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Surfactant gene polymorphisms and interstitial lung diseases
Respiratory Research volume 3, Article number: 14 (2001)
Pulmonary surfactant is a complex mixture of phospholipids and proteins, which is present in the alveolar lining fluid and is essential for normal lung function. Alterations in surfactant composition have been reported in several interstitial lung diseases (ILDs). Furthermore, a mutation in the surfactant protein C gene that results in complete absence of the protein has been shown to be associated with familial ILD. The role of surfactant in lung disease is therefore drawing increasing attention following the elucidation of the genetic basis underlying its surface expression and the proof of surfactant abnormalities in ILD.
The role of surfactant in interstitial lung disease (ILD) has drawn increasing attention in recent years, particularly with the publication of the genetic determinants of surfactant expression. This review will focus on surfactant abnormalities in ILD, with emphasis on surfactant protein (SP) gene polymorphisms.
Pulmonary surfactant is a mixture of phospholipids and surfactant-specific proteins, which are essential for normal lung function. The main function of pulmonary surfactant is to stabilize the alveoli throughout the respiratory cycle, preventing alveolar collapse at the end of expiration. Surfactant-specific proteins are also involved in host defense and inflammatory processes in the lung.
Between 90% and 95% of lung surfactant is made up of lipids, with the remainder being proteins. Roughly 65% of the lipid component of surfactant is phosphatidylcholine. The remaining 30–35% consists predominantly of phosphatidylglycerol, while phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine and sphingomyelin are also present in small amounts. The surfactant-specific proteins are mainly composed of four surfactant-associated proteins: SP-A, SP-B, SP-C and SP-D, along with a minor component of mainly serum-derived proteins. SP-A and SP-D are hydrophilic, while SP-B and SP-C are highly hydrophobic proteins.
Surfactant phospholipids and SP-C are synthesized only in the type II alveolar epithelial cells. The proteins SP-A, SP-B and SP-D are produced by Clara cells and type II alveolar epithelial cells in the lung. SP-A is the most abundant surfactant protein and is completely lipid-bound. It is a multimer containing the product of two genes: SP-A1 and SP-A2. SP-A and SP-D proteins are structurally similar collagenous glycoproteins belonging to the collectin superfamily. They are involved in host defense and recognize the carbohydrate moiety on the surface of pathogens. SP-B and SP-C are crucial in reducing surface tension by enhancing the adsorption and spreading of phospholipid at the air–liquid interface. Absence of SP-B production is lethal in infants and experimental animals .
Surfactant in interstitial lung disease
Several studies have explored the surfactant levels in bronchoalveolar lavage (BAL) fluid in patients with ILDs. More recently, serum levels of SPs have been studied and correlated with disease progression.
Bronchoalveolar lavage studies
Idiopathic pulmonary fibrosis (IPF)
Early studies of surfactant in the bleomycin animal model of lung injury showed significant alterations in the composition and biophysical properties of surfactant. Studies of phospholipid content of surfactant in BAL from IPF patients showed significant abnormalities, including reduced alveolar phospholipid, decreased content of phosphatidylglycerol and a reduction in the phosphatidylglycerol/phosphotidylinositol ratio . Gunther et al. studied the biophysical properties of the surfactant obtained from normal control subjects and IPF patients, and showed that the adsorption and surface-tension-reducing properties were largely lost in virtually all patients with IPF.
McCormack and colleagues  hypothesized that the alteration in the surfactant lipid composition changes its biophysical activity, diminishes lung compliance and promotes lung fibrosis. Since SP-A plays an important role in the surface-tension-lowering abilities of surfactant, they measured the SP-A levels in BAL fluid. In addition to reduction in phospholipid content, SP-A levels were also significantly reduced in patients with IPF. The SP-A/phospholipid ratio correlated with disease course over a six-month period and with mortality. In a follow-up study, surfactant levels in BAL fluid were correlated with survival. The mean SP-A/phospholipid ratio was lower in patients with IPF than in healthy volunteers, and the magnitude of reduction was predictive of survival in patients at two years . Others have found a similar reduction in the SPA levels in patients with IPF but no change in SP-B or SP-D levels [1, 3]. Levels of SP-C in BAL fluid of IPF patients are not known. It is clear that there are alterations to the biochemical composition of surfactant in IPF. It is possible that these alterations play an important role in the progression of the disease. Whether the immunological properties of the SPs play a role in the development of the disease needs to be studied.
Other interstitial lung diseases
In sarcoidosis, no substantial changes in surfactant phospholipid profile have been reported in several studies . However, conflicting results have been reported regarding SP-A levels. While van de Graaf et al. found unchanged levels of SP-A , others have found increased  or decreased levels . Although it is possible that the abnormalities may reflect different clinical stages of the disease, it is thought, in general, that sarcoidosis is not associated with major pulmonary surfactant abnormalities . In hypersensitivity pneumonitis, moderate changes in phospholipid profile with reduction in phosphatidylglycerol have been noted . While elevated SP-A levels have been reported in acute disease , both low and high levels have been reported in other studies [3, 6]. Pulmonary alveolar proteinosis is characterized by the abundance of periodic acid Schiff (PAS) material, which fills the alveolar spaces. In the adult form of the disease, the material is composed of glycoprotein and lipids. SPs A, B, C, and D are all increased in BAL fluid. While the phospholipids have been found to be normal, structural alterations in SP-A and SP-B have been described [8, 9].
Recently, Takahashi and colleagues reported the serum levels of SP-A and SP-D, and disease extent in IPF and lung fibrosis associated with scleroderma . In IPF, both SP-A and SP-D concentrations correlated significantly with the extent of alveolitis but not progression of fibrosis. As opposed to lower BAL fluid SP-A levels predicting poor prognosis in other studies, they found that the serum levels were higher in patients who died within three years when compared with patients who lived longer. In scleroderma, the serum levels of SP-A and SP-D were higher in patients with ILD (based on computerized tomography) when compared with patients without any interstitial disease [10, 11].
In summary, both lipid and protein components of surfactant can be abnormal in most ILDs, particularly IPF, and there is evidence to suggest that SP abnormalities may be related to survival in specific diseases. Are these changes genetic or do they merely reflect prior tissue damage? An understanding of the genetics of the underlying lung disease in general, and SP expression in particular, may be important in defining susceptibility to and progression of these conditions.
Genetics of interstitial lung disease
The development of ILDs is thought to occur in genetically susceptible individuals, following exposure to a variety of potential environmental triggers. Support for a genetic influence in the development of ILDs comes from two types of observation. First, there is variable susceptibility to environmental causes, and second, familial disease has been reported in most ILDs, including sarcoidosis, IPF, alveolar proteinosis, Langerhans cell histiocytosis, hypersensitivity pneumonitis and desquamative interstitial pneumonia (see Supplementary Table 1).
ILDs are relatively rare and susceptibility does not follow single-gene Mendelian patterns. They are referred to genetically as 'complex diseases'. Variations at multiple loci, each exerting variable and relatively small effects, are likely to be involved. Further complications in assigning susceptibility involve the assessment of interactions with environmental factors that are thought to induce a specific clinical phenotype, and the knowledge that interactions between genes and the environment can affect the relationships of severity and progression as well as predisposition to disease. Finally, some conditions, such as IPF, manifest in the later stages of life, making family-association studies difficult. For these reasons, most studies of the genetics of ILDs have applied the direct case-controlled, association-based approach. In such studies, the prevalence of alleles in single-nucleotide polymorphisms (SNPs) in biologically important candidate genes is examined in populations of unrelated affected individuals, and compared with prevalence in unrelated normal controls.
Genetic studies in interstitial lung disease
Very few studies have examined the genetic components predisposing to ILDs and, of these, most have focused on the region of chromosome 6, which incorporates the major histocompatibility complex (MHC) and its associated genes. The consensus from the majority of the studies is that susceptibility to sarcoidosis is associated with HLA-DRB1*03, *11, *12, *13, *14. Other associations include alleles in the genes encoding TAP2, the CC chemokine receptor 2, the angiotensin-converting enzyme and vitamin D receptor . Polymorphisms in the fibronectin gene  and the HLA-DPB1*1301 allele  have been associated with fibrosing alveolitis in the context of systemic sclerosis. Susceptibility to IPF has not been associated with polymorphisms in TNFα, LTα, TNF receptor II and IL-6 genes , nor with polymorphisms in the IL-8 and IL-8 receptor (CXCR-1 and CXCR-2) genes . A reported association with the IL-1 receptor-antagonist gene  was not confirmed in a subsequent study.
Polymorphisms in the surfactant genes
The genes for the hydrophilic proteins SP-A1, SP-A2 and SP-D have been mapped to human chromosome 10q22-q23.1. The SP-A1 gene is telomeric to the SP-A2 and SP-D genes: the SP-A2 and SP-D genes are located 36 kb and 130 kb respectively from SP-A1. Both SP-A1 and SP-A2 genes have a number of 5'-untranslated region exons that splice under genetic control in different configurations to produce a number of alternatively spliced functional variants . Furthermore, there are a number of polymorphisms within the coding region of the genes that result in amino acid substitutions . In the SP-A1 gene there are five exonic polymorphisms, which correspond to amino acid (aa) positions 19, 50, 62, 133 and 219 of the protein. Two of these are silent (62 and 133), while the others result in a non-conservative amino acid substitution (Ala19→Val, Leu50→Val and Arg219→Trp). In the SP-A2 gene, there are four exonic polymorphisms (Thr9→Asn, Pro91→Ala and Lys223→Gln); the polymorphism at position 140 is silent. Nineteen haplotypes have been identified in the SP-A1 gene (designated 6A to 6A20), and 15 haplotypes have been identified in the SP-A2 gene (designated 1A to 1A13) . Of these haplotypes, the most frequent are the SP-A1 (6A2) and SP-A2 (1A0) haplotypes. These two haplotypes comprise the following amino acids: SP-A1 (6A2: Val19/Val50/Arg219) and SP-A2 (1A0: Asn9/Ala91/Gln223). In functional studies, these haplo-types correlated with low or moderate mRNA levels . In the SP-D gene there are two exonic polymorphisms that result in substitutions: Thr11→Met and Thr160→Ala .
Genes mapped to human chromosomes 2p12-p11.2 and 8p21 encode the hydrophobic proteins SP-B and SP-C respectively. Several SNPs have been identified in the SP-B gene. Four of these polymorphisms, which reside in the 5' flanking region, intron 2, exon 4 and 3' untranslated regions of the gene, have the potential to affect function . The exonic polymorphism substitutes residue 131 (Thr→Ile). There is also a variable nucleotide tandem repeat region, which is highly polymorphic, within intron 4 of the SP-B gene . For the SP-C gene, there may be several SNPs as there are a number of variations between published SP-C sequences . Figure 1 shows the intron/exon structure of the SP genes with the locations of polymorphisms discussed above.
Mutations in the surfactant genes
A locus is considered polymorphic if the less frequent allele has a population frequency of at least 1% and heterozygosity frequency of at least 2%. Below these frequencies, nucleotide variations are allelic variants or, if very rare, they are described as mutations . A number of mutations have been identified in association with hereditary surfactant deficiencies. The predominant, but not exclusive, mutation responsible for SP-B deficiency involves a substitution of a GAA nucleotide triplet for a single C in codon 121, which causes a frameshift and a premature termination signal and also interferes with SP-C processing . Mutations in the SP-B gene are also responsible for SP-B deficiency in congenital alveolar proteinosis . Until the recent work published by Nogee et al., there were no data on SP-C mutations and lung disease.
SP-C gene variations in ILD
Nogee et al.  recently reported an association between a mutation in the SP-C gene and ILD. A full-term baby was born to a woman with a history of desquamative interstitial pneumonia, which was diagnosed when she was one year old and had been treated with corticosteroids up to the age of 15. The baby was normal at birth but developed respiratory symptoms at six weeks of age. Lung biopsy revealed cellular, or non-specific, interstitial pneumonia. The infant improved with oxygen and corticosteroid therapy. The mother's lung disease worsened and she died of respiratory failure.
Genetic analysis showed a mutation in one allele of the SP-C gene. The heterozygous substitution of A to G was located in the first base of intron 4, abolishing the normal donor splice site and resulting in the skipping of exon 4 and the deletion of 37 amino acid residues in the SP-C precursor protein. Abnormal protein structure is known to result in abnormal tertiary structure and transport. Mature SP-C was completely absent from the BAL fluid and lung tissue of the patient and might have resulted from this aberrant folding and transport. The complete absence of protein with the mutation of a single allele is possibly due to a dominant-negative effect, in which the mutant allele suppresses production of the normal allele .
The authors subsequently studied the SP-C gene in 34 infants with nonfamilial chronic lung disease of unknown origin (Nogee et al., personal communication, 2001). They were able to identify mutations of the SP-C gene in 11 infants, which resulted in a phenotype similar to that of the index patient. The occurrence of a de novo mutation that is functionally identical to a familial mutation strongly supports the hypothesis that the mutations were causally related to the lung disease. This suggests that SP-C is necessary for normal lung function in the postnatal period.
Surfactant SNP disease-association studies
No other studies have examined surfactant-gene polymorphisms in the context of ILDs, although these have been evaluated in other pulmonary conditions. In a recent publication , the SP-B Thr131→Ile polymorphism was found to be associated with the acute respiratory distress syndrome. Alleles in the SP-B variable nucleotide tandem repeat region and SP-A polymorphisms have been reported to be associated with the infant respiratory distress syndrome [21, 28], but more recent data suggest that genetic susceptibility to infant respiratory distress syndrome is dependent on SP-A alleles in the context of SP-B Thr131 homozygosity . The SP-A1 polymorphism 6A6 is also over-represented in infants with bronchopulmonary dysplasia .
In summary, genetic variations are factors in determining the development and severity of many ILDs. Surfactant plays an important role in lung physiology and defense, and surfactant gene variations have been associated with several lung diseases. The recent finding of surfactant gene variations in familial and nonfamilial ILD opens up a new area for more detailed analysis, to explore whether these variations play a role in a wider range of ILDs.
idiopathic pulmonary fibrosis
interstitial lung disease
single nucleotide polymorphism
Griese M: Pulmonary surfactant in health and human lung diseases: state of the art. Eur Respir J. 1999, 13: 1455-1476. 10.1034/j.1399-3003.1999.13f36.x.
Low RB: Bronchoalveolar lavage lipids in idiopathic pulmonary fibrosis. Chest. 1989, 95: 3-5.
Gunther A, Schmidt R, Nix F, Yabut-Perez M, Guth C, Rosseau S, Siebert C, Grimminger F, Morr H, Velcovsky HG, Seeger W: Surfactant abnormalities in idiopathic pulmonary fibrosis, hypersensitivity pneumonitis and sarcoidosis. Eur Respir J. 1999, 14: 565-573. 10.1183/09031936.99.14356599.
McCormack FX, King TE, Bucher BL, Nielsen L, Mason RJ: Surfactant protein A predicts survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1995, 152: 751-759.
van de Graaf EA, Jansen HM, Lutter R, Alberts C, Kobesen J, De Vries IJ, Out TA: Surfactant protein A in bronchoalveolar lavage fluid. J Lab Clin Med. 1992, 120: 252-263.
Hamm H, Luhrs J, Rotaeche J, Costabel U, Fabel H, Bartsch W: Elevated surfactant protein A in bronchoalveolar lavage fluids from sarcoidosis and hypersensitivity pneumonitis patients. Chest. 1994, 106: 1766-1770.
Cormier Y, Israel-Assayag E, Desmeules M, Lesur O: Effect of contact avoidance or treatment with oral prednisolone on bronchoalveolar lavage surfactant protein A levels in subjects with farmer's lung. Thorax. 1996, 51: 1210-1215.
Voss T, Schafer KP, Nielsen PF, Schafer A, Maier C, Hannappel E, Maassen J, Landis B, Klemm K, Przybylski M: Primary structure differences of human surfactant-associated proteins isolated from normal and proteinosis lung. Biochim Biophys Acta. 1992, 1138: 261-267. 10.1016/0925-4439(92)90002-5.
Hattori A, Kuroki Y, Katoh T, Takahashi H, Shen HQ, Suzuki Y, Akino T: Surfactant protein A accumulating in the alveoli of patients with pulmonary alveolar proteinosis: oligomeric structure and interaction with lipids. Am J Respir Cell Mol Biol. 1996, 14: 608-619.
Takahashi H, Fujishima T, Koba H, Murakami S, Kurokawa K, Shibuya Y, Shiratori M, Kuroki Y, Abe S: Serum surfactant proteins A and D as prognostic factors in idiopathic pulmonary fibrosis and their relationship to disease extent. Am J Respir Crit Care Med. 2000, 162: 1109-1114.
Takahashi H, Kuroki Y, Tanaka H, Saito T, Kurokawa K, Chiba H, Sagawa A, Nagae H, Abe S: Serum levels of surfactant proteins A and D are useful biomarkers for interstitial lung disease in patients with progressive systemic sclerosis. Am J Respir Crit Care Med. 2000, 162: 258-263.
McGrath DS, Goh N, Foley PJ, du Bois RM: Sarcoidosis: genes and microbes–soil or seed?. Sarcoidosis Vasc Diffuse Lung Dis. 2001, 18: 149-164.
Avila JJ, Lympany PA, Pantelidis P, Welsh KI, Black CM, du Bois RM: Fibronectin gene polymorphisms associated with fibrosing alveolitis in systemic sclerosis. Am J Respir Cell Mol Biol. 1999, 20: 106-112.
Gilchrist FC, Bunn C, Foley PJ, Lympany PA, Black CM, Welsh KI, du Bois RM: Class II HLA associations with autoantibodies in scleroderma: a highly significant role for HLA-DP. Genes Immun. 2001, 2: 76-81. 10.1038/sj/gene/6363734.
Pantelidis P, Fanning GC, Wells AU, Welsh KI, du Bois RM: Analysis of tumor necrosis factor-alpha, lymphotoxin-alpha, tumor necrosis factor receptor II, and interleukin-6 polymorphisms in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2001, 163: 1432-1436.
Renzoni E, Lympany P, Sestini P, Pantelidis P, Wells A, Black C, Welsh K, Bunn C, Knight C, Foley P, du Bois RM: Distribution of novel polymorphisms of the interleukin-8 and CXC receptor 1 and 2 genes in systemic sclerosis and cryptogenic fibrosing alveolitis. Arthritis Rheum. 2000, 43: 1633-1640. 10.1002/1529-0131(200007)43:7<1633::AID-ANR29>3.3.CO;2-0.
Whyte M, Hubbard R, Meliconi R, Whidborne M, Eaton V, Bingle C, Timms J, Duff G, Facchini A, Pacilli A, Fabbri M, Hall I, Britton J, Johnston I, Di Giovine F: Increased risk of fibrosing alveolitis associated with interleukin-1 receptor antagonist and tumor necrosis factor-alpha gene polymorphisms. Am J Respir Crit Care Med. 2000, 162: 755-758.
Karinch AM, deMello DE, Floros J: Effect of genotype on the levels of surfactant protein A mRNA and on the SP-A2 splice variants in adult humans. Biochem J. 1997, 321 (Pt 1): 39-47.
DiAngelo S, Lin Z, Wang G, Phillips S, Ramet M, Luo J, Floros J: Novel, non-radioactive, simple and multiplex PCR-cRFLP methods for genotyping human SP-A and SP-D marker alleles. Dis Markers. 1999, 15: 269-281.
Lin Z, deMello DE, Batanian JR, Khammash HM, DiAngelo S, Luo J, Floros J: Aberrant SP-B mRNA in lung tissue of patients with congenital alveolar proteinosis (CAP). Clin Genet. 2000, 57: 359-369. 10.1034/j.1399-0004.2000.570506.x.
Floros J, Veletza SV, Kotikalapudi P, Krizkova L, Karinch AM, Friedman C, Buchter S, Marks K: Dinucleotide repeats in the human surfactant protein-B gene and respiratory-distress syndrome. Biochem J. 1995, 305 (Pt 2): 583-590.
Glasser SW, Korfhagen TR, Perme CM, Pilot-Matias TJ, Kister SE, Whitsett JA: Two SP-C genes encoding human pulmonary surfactant proteolipid. J Biol Chem. 1988, 263: 10326-10331.
Gelehrter TD, Collins FS: Population genetics and multifactor-ial inheritance. In: Principles of Medical Genetics, International Edition. Baltimore: Williams and Wilkins;. 1990, 49-68.
Nogee LM, Wert SE, Proffit SA, Hull WM, Whitsett JA: Allelic heterogeneity in hereditary surfactant protein B (SP-B) deficiency. Am J Respir Crit Care Med. 2000, 161: 973-981.
Lin Z, deMello DE, Wallot M, Floros J: An SP-B gene mutation responsible for SP-B deficiency in fatal congenital alveolar proteinosis: evidence for a mutation hotspot in exon 4. Mol Genet Metab. 1998, 64: 25-35. 10.1006/mgme.1998.2702.
Nogee LM, Dunbar AE, Wert SE, Askin F, Hamvas A, Whitsett JA: A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 2001, 344: 573-579. 10.1056/NEJM200102223440805.
Lin Z, Pearson C, Chinchilli V, Pietschmann SM, Luo J, Pison U, Floros J: Polymorphisms of human SP-A, SP-B, and SP-D genes: association of SP-B Thr131Ile with ARDS. Clin Genet. 2000, 58: 181-191. 10.1034/j.1399-0004.2000.580305.x.
Kala P, Ten Have T, Nielsen H, Dunn M, Floros J: Association of pulmonary surfactant protein A (SP-A) gene and respiratory distress syndrome: interaction with SP-B. Pediatr Res. 1998, 43: 169-177.
Haataja R, Ramet M, Marttila R, Hallman M: Surfactant proteins A and B as interactive genetic determinants of neonatal respiratory distress syndrome. Hum Mol Genet. 2000, 9: 2751-2760. 10.1093/hmg/9.18.2751.
Weber B, Borkhardt A, Stoll-Becker S, Reiss I, Gortner L: Polymorphisms of surfactant protein A genes and the risk of bronchopulmonary dysplasia in preterm infants. Turk J Pediatr. 2000, 42: 181-185.
Varpela E, Tiilikainen A, Varpela M, Tukiainen P: High prevalences of HLA-B15 and HLA-Dw6 in patients with cryptogenic fibrosing alveolitis. Tissue Antigens. 1979, 14: 68-71.
Freeburn RW, Kendall H, Dobson L, Egan J, Simler NJ, Millar AB: The 3'-untranslated region of tumor necrosis factor-alpha is highly conserved in idiopathic pulmonary fibrosis (IPF). Eur Cytokine Netw. 2001, 12: 33-38.
Morrison CD, Papp AC, Hejmanowski AQ, Addis VM, Prior TW: Increased D allele frequency of the angiotensin-converting enzyme gene in pulmonary fibrosis. Hum Pathol. 2001, 32: 521-528. 10.1053/hupa.2001.24321.
Pasturenzi L, Martinetti M, Cuccia M, Cipriani A, Semenzato G, Luisetti M: HLA class I, II, and III polymorphism in Italian patients with sarcoidosis. The Pavia-Padova Sarcoidosis Study Group. Chest. 1993, 104: 1170-1175.
Gardner J, Kennedy HG, Hamblin A, Jones E: HLA associations in sarcoidosis: a study of two ethnic groups. Thorax. 1984, 39: 19-22.
Hedfors E, Lindstrom F: HLA-B8/DR3 in sarcoidosis. Correlation to acute onset disease with arthritis. Tissue Antigens. 1983, 22: 200-203.
Smith MJ, Turton CW, Mitchell DN, Turner-Warwick M, Morris LM, Lawler SD: Association of HLA-B8 with spontaneous resolution in sarcoidosis. Thorax. 1981, 36: 296-298.
Berlin M, Fogdell-Hahn A, Olerup O, Eklund A, Grunewald J: HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis. Am J Respir Crit Care Med. 1997, 156: 1601-1605.
Swider C, Schnittger L, Bogunia-Kubik K, Gerdes J, Flad H, Lange A, Seitzer U: TNF-alpha and HLA-DR genotyping as potential prognostic markers in pulmonary sarcoidosis. Eur Cytokine Netw. 1999, 10: 143-146.
Bogunia-Kubik K, Tomeczko J, Suchnicki K, Lange A: HLA-DRB1*03, DRB1*11 or DRB1*12 and their respective DRB3 specificities in clinical variants of sarcoidosis. Tissue Antigens. 2001, 57: 87-90. 10.1034/j.1399-0039.2001.057001087.x.
Schurmann M, Bein G, Kirsten D, Schlaak M, Muller-Quernheim J, Schwinger E: HLA-DQB1 and HLA-DPB1 genotypes in familial sarcoidosis. Respir Med. 1998, 92: 649-652.
Naruse TK, Matsuzawa Y, Ota M, Katsuyama Y, Matsumori A, Hara M, Nagai S, Morimoto S, Sasayama S, Inoko H: HLA-DQB1*0601 is primarily associated with the susceptibility to cardiac sarcoidosis. Tissue Antigens. 2000, 56: 52-57. 10.1034/j.1399-0039.2000.560107.x.
Ishihara M, Ohno S, Ishida T, Naruse T, Inoko H: Genetic polymorphism in intron 6 of the LMP7 gene in Japanese and its association with sarcoidosis. Tissue Antigens. 1997, 50: 650-653.
Ishihara M, Naruse T, Ohno S, Kawata H, Mizuki N, Yamagata N, Ishida T, Nose Y, Inoko H: Analysis of HLA-DM polymorphisms in sarcoidosis. Hum Immunol. 1996, 49: 144-146. 10.1016/0198-8859(96)82496-7.
Maliarik MJ, Chen KM, Major ML, Sheffer RG, Popovich J, Rybicki BA, Iannuzzi MC: Analysis of HLA-DPB1 polymorphisms in African-Americans with sarcoidosis. Am J Respir Crit Care Med. 1998, 158: 111-114.
Schurmann M, Lympany PA, Reichel P, Muller-Myhsok B, Wurm K, Schlaak M, Muller-Quernheim J, du Bois RM, Schwinger E: Familial sarcoidosis is linked to the major histocompatibility complex region. Am J Respir Crit Care Med. 2000, 162: 861-864.
Foley PJ, Lympany PA, Puscinska E, Zielinski J, Welsh KI, du Bois RM: Analysis of MHC-encoded antigen-processing genes TAP1 and TAP2 polymorphisms in sarcoidosis. Am J Respir Crit Care Med. 1999, 160: 1009-1014.
Foley PJ, Lympany PA, Puscinska E, Gilchrist F, Avila J, Thackray I, Pantelides P, du Bois RM: HLA-DPB1 and TAP1 polymorphisms in sarcoidosis. Chest. 1997, 111: 73S-
Lympany PA, Petrek M, Southcott AM, Newman Taylor AJ, Welsh KI, du Bois RM: HLA-DPB polymorphisms: Glu 69 association with sarcoidosis. Eur J Immunogenet. 1996, 23: 353-359.
Ishihara M, Ohno S, Mizuki N, Yamagata N, Ishida T, Naruse T, Kuwata S, Inoko H: Genetic polymorphisms of the major histocompatibility complex-encoded antigen-processing genes TAP and LMP in sarcoidosis. Hum Immunol. 1996, 45: 105-110. 10.1016/0198-8859(95)00167-0.
Ishihara M, Ohno S, Ishida T, Naruse T, Kagiya M, Mizuki N, Maruya E, Saji H, Inoko H: Analysis of allelic variation of the TAP2 gene in sarcoidosis. Tissue Antigens. 1997, 49: 107-110.
Maliarik MJ, Rybicki BA, Malvitz E, Sheffer RG, Major M, Popovich J, Iannuzzi MC: Angiotensin-converting enzyme gene polymorphism and risk of sarcoidosis. Am J Respir Crit Care Med. 1998, 158: 1566-1570.
McGrath DS, Foley PJ, Petrek M, Izakovicova-Holla L, Dolek V, Veeraraghavan S, Lympany PA, Pantelidis P, Vasku A, Wells AU, Welsh KI, du Bois RM: ACE gene I/D polymorphism and sarcoidosis pulmonary disease severity. Am J Respir Crit Care Med. 2001, 164: 197-201.
Pietinalho A, Furuya K, Yamaguchi E, Kawakami Y, Selroos O: The angiotensin-converting enzyme DD gene is associated with poor prognosis in Finnish sarcoidosis patients. Eur Respir J. 1999, 13: 723-726. 10.1183/09031936.99.13472399.
Papadopoulos KI, Melander O, Orho-Melander M, Groop LC, Carlsson M, Hallengren B: Angiotensin-converting enzyme (ACE) gene polymorphism in sarcoidosis in relation to associated autoimmune diseases. J Intern Med. 2000, 247: 71-77. 10.1046/j.1365-2796.2000.00575.x.
Furuya K, Yamaguchi E, Itoh A, Hizawa N, Ohnuma N, Kojima J, Kodama N, Kawakami Y: Deletion polymorphism in the angiotensin I converting enzyme (ACE) gene as a genetic risk factor for sarcoidosis. Thorax. 1996, 51: 777-780.
Schurmann M, Reichel P, Muller-Myhsok B, Dieringer T, Wurm K, Schlaak M, Muller-Quernheim J, Schwinger E: Angiotensin-converting enzyme (ACE) gene polymorphisms and familial occurrence of sarcoidosis. J Intern Med. 2001, 249: 77-83. 10.1046/j.1365-2796.2001.00776.x.
Takemoto Y, Sakatani M, Takami S, Tachibana T, Higaki J, Ogihara T, Miki T, Katsuya T, Tsuchiyama T, Yoshida A, Yu H, Tanio Y, Ueda E: Association between angiotensin II receptor gene polymorphism and serum angiotensin-converting enzyme (SACE) activity in patients with sarcoidosis. Thorax. 1998, 53: 459-462.
Arbustini E, Grasso M, Leo G, Tinelli C, Fasani R, Diegoli M, Banchieri N, Cipriani A, Gorrini M, Semenzato G, Luisetti M: Polymorphism of angiotensin-converting enzyme gene in sarcoidosis. Am J Respir Crit Care Med. 1996, 153: 851-854.
Seitzer U, Swider C, Stuber F, Suchnicki K, Lange A, Richter E, Zabel P, Muller-Quernheim J, Flad HD, Gerdes J: Tumour necrosis factor-alpha promoter gene polymorphism in sarcoidosis. Cytokine. 1997, 9: 787-790. 10.1006/cyto.1997.0224.
Takashige N, Naruse TK, Matsumori A, Hara M, Nagai S, Morimoto S, Hiramitsu S, Sasayama S, Inoko H: Genetic polymorphisms at the tumour necrosis factor loci (TNFA and TNFB) in cardiac sarcoidosis. Tissue Antigens. 1999, 54: 191-193. 10.1034/j.1399-0039.1999.540211.x.
Ishihara M, Ohno S, Ishida T, Mizuki N, Ando H, Naruse T, Ishihara H, Inoko H: Genetic polymorphisms of the TNFB and HSP70 genes located in the human major histocompatibility complex in sarcoidosis. Tissue Antigens. 1995, 46: 59-62.
Yamaguchi E, Itoh A, Hizawa N, Kawakami Y: The gene polymorphism of tumor necrosis factor-beta, but not that of tumor necrosis factor-alpha, is associated with the prognosis of sarcoidosis. Chest. 2001, 119: 753-761. 10.1378/chest.119.3.753.
Foley PJ, Lympany PA, Fanning GC, Welsh KI, du Bois RM: TNF-alpha and lymphotoxin-alpha polymorphisms in sarcoidosis – no association. Thorax. 1997, 52: A64-
Hizawa N, Yamaguchi E, Furuya K, Jinushi E, Ito A, Kawakami Y: The role of the C-C chemokine receptor 2 gene polymorphism V64I (CCR2-64I) in sarcoidosis in a Japanese population. Am J Respir Crit Care Med. 1999, 159: 2021-2023.
Petrek M, Drabek J, Kolek V, Zlamal J, Welsh KI, Bunce M, Weigl E, du Bois RM: CC chemokine receptor gene polymorphisms in Czech patients with pulmonary sarcoidosis. Am J Respir Crit Care Med. 2000, 162: 1000-1003.
Maliarik MJ, Chen KM, Sheffer RG, Rybicki BA, Major ML, Popovich J, Iannuzzi MC: The natural resistance-associated macrophage protein gene in African-Americans with sarcoidosis. Am J Respir Cell Mol Biol. 2000, 22: 672-675.
Foley PJ, Mullighan CG, McGrath DS, Pantelidis P, Marshall S, Lympany PA, Welsh KI, du Bois RM: Mannose-binding lectin promoter and structural gene variants in sarcoidosis. Eur J Clin Invest. 2000, 30: 549-552. 10.1046/j.1365-2362.2000.00656.x.
Niimi T, Tomita H, Sato S, Akita K, Maeda H, Kawaguchi H, Mori T, Sugiura Y, Yoshinouchi T, Ueda R: Vitamin D receptor gene polymorphism and calcium metabolism in sarcoidosis patients. Sarcoidosis Vasc Diffuse Lung Dis. 2000, 17: 266-269.
Niimi T, Tomita H, Sato S, Kawaguchi H, Akita K, Maeda H, Sugiura Y, Ueda R: Vitamin D receptor gene polymorphism in patients with sarcoidosis. Am J Respir Crit Care Med. 1999, 160: 1107-1109.
Niimi T, Sato S, Tomita H, Yamada Y, Akita K, Maeda H, Kawaguchi H, Sugiura Y, Ueda R: Lack of association with interleukin-1 receptor antagonist and interleukin-1 beta gene polymorphisms in sarcoidosis patients. Respir Med. 2000, 94: 1038-1042. 10.1053/rmed.2000.0892.
Schaaf BM, Seitzer U, Pravica V, Aries SP, Zabel P: Tumor necrosis factor-alpha-308 promoter gene polymorphism and increased tumor necrosis factor serum bioactivity in farmer's lung patients. Am J Respir Crit Care Med. 2001, 163: 379-382.
Wu WS, McClain KL: DNA polymorphisms and mutations of the tumor necrosis factor-alpha (TNF-alpha) promoter in Langerhans cell histiocytosis (LCH). J Interferon Cytokine Res. 1997, 17: 631-635.
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Pantelidis, P., Veeraraghavan, S. & du Bois, R.M. Surfactant gene polymorphisms and interstitial lung diseases. Respir Res 3, 14 (2001). https://doi.org/10.1186/rr163
- interstitial lung disease