Differences in serum SP-D levels between German and Japanese subjects are associated with SFTPDgene polymorphisms
© Horimasu et al.; licensee BioMed Central Ltd. 2014
Received: 1 August 2013
Accepted: 6 January 2014
Published: 8 January 2014
Surfactant protein A (SP-A) and SP-D are clinically established in Japan as serum biomarkers for diagnosing interstitial lung diseases (ILDs). Serum SP-D levels are affected by genetic variants. We conducted the present study to examine whether serum SP-A and/or SP-D levels in healthy subjects (HS) and patients with ILDs differ between populations with different genetic backgrounds.
German subjects (n = 303; 138 patients with idiopathic interstitial pneumonias [IIPs] and 165 HS) and Japanese subjects (n = 369; 94 patients with IIPs and 275 HS) were enrolled. Serum SP-A and SP-D levels were measured using an enzyme-linked immunosorbent assay, and four single-nucleotide polymorphisms (SNPs) in the SFTPD gene were genotyped using genomic DNA extracted from blood samples.
In both the German and Japanese cohorts, serum SP-A and SP-D levels were significantly higher in patients with IIPs than in HS. There were no significant differences in SP-A levels between the German and Japanese cohorts; however, we found that serum SP-D levels were significantly higher in the German cohort, both in patients with IIPs and in HS (p < 0.001 and p = 0.005, respectively). Furthermore, the genotype distributions of the four SNPs in the SFTPD gene (rs721917, rs1998374, rs2243639, and rs3088308) were significantly different between German and Japanese cohorts (p < 0.001, p < 0.001, p = 0.022, and p < 0.001, respectively), and univariate linear regression analyses revealed that the genotypes of rs721917, rs1998374, and rs2243639 significantly correlated with serum SP-D levels (p < 0.001, p < 0.001, and p = 0.011, respectively). Furthermore, multivariate analyses revealed that the genotypes of these three SNPs correlated independently with serum SP-D levels (p < 0.001, p = 0.001, and p = 0.038, respectively), whereas ethnicity did not significantly correlate with serum SP-D levels.
In patients with IIPs and HS, serum SP-D, but not SP-A, levels were significantly higher in the German than in the Japanese cohort, in part, because of the different frequencies of SFTPD gene polymorphisms.
KeywordsBiological marker Idiopathic interstitial pneumonia Single nucleotide polymorphism Surfactant protein-A (SP-A) Surfactant protein-D (SP-D)
Idiopathic interstitial pneumonias (IIPs) are a group of diffuse parenchymal lung diseases characterized by interstitial involvement resulting from various patterns of inflammation and fibrosis of unknown cause. The prevalence of IIPs has been generally reported as 5–20 per 100,000 persons [1–4], with a recommendation that the diagnosis of IIPs be made according to clinical history, physical findings, chest radiographs, and/or lung function tests [5, 6]. However, some patients may not complain of symptoms or present with abnormal chest radiographs and/or lung function tests, even though they already suffer from IIPs. Therefore, the availability of diagnostic tools that can discriminate patients with IIPs from healthy subjects (HS) at an early stage will be undoubtedly useful in clinical practice. In this regard, serum biomarkers draw particular interest because they are easy to obtain from patients.
Pulmonary surfactant protein A (SP-A) and SP-D are water-soluble proteins derived mainly from type II pneumocytes and belong to the collectin subgroup of the C-type lectin superfamily . Because one of the key histological feature of the lung affected with interstitial lung diseases (ILDs) involves injury and/or regeneration of Type II pneumocytes , soluble proteins derived from Type II pneumocytes, such as SP-A, SP-D, and Krebs von den Lungen 6 (KL-6), have been studied as potential biomarkers for ILDs [9–15]. These biomarkers can be useful for early detection of ILDs, predicting disease outcome, and monitoring the clinical course [16–18]. On the basis of these findings, serum SP-A, SP-D, and KL-6 have been clinically approved by Japan’s Health Insurance Program as diagnostic markers for ILDs in 1999, and more than 2,000,000 samples of these biomarkers are now examined yearly in Japan. However, in most countries, assays for these biomarkers are limited to research and are currently unavailable for clinical practice.
We recently conducted an international study to measure the serum levels of KL-6 and analyze the rs4072037 genotypes of Mucin 1 (MUC1) in German and Japanese cohorts that included patients with ILDs and healthy subjects. We demonstrated that the cutoff value of KL-6 that discriminated patients with ILDs from HS was significantly higher in the German than in the Japanese cohort because of differences in the distribution of rs4072037 genotypes between them . The correlations between rs4072037 genotypes and serum KL-6 levels have also been demonstrated in a Dutch cohort . Moreover, serum SP-D levels were found to be correlated with genetic polymorphisms of surfactant protein D (SFTPD) [21–23]. According to the International HapMap project , the genotype distributions of some single-nucleotide polymorphisms (SNPs) in the SFTPD gene differ according to ethnicities. We hypothesized, therefore, that differences exist in serum SP-D and/or SP-A levels between different ethnic populations. To test this hypothesis, we first measured serum SP-A and SP-D levels and compared them between German and Japanese cohorts that included patients with IIPs and healthy subjects. Next, we evaluated the correlations between serum SP-D levels and SFTPD gene polymorphisms in the German and Japanese cohorts.
Between February 2007 and December 2011, 138 consecutive German-Caucasian patients with IIPs at Ruhrlandklinik, University Hospital Essen (Essen, Germany) and 94 Japanese patients with IIPs at Hiroshima University Hospital (Hiroshima, Japan) were enrolled in the present study. 165 German-Caucasian and 275 Japanese HS were recruited from the subjects who visited these hospitals to undergo health checkup. Diagnoses of IIPs were made according to the criteria of the American Thoracic Society (ATS)/European Respiratory Society (ERS) published in 2002 . We excluded patients with ILDs of known cause, including drugs, collagen vascular diseases, and hypersensitivity pneumonia. Each HS underwent pulmonary function tests and chest X-ray studies, and we excluded those with apparent lung disease such as ILDs or chronic obstructive pulmonary disease (COPD). The Ethics Committees of Ruhrlandklinik (IRB 06-3170) and Hiroshima University Hospital (IRB 326) approved this study, which was conducted in accordance with the ethical standards established by the Helsinki Declaration of 1975. All patients and healthy volunteers provided written informed consent to participate in the study and permission to use their samples.
Lung function values
Physiologic assessment included measurements of thoracic gas volume, total lung capacity, forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and single-breath diffusing capacity of the lung for carbon monoxide (DLCO) as previously described [25–28]. The protocol for lung function measurements conformed to ATS recommendations .
Measurement of serum SP-A and SP-D levels
Serum samples were obtained from 234 patients with IIPs and 440 HS and stored at -80°C. Serum SP-A and SP-D levels were measured using a sandwich-type enzyme-linked immunosorbent assay (ELISA) by using commercially available ELISA kits (SP-A test Kokusai-F kit, Sysmex Corporation Kobe, Japan; SP-D kit YAMASA EIA II, Yamasa Corporation Choshi, Japan) as previously described [28, 30].
DNA preparation and SNP genotyping
Data are presented as the mean ± standard error of the mean (SEM). Data for individual variables for 2 groups were analyzed using the Mann–Whitney U-test or the chi-square test. The significance levels for multiple pairwise comparisons were set according to Bonferroni’s correction. Receiver operating characteristic (ROC) curves were generated to assess the diagnostic abilities of SP-A and SP-D. Linear regression analyses were conducted to study the correlations between serum SP-D levels and each of the four SNPs. If the correlation was statistically significant, multivariate regression analysis was performed to determine whether the SNPs in the SFTD gene independently affect serum SP-D levels even when adjusted by the covariates as follows: age, ethnicity, and case-control status. All statistical analyses were performed using SPSS for Windows, version 18.0 (SPSS Inc. Chicago, USA).
Serum SP-D but not SP-A levels were significantly higher in the German cohort
Characteristics of study subjects
Patients with IIPs
Number of the subjects
67.4 ± 0.8
68.0 ± 1.0
88 (63.8%)/50 (36.2%)
64 (68.1%)/30 (31.9%)
14 (10.1%)/54 (39.1%)/
11 (11.7%)/46 (49.0%)/
64 (46.4%)/6 (4.4%)
35 (37.2%)/2 (2.1%)
VC (percent predicted)
66.1 ± 1.6
70.3 ± 2.2
DLCO (percent predicted)
47.7 ± 1.6
44.8 ± 1.8
Diagnostic category (IPF/NSIP)
94 (68.1%)/44 (31.9%)
61 (64.9%)/33 (35.1%)
Number of the subjects
36.5 ± 0.9
49.8 ± 0.4
60 (36.4%)/105 (63.6%)
227 (82.5%)/48 (17.5%)
41 (24.8%)/20 (12.1%)/
82 (29.8%)/62 (22.6%)/
90 (54.6%)/14 (8.5%)
131 (47.6%)/0 (0.0%)
To evaluate the ability of the serum levels of SP-A and SP-D to discriminate patients with IIPs from HS, ROC curves were drawn for each cohort. The areas under the curves (AUCs) for serum SP-A in the German (AUC = 0.940, 95% confidence interval [CI] = 0.915–0.966; p < 0.001) and Japanese cohorts (AUC = 0.902, 95% CI = 0.868–0.936; p < 0.001) were sufficiently high to distinguish patients with IIPs from HS (Figure 2C). This was true for the AUCs for serum SP-D levels in the German (AUC = 0.977, 95% CI = 0.957–0.996; p < 0.001) and Japanese cohorts as well (AUC = 0.973, 95% CI = 0.952–0.994; p < 0.001; Figure 2D).
Distributions of SFTPDgene polymorphisms are not different between patients with IIPs and healthy subjects
Genotype distributions of single nucleotide polymorphisms in SFTPD gene – patients with IIPs vs HS –
Patients with IIPs
p = 0.140
p = 0.476
Patients with IIPs
p = 0.464
p = 0.102
Patients with IIPs
p = 0.324
p = 0.563
Patients with IIPs
p = 0.752
p = 0.330
Serum SP-D levels differ according to SFTPDgene polymorphisms
Correlation between serum SP-D levels and SFTPDgene polymorphisms is statistically independent
Correlations between serum SP-D levels and SFTPD gene polymorphisms
Regression coefficient (95% CI.)
C/C vs T/C vs T/T
55.276 (28.473 – 82.079)
C/C vs T/C vs T/T
35.149 (15.341 – 54.957)
-0.444 (-2.009 – 1.121)
Japanese vs German
24.061 (-13.125 – 61.246)
HS vs patients with IIPs
307.740 (260.743 – 354.736)
C/C vs T/C vs T/T
86.550 (59.832 – 113.269)
C/C vs T/C vs T/T
36.172 (14.289 – 58.056)
-0.353 (-1.918 – 1.213)
Japanese vs German
11.114 (-28.165 – 50.393)
HS vs patients with IIPs
304.645 (257.602 – 351.689)
C/C vs T/C vs T/T
38.179 (8.965 – 67.393)
C/C vs T/C vs T/T
22.707 (1.310 – 44.104)
-0.360 (-0.449 – 0.654)
Japanese vs German
29.314 (-8.000 – 66.627)
HS vs patients with IIPs
306.421 (259.045 – 353.798)
A/A vs A/T
37.750 (-37.732 – 113.231)
In the present study, we demonstrated that serum SP-A and SP-D levels were significantly higher in patients with IIPs than in HS in both German and Japanese subjects. Moreover, we found that in patients with IIPs and HS, serum SP-D levels were significantly higher in the German than in the Japanese cohort, whereas there were no significant differences in serum SP-A levels between the two cohorts. The genotype distributions of SNPs in the SFTPD gene, which affect the serum SP-D levels, differed between the cohorts. Furthermore, multivariate analyses demonstrated that there were statistically independent correlations between serum SP-D levels and the rs721917, rs1998374, and rs2243639 genotypes of the SFTPD gene, regardless of ethnicity and presence of IIPs.
The significantly higher serum SP-A and SP-D levels in patients with IIPs compared with those of the German HS suggest their utility as diagnostic biomarkers for IIPs, even in the German population. Serum SP-A levels in the German patients with IIPs or HS were comparable to those in their Japanese counterparts (Figure 2A); however, the serum SP-D levels in German patients with IIPs or HS were significantly higher than those in their Japanese counterparts (Figure 2B). These results imply that serum SP-D levels are affected by the different ethnicity, whereas serum SP-A levels are not. In agreement with our present study results, serum SP-D levels in Caucasian HS were reported to be higher than those in Asian HS .
To explain the differences in serum SP-D levels between the German and Japanese cohorts, we determined the relationship between serum SP-D levels and genotypic differences in the SFTPD gene. We found that among the SNPs in SFTPD gene, rs721917, rs1998374, and rs2243639, but not rs3088308, affected the serum SP-D levels (Figure 3), and the distributions of these polymorphisms were different between the German and Japanese cohorts. SP-A and SP-D molecules comprise an N-terminal domain (NTD), a collagen domain, an α-helical neck region, and a carbohydrate recognition domain (CRD; Figure 1) . SP-D polypeptide chains bind together through interpolypeptide disulfide bonds in the NTD to form oligomers, and the degree of oligomerization is affected by the genotypes of coding SNP rs721917 in the NTD. Thus, the T/T and C/C genotypes correlate with higher and lower-order oligomers, respectively [33–36]. These structural variations of SP-Ds might affect their serum levels, and our results demonstrate that serum SP-D levels differed according to the rs721917 genotype (Figure 3A). Furthermore, we also found that serum SP-D levels were affected by the genotypes of rs1998374 and rs2243639, both of which are located in the collagen domain (Figures 1, 3B and C), but they were not affected by the genotypes of rs3088308, the coding SNP in the CRD (Figures 1 and 3D). These findings suggest the possibility that the collagen domain is also associated with the degree of oligomerization of the SP-D molecule.
To determine whether serum SP-D levels were independently correlated with SFTPD gene polymorphisms and/or ethnicity, we performed multivariate regression analyses and found that the correlations between the genotypes of three SNPs in the SFTPD gene and serum SP-D levels remained statistically significant in the multivariate models (Table 3). In contrast, the correlations between ethnicity and serum SP-D levels were insignificant (Table 3). These findings suggest that serum SP-D levels are more strongly affected by SFTPD gene polymorphisms than by ethnicity. Therefore, the difference in serum SP-D levels that were observed between German and Japanese cohorts might be partially explained by the differences in the frequencies of SFTPD gene polymorphisms between the cohorts.
In contrast, we found that the genotype distributions of four SNPs in the SFTPD gene did not differ between patients with IIPs and HS in both cohorts (Table 2). SP-A and SP-D play important roles in surfactant-related functions and in host defense against inhaled pathogens . Moreover, SFTPD gene polymorphisms, rs721917 in particular, have been reported to correlate with susceptibility to COPD, community-acquired pneumonia, ILDs, and lung cancer [23, 38–41]. As discussed above, rs721917 is known to be associated with the degree of oligomerization of the SP-D molecules [33–36]. This difference in oligomerization might affect the surfactant and/or host defense functions of SP-D and thus correlate with susceptibility to various respiratory diseases. In the present study, however, no significant correlation between SFTPD gene polymorphisms and susceptibility to IIPs was demonstrated. We believe that a larger sample size of study is needed to determine the correlations between SFTPD gene polymorphisms and susceptibility to IIPs.
We are aware that there are some limitations in this study. First, age, gender, and smoking status were significantly different between German HS and Japanese HS because the populations who undergo health checkup were different between Germany and Japan. We performed linear regression analysis to assess the interference between these factors and serum SP-D levels, and we found a significant correlation between age and serum SP-D levels. Thus, we included age into the multivariate analyses and confirmed that our results were significant and independent of age differences. Second, the number of subjects available for genomic analyses was relatively small. Third, only German and Japanese populations were studied. It remains unclear whether the findings of the present study can be applied to other ethnic groups such as African Americans.
In conclusion, we demonstrated that the serum levels of SP-A and SP-D were significantly elevated in patients with IIPs in the German and Japanese cohorts, whereas serum SP-D but not SP-A levels were significantly higher in the German cohort. We have explained the differences in serum SP-D levels between these cohorts, at least in part, by the different frequencies of SFTPD gene polymorphisms. Although we believe that these data are compelling, further investigations with larger number of subjects are required to assess the utility of serum SP-A and SP-D in non-Japanese cohorts.
Idiopathic interstitial pneumonia
Surfactant protein A
Surfactant protein D
Interstitial lung disease
Krebs von den Lungen 6
Surfactant protein D
Single nucleotide polymorphism
American Thoracic Society
European Respiratory Society
Chronic obstructive pulmonary disease
Forced vital capacity
Forced expiratory volume in one second
Single-breath diffusing capacity of the lung for carbon monoxide
Enzyme-linked immunosorbent assay
Receiver operating characteristic
Area under the curve
Carbohydrate recognition domain.
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Arbeitsgemeinschaft zur Förderung der Pneumologie an der Ruhrlandklinik (AFPR).
- Ohono S, Nakaya T, Bando M, Sugiyama Y: Idiopathic pulmonary fibrosis - results from a Japanese nationwide epidemiological survey using individual clinical records. Respirology. 2008, 13: 926-928. 10.1111/j.1440-1843.2008.01349.x.View ArticleGoogle Scholar
- Coultas DB, Zumwalt RE, Black WC, Sobonya RE: The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med. 1994, 150: 967-972. 10.1164/ajrccm.150.4.7921471.View ArticlePubMedGoogle Scholar
- Hodgson U, Laitinen T, Tukiainen P: Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland. Thorax. 2002, 57: 338-342. 10.1136/thorax.57.4.338.View ArticlePubMedPubMed CentralGoogle Scholar
- Karakatsani A, Papakosta D, Rapti A, Antoniou KM, Dimadi M, Markopoulou A, Latsi P, Polychronopoulos V, Birba G, Ch L, Bouros D, Hellenic Interstitial Lung Diseases Group: Epidemiology of interstitial lung diseases in Greece. Respir Med. 2009, 103: 1122-1129. 10.1016/j.rmed.2009.03.001.View ArticlePubMedGoogle Scholar
- American Thoracic Society, European Respiratory Society: American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002, 165: 277-304.View ArticleGoogle Scholar
- Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE, Kondoh Y, Myers J, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, et al: ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis: an official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011, 183: 788-824. 10.1164/rccm.2009-040GL.View ArticlePubMedGoogle Scholar
- Kuroki Y, Tsutahara S, Shijubo N, Takahashi H, Shiratori M, Hattori A, Honda Y, Abe S, Akino T: Elevated levels of lung surfactant protein A in sera from patients with idiopathic pulmonary fibrosis and pulmonary alveolar proteinosis. Am Rev Respir Dis. 1993, 147: 723-729. 10.1164/ajrccm/147.3.723.View ArticlePubMedGoogle Scholar
- Selman M, Pardo A: Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers. Proc Am Thorac Soc. 2006, 3: 364-372. 10.1513/pats.200601-003TK.View ArticlePubMedGoogle Scholar
- Greene KE, King TE, Kuroki Y, Bucher-Bartelson B, Hunninghake GW, Newman LS, Nagae H, Mason RJ: Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis. Eur Respir J. 2002, 19: 439-446. 10.1183/09031936.02.00081102.View ArticlePubMedGoogle Scholar
- Prasse A, Müller-Quernheim J: Non-invasive biomarkers in pulmonary fibrosis. Respirology. 2009, 14: 788-795. 10.1111/j.1440-1843.2009.01600.x.View ArticlePubMedGoogle Scholar
- Thomeer M, Grutters JC, Wuyts WA, Willems S, Demedts MG: Clinical use of biomarkers of survival in pulmonary fibrosis. Respir Res. 2010, 11: 89-10.1186/1465-9921-11-89.View ArticlePubMedPubMed CentralGoogle Scholar
- van den Blink B, Wijsenbeek MS, Hoogsteden HC: Serum biomarkers in idiopathic pulmonary fibrosis. Pulm Pharmacol Ther. 2010, 23: 515-520. 10.1016/j.pupt.2010.08.001.View ArticlePubMedGoogle Scholar
- Nukiwa T: The role of biomarkers in management of interstitial lung disease: implications of biomarkers derived from type II pneumocytes. European Respiratory Monograph. Volume 46. Edited by: Du Bois RM, Richeldi L. 2009, UK: ERS Journals Ltd, 47-66.Google Scholar
- Ishikawa N, Hattori N, Yokoyama A, Kohno N: Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respir Investig. 2012, 50: 3-13. 10.1016/j.resinv.2012.02.001.View ArticlePubMedGoogle Scholar
- Zhang Y, Kaminski N: Biomarkers in idiopathic pulmonary fibrosis. Curr Opin Pulm Med. 2012, 18: 441-446. 10.1097/MCP.0b013e328356d03c.View ArticlePubMedPubMed CentralGoogle Scholar
- Kashiwabara K: Characteristics and disease activity of early interstitial lung disease in subjects with true parenchymal abnormalities in the posterior subpleural aspect of the lung. Chest. 2006, 129: 402-406. 10.1378/chest.129.2.402.View ArticlePubMedGoogle Scholar
- Takahashi H, Shiratori M, Kanai A, Chiba H, Kuroki Y, Abe S: Monitoring markers of disease activity for interstitial lung diseases with serum surfactant proteins A and D. Respirology. 2006, 11: S51-S54. 10.1111/j.1440-1843.2006.00809.x.View ArticlePubMedGoogle Scholar
- Tsushima K, Sone S, Yoshikawa S, Yokoyama T, Suzuki T, Kubo K: The radiological patterns of interstitial change at an early phase: over a 4-year follow-up. Respir Med. 2010, 104: 1712-1721. 10.1016/j.rmed.2010.05.014.View ArticlePubMedGoogle Scholar
- Horimasu Y, Hattori N, Ishikawa N, Kawase S, Tanaka S, Yoshioka K, Yokoyama A, Kohno N, Bonella F, Guzman J, Ohshimo S, Costabel U: Different MUC1 gene polymorphisms in German and Japanese ethnicities affect serum KL-6 levels. Respir Med. 2012, 106: 1756-1764. 10.1016/j.rmed.2012.09.001.View ArticlePubMedGoogle Scholar
- Janssen R, Kruit A, Grutters JC, Ruven HJ, Gerritsen WB, van den Bosch JM: The mucin-1 568 adenosine to guanine polymorphism influences serum Krebs von den Lungen-6 levels. Am J Respir Cell Mol Biol. 2006, 34: 496-499. 10.1165/rcmb.2005-0151OC.View ArticlePubMedGoogle Scholar
- Heidinger K, König IR, Bohnert A, Kleinsteiber A, Hilgendorff A, Gortner L, Ziegler A, Chakraborty T, Bein G: Polymorphisms in the human surfactant protein-D (SFTPD) gene: strong evidence that serum levels of surfactant protein-D (SP-D) are genetically influenced. Immunogenetics. 2005, 57: 1-7. 10.1007/s00251-005-0775-5.View ArticlePubMedGoogle Scholar
- Sørensen GL, Hjelmborg JB, Kyvik KO, Fenger M, Høj A, Bendixen C, Sørensen TI, Holmskov U: Genetic and environmental influences of surfactant protein D serum levels. Am J Physiol Lung Cell Mol Physiol. 2006, 290: L1010-L1017. 10.1152/ajplung.00487.2005.View ArticlePubMedGoogle Scholar
- Foreman MG, Kong X, DeMeo DL, Pillai SG, Hersh CP, Bakke P, Gulsvik A, Lomas DA, Litonjua AA, Shapiro SD, Tal-Singer R, Silverman EK: Polymorphisms in surfactant protein-D are associated with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2011, 44: 316-322. 10.1165/rcmb.2009-0360OC.View ArticlePubMedGoogle Scholar
- International HapMap Project. [http://hapmap.ncbi.nlm.nih.gov/index.html.en]
- Kanehara M, Yokoyama A, Tomoda Y, Shiota N, Iwamoto H, Ishikawa N, Taooka Y, Haruta Y, Hattori N, Kohno N: Anti-inflammatory effects and clinical efficacy of theophylline and tulobuterol in mild-to-moderate chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2008, 21: 874-878. 10.1016/j.pupt.2008.09.003.View ArticlePubMedGoogle Scholar
- Iwamoto H, Yokoyama A, Kitahara Y, Ishikawa N, Haruta Y, Yamane K, Hattori N, Hara H, Kohno N: Airflow limitation in smokers is associated with subclinical atherosclerosis. Am J Respir Crit Care Med. 2009, 179: 35-40. 10.1164/rccm.200804-560OC.View ArticlePubMedGoogle Scholar
- Yamane T, Hattori N, Kitahara Y, Haruta Y, Sasaki H, Yokoyama A, Kohno N: Productive cough is an independent risk factor for the development of COPD in former smokers. Respirology. 2010, 15: 313-318. 10.1111/j.1440-1843.2009.01682.x.View ArticlePubMedGoogle Scholar
- Ishikawa N, Hattori N, Tanaka S, Horimasu Y, Haruta Y, Yokoyama A, Kohno N, Kinnula VL: Levels of surfactant proteins A and D and KL-6 are elevated in the induced sputum of chronic obstructive pulmonary disease patients: a sequential sputum analysis. Respiration. 2011, 82: 10-18. 10.1159/000324539.View ArticlePubMedGoogle Scholar
- Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med. 1995, 152: 1107-1136.
- Ohnishi H, Yokoyama A, Kondo K, Hamada H, Abe M, Nishimura K, Hiwada K, Kohno N: Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. Am J Respir Crit Care Med. 2002, 165: 378-381. 10.1164/ajrccm.165.3.2107134.View ArticlePubMedGoogle Scholar
- Hiyama E, Yokohama T, Hiyama K, Yamakido M, Santo T, Kodama T, Ichikawa T, Matsuura Y: Alteration of telomeric repeat length in adult and childhood solid neoplasias. Int J Oncol. 1995, 6: 13-16.PubMedGoogle Scholar
- Shiels MS, Chaturvedi AK, Katki HA, Gochuico BR, Caporaso NE, Engels EA: Circulating markers of interstitial lung disease and subsequent risk of lung cancer. Cancer Epidemiol Biomarkers Prev. 2011, 20: 2262-2272. 10.1158/1055-9965.EPI-11-0326.View ArticlePubMedPubMed CentralGoogle Scholar
- Holmskov U, Thiel S, Jensenius JC: Collections and ficolins: humoral lectins of the innate immune defense. Annu Rev Immunol. 2003, 21: 547-578. 10.1146/annurev.immunol.21.120601.140954.View ArticlePubMedGoogle Scholar
- Crouch E, Persson A, Chang D: Accumulation of surfactant protein D in human pulmonary alveolar proteinosis. Am J Pathol. 1993, 142: 241-248.PubMedPubMed CentralGoogle Scholar
- Crouch E, Persson A, Chang D, Heuser J: Molecular structure of pulmonary surfactant protein D (SP-D). J Biol Chem. 1994, 269: 17311-17319.PubMedGoogle Scholar
- Leth-Larsen R, Garred P, Jensenius H, Meschi J, Hartshorn K, Madsen J, Tornoe I, Madsen HO, Sørensen G, Crouch E, Holmskov U: A common polymorphism in the SFTPD gene influences assembly, function, and concentration of surfactant protein D. J Immunol. 2005, 174: 1532-1538.View ArticlePubMedGoogle Scholar
- Wright JR: Immunoregulatory functions of surfactant proteins. Nat Rev Immunol. 2005, 5: 58-68. 10.1038/nri1528.View ArticlePubMedGoogle Scholar
- Selman M, Lin HM, Montaño M, Jenkins AL, Estrada A, Lin Z, Wang G, DiAngelo SL, Guo X, Umstead TM, Lang CM, Pardo A, Phelps DS, Floros J: Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis. Hum Genet. 2003, 113: 542-550. 10.1007/s00439-003-1015-4.View ArticlePubMedGoogle Scholar
- García-Laorden MI, Rodríguez de Castro F, Solé-Violán J, Rajas O, Blanquer J, Borderías L, Aspa J, Briones ML, Saavedra P, Marcos-Ramos JA, González-Quevedo N, Sologuren I, Herrera-Ramos E, Ferrer JM, Rello J, Rodríguez-Gallego C: Influence of genetic variability at the surfactant proteins A and D in community-acquired pneumonia: a prospective, observational, genetic study. Crit Care. 2011, 15: R57-10.1186/cc10030.View ArticlePubMedPubMed CentralGoogle Scholar
- Ishii T, Hagiwara K, Kamio K, Ikeda S, Arai T, Mieno MN, Kumasaka T, Muramatsu M, Sawabe M, Gemma A, Kida K: Involvement of surfactant protein D in emphysema revealed by genetic association study. Eur J Hum Genet. 2012, 20: 230-235. 10.1038/ejhg.2011.183.View ArticlePubMedGoogle Scholar
- Ishii T, Hagiwara K, Ikeda S, Arai T, Mieno MN, Kumasaka T, Muramatsu M, Sawabe M, Gemma A, Kida K: Association between genetic variations in surfactant protein d and emphysema, interstitial pneumonia, and lung cancer in a Japanese population. COPD. 2012, 9: 409-416.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/15/4/prepub
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.