to have specific susceptibility factors that cause these infections.12 Although the lack of normal interferon-{gamma} receptor expression1314 or interleukin-12 receptor expression151617 has been reported to be associated with disseminated NTM infection in some young pediatric patients, there is currently no evidence of similar genetic defects in adult patients with isolated NTM lung disease.1218

In addition to the above-mentioned specific genetic defects such as interferon-{gamma} receptor deficiency or interleukin-12 receptor deficiency, there is a growing interest in the role of genetic polymorphisms in mycobacterial susceptibility in humans. For mice, innate immunity to tuberculosis is under the control of a single gene, which is designated as the natural resistance-associated macrophage protein 1 (Nramp1 [also called Slc11a1]) gene.1920 The NRAMP1 gene is the human equivalent of the murine Nramp1 gene for resistance to intracellular parasites, including bacillus Calmette-Guérin, Leishmania, and Salmonella.21 NRAMP1 encodes an ion transporter that localizes to the lysosomal membrane during the phagocytosis of mycobacteria and other pathogens, and it might regulate ion or divalent cation transport.2223 It is, therefore, a strong candidate gene for investigating human susceptibility to tuberculosis. The potential roles of NRAMP1 polymorphisms in the development of tuberculosis have been investigated in various studies, and the results have shown some discrepancies.242526272829303132

However, the association of NRAMP1 polymorphisms and NTM lung disease has not been well-studied until now. A small study18 in eight elderly women with Mycobacterium avium complex (MAC) lung disease did not find evidence for a genetic NRAMP1 defect, and another study33 did not find evidence that an abnormal NRAMP1 gene was causative in two Japanese families affected by MAC pulmonary disease. The purpose of this study was to evaluate whether NRAMP1 polymorphisms are associated with susceptibility to NTM lung disease in otherwise healthy adult patients.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patients and Control Subjects
A total of 41 patients (7 men and 34 women) with the nodular bronchiectatic form of NTM lung disease were consecutively enrolled at the Samsung Medical Center (Seoul, South Korea) from January 2002 to December 2003. All patients had characteristic findings on high-resolution CT scans, such as bilateral bronchiectasis combined with multiple small nodules and branching linear structures.891011 During the study period, it was our policy to perform, at least three times and usually five times, sputum acid-fast bacilli staining and culture examinations for mycobacteria in the patients with bilateral bronchiectasis and multiple nodules. Bronchoscopy was performed for bronchial washing and/or transbronchial lung biopsies in 37 of these 41 patients for a confirmatory diagnosis of NTM lung disease. The summarized results of the diagnostic tests are shown in Table 1 . The diagnosis of NTM lung disease was made when the patients fulfilled the clinical, radiologic, and microbiological diagnostic criteria published by the American Thoracic Society.1


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  		Table 1. The Results of Diagnostic Tests in Patients With NTM Lung Disease*

 
Patients ranged in age between 25 and 78 years, with an average age of 58 years. Of 41 patients, 18 patients were identified as having MAC infection (Mycobacterium intracellulare, 13 patients; M avium, 5 patients), and 23 patients were identified as having Mycobacterium abscessus pulmonary infection. If the patient had previously received a diagnosis of pulmonary tuberculosis and had been treated with antituberculous drugs, then those patients were regarded as having a positive history of tuberculosis. This study was approved by the Institutional Review Board at Samsung Medical Center, and written informed consent was obtained from each participant.

The control subjects were 50 healthy individuals (23 men and 27 women) who had visited Samsung Medical Center for routine health examinations and had participated in the previous study of NRAMP1 polymorphisms in patients with rheumatoid arthritis.34 Control subjects had an average age of 50 years (age range, 37 to 76 years). None of the control subjects had any pulmonary disease, including a history of tuberculosis and bronchiectasis at the time of participation, and all were confirmed to be disease-free as determined by the findings of medical histories, physical examinations, routine blood tests, and chest radiograph examinations. Also, control subjects did not have possible risk factors, including diabetes, underlying malignancy, and immunosuppressive treatment. The results of testing for antibodies to HIV were negative for all patients and control subjects. All participants included in the study group and control group were inhabitants of South Korea and of Korean descent. No subjects belonged to another ethnic group. Therefore, patients and control subjects were matched in their geographic and racial origin, but they were not individually matched for age and gender (Table 2 ).


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  		Table 2. Baseline Characteristics of Patients With NTM Lung Disease and Healthy Control Subjects*

 
NRAMP1 Genotyping
The following three NRAMP1 polymorphisms were typed: a single-nucleotide change in intron 4 (469 + 14G/C) [INT4]; a nonconservative single-base substitution at codon 543 in exon 15 that changes aspartic acid to asparagines (D543N); and a TGTG deletion in the 3' untranslated region (3'UTR) located at 55 nucleotides downstream of the last codon in exon 15 (1729 + 55del4).35

Polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis was used to type polymorphisms of the NRAMP1 genes, as was described in the previous study,35 with some modifications. Briefly, DNA samples were extracted from whole venous blood (G-DEXTM Genomic DNA Extraction kits; iNtRON Biotechnology; Sungnam, South Korea). PCR amplifications were performed in 50-µL reaction volumes containing 200 ng genomic DNA, 2.0 mmol/L MgCl2, 200 µmol/L for each deoxynucleotide triphosphate, 10 pmol each primer, and 2 U Taq DNA polymerase (Promega; Madison, WI) using a thermal cycler (model 9600; Perkin Elmer; Branchburg, NJ). The primers used for amplification of NRAMP1 gene polymorphisms were as previously reported,35 encompassing the sequence variants at INT4, D543N, and 3'UTR. The PCR products amplified from the genomic DNA were subjected to digestion using 5 U restriction endonuclease per reaction under the conditions recommended by the manufacturer (Roche Applied Science; Mannheim, Germany). The digestion products were separated by electrophoresis on 4% agarose gels (Promega), which were stained with ethidium bromide and then visualized under ultraviolet light. The genotypes were defined according to the generated fragment patterns, as described in the previous study35 (Fig 1 ).



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  		Figure 1. Agarose gel electrophoresis of PCR-restriction fragment length polymorphism products. bp = base pair.

 
Statistical Analysis
The exact test of Hardy-Weinberg equilibrium for multiple alleles was performed by the Markov chain method within a statistical software package (GENEPOP; Curtin University of Technology; Bentley, Australia).36 For each polymorphism, genotype frequency differences in each group were examined using the {chi}2 test or Fisher Exact Test, as appropriate. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to quantitatively assess the degree of association between the NRAMP1 polymorphisms and NTM lung disease. The influence of linked variation on genotypic associations was assessed by logistic regression analysis. A p value of < 0.05 was considered to be statistically significant. All statistical analyses were performed using a statistical software package (SPSS, version 11.0; SPSS Inc; Chicago, IL).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
The genotype frequencies in the patient and control groups did not deviate from the Hardy-Weinberg equilibrium (p > 0.05). The three polymorphisms, INT4, D543N, and 3'UTR, were each significantly associated with NTM lung disease (p = 0.026, p = 0.006, and p < 0.001, respectively). The ORs were 2.78 (95% CI, 1.12 to 6.89) for the INT4 G/C allele, 5.74 (95% CI, 1.48 to 22.30) for the D543 G/A allele, and 9.54 (95% CI, 2.49 to 36.53) for the 3'UTR TGTG+/del allele (Table 3 ).


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  		Table 3. NRAMP1 Gene Polymorphisms in Patients With NTM Lung Disease and Healthy Control Subjects*

 
The D543N G allele was significantly associated with the 3'UTR TGTG allele (p < 0.001), indicating that both polymorphisms were in strong linkage disequilibrium and were not independent of each other. The INT4 and D543N alleles or INT4 and 3'URT alleles were not significantly associated with each other (p = 0.362 and p = 0.912, respectively). Logistic regression analyses were conducted, with disease status used as the dependent variable, and INT4 and D543N polymorphisms used as the independent variables. INT4 G/C and D543N G/A alleles were still significantly associated with the NTM lung disease (p = 0.043 [OR, 2.66; 95% CI, 1.03 to 6.85] and p = 0.016 [OR, 5.50; 95% CI, 1.38 to 21.88], respectively).

Combined analysis of the INT4 and D543N polymorphisms showed a strong association with the NTM lung disease (Table 4 ). Compared with GG/GG homozygotes, heterozygotes for the INT4 C allele, or the D543N A allele were overrepresented among the patients with NTM lung disease (INT4 C allele: OR, 2.83; 95% CI, 1.04 to 7.73; p = 0.042; D543N A allele: OR, 6.53; 95% CI, 1.19 to 35.75; p = 0.031). Heterozygosity for both of these variants was associated with the highest risk of NTM lung disease (OR, 10.88; 95% CI, 1.18 to 100.45; p = 0.035).


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  		Table 4. Combined Analysis of NRAMP1 INT4 and D543N Variants

 
On the other hand, there were no statistically significant differences found between patients with MAC lung disease and those patients with M abscessus lung disease, with regard to INT4, D543N, and 3'UTR polymorphisms (Table 5 ). Twenty-four of 41 patients (59%) with NTM lung disease had a history of pulmonary tuberculosis. There were also no significant differences in the frequencies of INT4, D543N, and 3'UTR polymorphisms between the patients with and without a history of tuberculosis (Table 5).


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  		Table 5. NRAMP1 Gene Polymorphisms and Etiology, and Histories of Tuberculosis in 41 Patients With NTM Lung Disease*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
In the present case-control study, we found a significant association between NTM lung disease and the genetic variation in NRAMP1 such as INT4, D543N, and 3'UTR polymorphisms. INT4 G/C, D543N G/A, and 3'UTR TGTG+/del heterozygotes occurred more frequently in patients than in healthy control subjects. This is the first study showing a significant association between NRAMP1 gene polymorphisms and NTM lung disease. Our findings suggest that the development of NTM lung disease in otherwise healthy adult patients is at least partly associated with genetic factors.

NTM is well-known to be one of the most common pathogens seen in cases of immunodeficiency, such as those people with HIV infection. However, it is unclear why otherwise healthy subjects without definite immunodeficiency experience pulmonary disease caused by these opportunistic pathogens. Traditionally, it has been recognized that the upper lobe cavitary form of NTM lung disease usually developed in older men who were heavy smokers or who had pulmonary lesions such as those associated with COPD.1 This may suggest that the impairment of mucociliary clearance might be an important risk factor.

In addition, the nodular bronchiectatic form of NTM lung disease occurs in nonsmoking middle-aged or elderly women without apparent predisposing lung disease.1234567 Some tentative hypotheses have been proposed to explain the development of NTM lung disease in this population. The previous theories have focused mainly on increased host susceptibility owing to an altered anatomic defense, such as an unidentified systemic connective tissue disorder37 or voluntary cough suppression causing bronchiectasis in the dependent lobes that predisposes these persons to NTM infection.38

However, it is reasonable to suppose that this disease susceptibility could also be explained by an immune deficiency that is caused by alterations occurring at the genetic level rather than at the anatomic level.1239 Studies by Japanese investigators4041 have demonstrated that the association between specific human leukocyte-associated antigen phenotypes and MAC lung disease could raise the possibility of genetic defects for patients with NTM lung disease. A genetic basis for the increased susceptibility to NTM lung disease has been suggested in some reports linking disseminated familial childhood disease to the lack of normal interferon-{gamma} receptor expression1314 or to interleukin-12 receptor expression.151617 However, until now, there has been no evidence of similar genetic defects in adult patients with isolated pulmonary NTM disease.1218

The Nramp1 gene has been identified as a critical factor for host defenses against some mycobacterial species among inbred mouse strains.19 The protein encoded by the Nramp1 gene is exclusively expressed in the macrophage/monocyte, and it is assembled onto the subcellular membrane of the lysosome/endosome and phagolysosome.22 It is likely to restrict mycobacterial replication by influencing the transmembrane transportation of divalent cations, which are essential for the survival of mycobacteria.42 Several case-control studies24262732 have indicated that polymorphisms of the human NRAMP1 gene (ie, INT4, D543N, and 3'UTR polymorphisms) modify the susceptibility of the host to tuberculosis, with the groups affected including Africans and Asians.

However, the association of NRAMP1 polymorphisms and NTM lung disease has not been well-studied until now. Huang et al18 have analyzed the association between the NRAMP1 gene polymorphisms and MAC lung disease in eight elderly women, and they found no evidence of a genetic defect in the NRAMP1 gene to be correlated with the disease. In addition, Tanaka et al33 did not find evidence that an abnormal NRAMP1 gene was causative in two Japanese families affected by MAC lung disease. Our study included > 40 patients, which is a relatively large study population compared to that of previous studies,1833 and we demonstrated that NRAMP1 genetic polymorphisms might be associated with susceptibility to NTM lung disease. There were significant differences in the allele and genotype frequencies for INT4, D543N, and 3'UTR polymorphisms between the patients and the control subjects.

Our study showed that there were no differences in the frequencies of NRAMP1 gene polymorphisms between patients with MAC infection and those with M abscessus infection. Therefore, NRAMP1 gene polymorphisms may be associated with host susceptibility to NTM lung diseases having various etiologies. Interestingly, a comparable percentage of patients with the nodular bronchiectatic form of MAC infection (or M abscessus infection) also had M abscessus (or MAC) recovered from sputum.743 This suggests that the risk factor for the two diseases may be similar. Further study may be needed to extend these observations to other NTM species.

Fifty-nine percent of the patients with NTM lung disease in this study had histories of tuberculosis, and these findings suggested that pulmonary lesions caused by pulmonary tuberculosis may have predisposed these patients to subsequent NTM infection. However, there was no difference in the frequencies of NRAMP1 gene polymorphisms between patients with NTM lung disease with and without histories of tuberculosis. In fact, it was at best uncertain whether or not the patients with histories of tuberculosis had really experienced pulmonary tuberculosis caused by Mycobacterium tuberculosis. In the countries with high prevalence rates of tuberculosis like Korea, those patients with sputum samples that are positive for acid-fast bacilli on direct microscopic examination or with chest radiographic findings suggesting active tuberculosis were presumed to have pulmonary tuberculosis and were treated empirically with antituberculous drugs.4445 Therefore, unnecessary or inappropriate antituberculous treatment was instituted for many patients with NTM lung disease, and some patients were even treated for presumed multidrug-resistant tuberculosis.464748

Strictly speaking, it was not known whether the control subjects in this study were really exposed and infected with NTM species. So, it is not certain whether the NRAMP1 polymorphisms are associated with a susceptibility to infection with NTM or are associated with a susceptibility to disease progression after NTM infection. However, NTM species are natural inhabitants of the human environment, and they are present in natural waters, drinking water, soil, aerosols, and even cigarettes.49 Thus, it is likely that everyone, including control subjects, in our study was exposed to them on a daily basis through inhalation or ingestion.49 Considering the above situation, we think that our study results suggested that the NRAMP1 genetic polymorphisms may be associated with a susceptibility to NTM lung disease rather than just a susceptibility to infection.

We hypothesized that bronchiectasis had resulted from NTM infection in our patients, based on published reports50515253 that supported the concept that bronchiectasis and disease progression were caused by NTM infection. However, it remains controversial as to whether bronchiectasis is truly caused by NTM infection or is a predisposing condition favoring NTM infection.12 Thus, the following alternative interpretation of our results could be possible: NRAMP1 gene polymorphisms were simply associated with the development of bronchiectasis rather than with NTM lung disease, and bronchiectasis predisposed the patients to be susceptible to NTM infection. Further research is required to address these questions using an additional control group of patients who have bronchiectasis without NTM infection.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
This case-control study showed that heterozygotes at INT4, D543N, and 3'UTR alleles in NRAMP1 gene polymorphisms were observed at significantly higher frequencies in patients with NTM lung disease than in control subjects. This is the first study to indicate a possible genetic risk factor associated with isolated NTM lung disease. Additional studies with patients from diverse ethnic backgrounds will be required to further investigate the relationships underlying these preliminary findings.


   Acknowledgements
 
We thank all of the subjects in this study for their participation. We also thank Seonwoo Kim, PhD (Samsung Biomedical Research Institute, Seoul, South Korea), for assistance in the statistical analysis, Shin-Hye Lee, BS (Samsung Biomedical Research Institute, Seoul, South Korea), for excellent technical assistance, and Gye Young Park, MD (Vanderbilt University, Nashville, TN), for very helpful advice.


   Footnotes
 
Abbreviations: CI = confidence interval; D543N = codon 543 in exon 15; INT4 = intron 4 (469 + 14G/C); MAC = Mycobacterium avium complex; NRAMP1 = natural resistance-associated macrophage protein 1; NTM = nontuberculous mycobacteria; OR = odds ratio; PCR = polymerase chain reaction; 3'UTR = 3' untranslated region

This work was supported by Samsung Biomedical Research Institute grant No. SBRI C-A3–000-1.

Received for publication October 25, 2004. Accepted for publication November 10, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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