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(Chest. 2003;123:1520-1526.)
© 2003 American College of Chest Physicians

Vascular Endothelial Growth Factor Gene Polymorphisms in Japanese Patients With Sarcoidosis*

Kazuaki Morohashi, MD; Toshinori Takada, MD, PhD; Kentaro Omori, MD; Eiichi Suzuki, MD and Fumitake Gejyo, MD

* From the Division of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.

Correspondence to: Toshinori Takada, MD, PhD, Division of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Niigata, 951-8510, Japan; e-mail: ttakada{at}med.niigata-u.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objectives: Vascular endothelial growth factor (VEGF) promotes angiogenesis, mediates vascular permeability, and activates and recruits monocytes. VEGF is produced in activated alveolar macrophages, in epithelioid cells, and in multinuclear giant cells of pulmonary sarcoid granulomas. Recent reports have shown that a polymorphism at - 627 of the VEGF gene is related to VEGF protein production, and a polymorphism at + 813 is associated with VEGF plasma levels. We investigated the roles of such polymorphisms in the development and extent of sarcoidosis.

Methods: We examined polymorphisms of the VEGF gene in 103 Japanese patients with sarcoidosis and 146 healthy Japanese control subjects. The position - 627 polymorphism was determined using the TaqMan (TaqMan Laboratory, University of Pittsburgh Cancer Institute; Pittsburgh, PA) polymerase chain reaction (PCR) method. For genotyping of the position + 813 polymorphism, the PCR restriction fragment length polymorphism method was performed.

Results: As for + 813 genotypes, the less-common genotypes CT and TT were found more often in control subjects than in patients (odds ratio, 0.490; 95% confidence interval, 0.276 to 0.868). A significant increase in the frequency of the T allele (p = 0.005, Pc = 0.020 after Bonferroni correction) was observed in control subjects. As for - 627 genotypes, the mean value of the FEV1/FVC percentage in GG type was lower than that in CC or CG type, however, the other clinical findings did not suggest airway diseases in the GG type.

Conclusions: We suggest that in VEGF gene polymorphisms the T allele at + 813 may decrease susceptibility to sarcoidosis.

Key Words: genetic susceptibility • polymorphism • sarcoidosis • vascular endothelial growth factor


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Sarcoidosis is a systemic granulomatous disorder of unknown etiology involving multiple organs. Sarcoid granuloma typically shows a center of epithelioid cells surrounded by CD4+ lymphocytes, some CD8+ lymphocytes, giant cells, and mature macrophages. The recruitment of macrophages and T cells into the affected organ is thought to be an important step in the development of sarcoidosis. Sarcoidosis is often associated with nongranulomatous microangiopathic lesions in various organs.1 Increased angiogenesis-inducing ability of activated alveolar macrophages is found in BAL specimens from patients with pulmonary sarcoidosis.2

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that promotes angiogenesis and is a potent mediator of vascular permeability.3 The biological activities of VEGF are mediated through two high-affinity receptor tyrosine kinases, fms-like tyrosine kinase-1 (Flt-1) [VEGF receptor-1] and fetal liver kinase-1 [VEGF receptor-2],4 whose expressions are mainly restricted to endothelial cells.5 A possible role of VEGF in the activation and recruitment of monocytes is mediated through the Flt-1 receptor.6 7 A study by Tolnay et al8 revealed an increased transcription and protein production of VEGF and an overexpression of Flt-1 in activated alveolar macrophages, in epithelioid cells, and in multinuclear giant cells of pulmonary sarcoid granulomas.

The current consensus regarding the pathogenesis of sarcoidosis is that it results from exposure of genetically susceptible hosts to particular environmental factors.9 Some polymorphisms have been reported to be involved in susceptibility to sarcoidosis, in disease severity and progression, or in disease prognosis.10 11 12 13 Polymorphisms within the VEGF gene have been identified.14 15 16 Of these polymorphisms, two single-nucleotide polymorphisms (SNPs) at - 627 and at + 813 have been associated with VEGF protein production.15 16 Our hypothesis was that these might affect sarcoidosis, and therefore we investigated SNPs of the VEGF gene in a series of patients with sarcoidosis and control subjects.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
One hundred three patients were recruited from the clinic at the Niigata University Hospital. Sarcoidosis was diagnosed on the basis of the typical features and the presence of epithelioid cell granulomas in biopsy specimens from the lung, skin, or lymph nodes. Forty-one of the patients were men, and 62 were women. All patients in the study were Japanese. The average age of patients at diagnosis was 45.1 years (range, 19 to 74 years). One hundred forty-six healthy subjects who had requested annual physical examinations were randomly selected; all were Japanese (73 women and 73 men; mean age, 43.0 years; range, 22 to 70 years). The control population consisted of unrelated women and men living in the same district who were matched for age, sex, and ethnic origin (p > 0.1 for sex and age, Table 1 ). The research was carried out in accordance with the Declaration of Helsinki (1989) of the World Medical Association, and the study was approved by the Committee of Ethics, Niigata University. All subjects in the study gave informed written consent for enrollment in the study.


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  		Table 1. Demographic Characteristics of the Study Population

 
Determination of the VEGF Genotype
DNA was extracted from peripheral leukocytes by standard techniques. Nucleotides are numbered from the translation start based on the sequence of the VEGF (Genebank accession number AF022375). The position - 627 SNP (referred to the position + 405 numbered from the major transcription site in a previous report15 ) in the promoter of the VEGF gene was determined using the TaqMan (Applied Biosystems; Foster City, CA) polymerase chain reaction (PCR) method.17 A primer pair and probes are shown in Table 2 . During the PCR cycle, two TaqMan probes hybridize competitively to a specific sequence of the target DNA, and the reporter dyes separate from the quencher dye, resulting in an increase in fluorescence of the reporter. The fluorescence level of the PCR products was measured with the ABI PRISM 7900HT Sequence Detector (Applied Biosystems), resulting in clear identification of three genotypes of SNP. Cycle sequencing using the BigDye terminator cycle sequencing kit (PE; Applied Biosystems) validated the genotypes. For genotyping of the position + 813 SNP (referred to the position + 936 numbered from the complementary DNA sequence of the VEGF 206 isoform in a previous report16 ) in the 3' untranslated region (UTR), PCR restriction fragment length polymorphism method was performed as previously described.16 Briefly, specific oligonucleotide primers (Table 2) were utilized with PCR to amplify a 208-base pair (bp) segment covering the polymorphic site. PCR products digested with Nla III (New England Biolabs; Beverly, MA) were visualized on a 4% NuSieve GTG (BioWhittaker Molecular Applications; East Rutherford, NJ) agarose gel (Fig. 1 ).


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  		Table 2. Primer Pairs and Fluorogenic Probes for VEGF Polymorphisms*

 


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  		Figure 1. VEGF position + 813 genotyping. Panel shows part of a representative 4% NuSieve GTG agarose gel stained with ethidium bromide and photographed under ultraviolet transillumination after PCR amplification and digestion by Nla III. The C allele does not cut and gives a band of 208 bp. The T allele is cleaved into two bands of 122 bp and 86 bp (arrows). The left lane contains a 100-bp ladder.

 
Pulmonary Function Testing
All patients who had pulmonary function performed at diagnosis were included for analysis. Ninety-three patients fulfilled the inclusion criteria for assessment of pulmonary function. Ten patients did not have pulmonary function tested because 7 patients showed no demonstrable pulmonary abnormality (initial chest radiograph stage 0 and I), 2 patients had been treated with systemic corticosteroid, and another patient was first suspected to have collagen vascular disease. The following parameters were recorded: vital capacity (VC), FEV1, and FVC (CHEST MI; Tokyo, Japan).

Statistical Analysis
The allele ratios and genotype distributions in patients with sarcoidosis and healthy control subjects, roentgenographic stages, and organ involvement among the three genotypes were analyzed with the {chi}2 test. The Fisher exact test was also applied for comparison of small populations with expected values of < 5. Tests for Hardy-Weinberg equilibrium were performed by the {chi}2 test. Haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (D’) for pairwise linkage disequilibrium testing were calculated using the Arlequin program (version 2.000; Genetics and Biometry Laboratory, University of Geneva; Geneva, Switzerland).18 Analyses of pulmonary function data were performed using the Kruskal-Wallis test and the Mann-Whitney U test. All p values were corrected for the number of comparisons made, comprising two separate loci with two alleles, through the Bonferroni method (Pc).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Allele frequencies and genotypes for VEGF SNPs are summarized in Table 3 . The genotype frequencies were in agreement with the Hardy-Weinberg equilibrium (p > 0.1 for all analyses). As for - 627 genotypes, of the 103 patients with sarcoidosis, 41 patients had the CC genotype (39.8%), 43 patients had the CG genotype (41.8%), and 19 patients had the GG type (18.4%). The frequency of C allele was 60.7%. Of the 146 healthy control subjects, 51 subjects were type CC (34.9%), 60 subjects were type CG (41.1%), and 35 subjects were type GG (24.0%). We found no significant difference in the genotype distribution or allele frequencies between the patients with sarcoidosis and healthy control subjects. As for + 813 genotypes, 80 patients with sarcoidosis had the CC genotype (77.7%), 23 patients had the CT genotype (22.3%), and no patients had the TT type. The frequency of C allele was 88.8%. Of the 146 healthy control subjects, 92 subjects were type CC (63.0%), 48 subjects were CT (32.9%), and 6 subjects were TT (4.1%). A significant difference in the allele frequency between patients with sarcoidosis and healthy control subjects, and a significant decrease in the frequency of the T allele in sarcoidosis were observed (p = 0.005, Pc = 0.020). Haplotype frequencies were estimated by maximum likelihood with Arlequin software (Table 4 ). The frequencies of haplotypes CC, CT, GC, and GT in control subjects were 43.4%, 12.1%, 36.0%, and 8.5%, respectively. There was a significant difference in the frequencies of haplotype CC and CT between patients with sarcoidosis and control subjects (p = 0.009, Pc = 0.036; and p = 0.011, Pc = 0.044, respectively). There was a strong linkage disequilibrium between the VEGF promoter and 3' UTR alleles with a standardized disequilibrium coefficient (D’) of 1.000 between the two loci.


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  		Table 3. Allele and Genotype Frequencies of Two VEGF Biallellic Polymorphisms*

 

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  		Table 4. Haplotype Frequencies of Two VEGF Biallellic Polymorphisms*

 
Then we examined the relationship with organ involvement. Cases of eye (n = 71), skin (n = 7, all papulonodular lesions with granulomas present pathologically, and no erythema nodosum or lupus pernio), heart (n = 11), involvement of three or more organs (n = 18), and initial chest radiograph stage II or higher (n = 49) were examined. We found no significant association between the genotypes of VEGF at - 627 or at + 813 and the organ involvement (Table 5 ). Next, we compared pulmonary function parameters among VEGF genotypes. As for - 627 genotypes, of the 93 patients with sarcoidosis assessed for pulmonary function, 38 patients had the CC genotype, 37 patients had the CG genotype, and 18 patients had the GG type. No difference was demonstrated in the smoking history or asthma history among the genotypes. Although the mean values of the FEV1/FVC percentage were not different among the genotypes (p = 0.015, Pc = 0.060), that in GG type was significantly lower than that in CC or CG type (p = 0.012, Pc = 0.048; and p = 0.006, Pc = 0.024, respectively). We reviewed clinical records of the 18 patients with GG genotypes. No wheezing on auscultation in all patients, no endobronchial lesions except capillary dilatation in 2 of the 17 patients on bronchoscopic examination, or no bronchial lesion except slight bronchial wall thickening in 2 of the 16 patients on CT scans of the chest were noted. As for + 813 genotypes, 74 patients had the CC genotype, 19 patients had the CT genotype, and no patients had the TT type. There was no difference in the mean value of the VC percentage of predicted value or the FEV1/FVC percentage between the groups (Table 6 ).


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  		Table 5. Relationship of VEGF Polymorphisms to Organ Involvement

 

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  		Table 6. Comparison of Pulmonary Function for VEGF Genotypes in a Sarcoidosis Population

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we investigated two VEGF SNPs to see whether the polymorphisms are associated with susceptibility to sarcoidosis in the Japanese population. We found a significant difference in the allele frequency at locus + 813 between healthy control subjects and patients with sarcoidosis. Compared with the most common C allele, the less common T allele was underrepresented in the sarcoidosis patient population, suggesting that polymorphism at + 813 is associated with decreased risk for sarcoidosis.

VEGF is a potent morphogenic cytokine that modulates embryonic angiogenesis and vasculogenesis by acting as a potent and essential endothelial cell mitogen.19 20 21 Sarcoidosis is often associated with nongranulomatous microangiopathic lesions, including basal lamina layering of the capillaries in the skeletal muscle, cardiac muscle, and lung, glomerulopathy in the kidney, vascular changes in the ocular fundus and bronchi, and impaired peripheral circulation that could be detected by thermography.1 VEGF has also been reported to enhance the activation and migration of monocytes through the Flt-1 receptor in vitro,6 7 which are key events in granuloma formation of granulomatous disorders such as sarcoidosis. SNPs within the VEGF gene have been identified.14 15 16 Watson and coworkers15 showed that a G allele at position - 627 affected the transcriptional activity and increased VEGF production in peripheral blood mononuclear cells. The effect of G allele was likely to be dose dependent. Whereas, a T allele at position + 813 was associated with significantly lower VEGF plasma levels in healthy men.16 In the present study of patients with sarcoidosis, a significant decrease of the frequency of T allele was observed at + 813 position of the VEGF gene, although no significant difference in allele frequencies at - 627 position was observed. The polymorphic site at + 813 was predicted to lie within a potential binding site for transcription factor activating enhancer binding protein 4.16 Activator protein 4 is a helix-loop-helix transcription factor enhancing the expression of several viral and cellular genes by binding to specific enhancer sites.22 23 24 Therefore, the T allele at + 813 might possibly reduce the binding specificity of this motif, resulting in a decrease of the VEGF expression. Individuals who carry the variant T allele might have decreased recruitment of monocytes, which is one of the key pathophysiologic features of sarcoidosis because of low VEGF production. Another possible explanation of the association between the SNP and the susceptibility of sarcoidosis could be a linkage disequilibrium between this SNP and another as yet unknown functional mutation elsewhere in the VEGF sequence. The mechanistic details remain unclear, but our results suggest that the VEGF gene SNP at + 813 might play an important role and that the T allele might have a protective effect on sarcoidosis.

The VEGF gene is expressed by a variety of cells including lung epithelial cells.25 Sarcoidosis is a systemic granulomatous disorder, nearly always with pulmonary manifestations. No correlation between genotypes and clinical form of the disease was apparent. Thus, VEGF might not have much effect in extrapulmonary organs in sarcoidosis. Angiogenesis is a feature of airway remodeling in bronchial asthma. Hoshino et al26 reported that VEGF may play an important role in angiogenesis and subsequent airway remodeling in bronchial asthma. VEGF may also contribute to chronic airway inflammation and angiogenesis in sarcoidosis. Although we obtained marginally significant evidence for association between the mean value of the FEV1/FVC percentage and the GG type at position - 627, we did not note any remarkable abnormalities on physical examination, bronchoscopic examination, or CT scans of the chest suggesting airway diseases except two patients with slight bronchial wall thickening on chest CT in the GG group. The mean value of the FEV1/FVC percentage in the GG group was decreased compared to the CC or the CG; however, it was in the normal range, > 70%. Taken together, the association is more likely a false-positive finding.

Recently, two association studies of VEGF polymorphisms have been reported. Awata et al27 reported that the C(- 627)G polymorphism (- 634 polymorphism in their report) in the 5' UTR of the VEGF gene is a novel genetic risk factor for diabetic retinopathy. Shahbazi et al28 indicated that the - 1154*G- and - 2578*C-containing genotypes, encoding higher VEGF production, are strongly associated with acute renal allograft rejection and may be useful markers of rejection risk. Studies to investigate the roles of such SNPs in the development and extent of sarcoidosis are currently underway.

The Pc values achieved in this study were borderline. The conservative Bonferroni approach is to use a corrected significance value calculated by multiplication of the observed p value by the number of alleles tested. Bonferroni corrections for the total number of alleles at one locus are probably too conservative29 because the alleles at one locus are not independent of each other and such closely linked loci as seen in this study are probably not independent either. Although sex, age, and race were matched in this study, numbers of the patients and control subjects were not matched. Further confirmation in other matched cohorts would be required.

In conclusion, our results suggest that in VEGF gene polymorphisms the T allele at + 813 may decrease susceptibility to sarcoidosis. The mean value of the FEV1/FVC percentage in GG type for - 627 position was lower than that in CC or CG type; however, other clinical findings did not suggest airway diseases in the GG type. Dysregulated VEGF expression has been implicated in the pathogenesis of a number of inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel diseases, and cystic fibrosis in addition to sarcoidosis and bronchial asthma.30 31 32 33 Further studies of the general association of VEGF polymorphisms with regard to VEGF-linked pathologies should be performed.


   Acknowledgements
 
The authors thank Ms. Takeuchi and Ms. Ikeda for help in extracting DNA from clinical specimens.


   Footnotes
 
Abbreviations: bp = base-pair; Flt-1 = fms-like tyrosine kinase-1; Pc = Bonferroni correction; PCR = polymerase chain reaction; SNP = single-nucleotide polymorphism; UTR = untranslated region; VC = vital capacity; VEGF = vascular endothelial growth factor

Received for publication March 11, 2002. Accepted for publication October 8, 2002.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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