Mechanisms of Allergy
Association of polymorphisms in the collagen region of SP-A2 with increased levels of total IgE antibodies and eosinophilia in patients with allergic bronchopulmonary aspergillosis☆,☆☆

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Abstract

Background: Studies from our group have shown a protective role of pulmonary surfactant protein A (SP-A) against lung allergy and infections caused by Aspergillus fumigatus . Objective: Present study investigated the association of polymorphisms in the collagen region of SP-A1 and SP-A2 (genes encoding SP-A) with allergic bronchopulmonary aspergillosis (ABPA) and its clinical markers. Methods: Genomic DNA was extracted from blood samples of patients with ABPA and age-matched, unrelated control subjects. The polymorphisms were detected by means of PCR amplification and sequencing of the collagen region of SP-A1 and SP-A2 . Results: Two exonic (SP-A2 G1649C and SP-A2 A1660G, 10 patients and 11 control subjects) and 2 intronic (SP-A2 T1492C, 8 patients and 8 control subjects; SP-A1 C1416T, 5 patients and 7 control subjects) polymorphisms in the collagen region of SP-A2 and SP-A1 showed significant association with patients with ABPA. A significantly higher frequency of the AGA allele (A1660G) of SP-A2 was observed in patients with ABPA in comparison with control subjects (P = .0156, odds ratio [OR] = 4.78, 95% CI = 1.23 < OR < 18.52). This polymorphism, when existing along with a nonredundant polymorphism, SP-A2 G1649C (Ala91Pro) resulted in a stronger association with ABPA (A1660G and G1649C: P = .0079, OR = 10.4, 95% CI = 1.62 < OR < 66.90). Patients with ABPA with GCT and AGG alleles showed significantly high levels of total IgE and percentage eosinophilia versus patients with ABPA with CCT and AGA alleles. Conclusion: The results indicated that SP-A2 G1649C and SP-A2 A1660G, polymorphisms in the collagen region of SP-A2 , might be one of the contributing factors to genetic predisposition and severity of clinical markers of ABPA. (J Allergy Clin Immunol 2003;111:1001-7.)

Section snippets

Study population

After approval of the institute's human ethics committee, Indian subjects (n = 45) were screened for single nucleotide polymorphisms (SNPs) in the collagen region of SP-A1 and SP-A2 . These subjects included patients with ABPA (n = 5 for SP-A1 , n = 10 for SP-A2 ) and unrelated and age-matched healthy control subjects (n = 7 for SP-A1 , n = 11 for SP-A2 ; from same ethnic origin [ie, North Indian population]) for the preliminary study. SNPs at 1649 and 1660 positions of SP-A2 were further

Results

Characteristics of SNPs observed in the collagen region of SP-A1 and SP-A2 of 45 subjects in an Indian population (patients with ABPA = 22, control subjects = 23) are shown in Table II.

. Characteristics of polymorphisms observed in collagen region of human SP-A1 and SP-A2 in Indian population

Gene locationNucleotideAmino acid
PositionChangePositionChange
SP-A1
Exon 21162C/T39thHis to His
Exon 21193C/G50thLeu to Val
Intron B1416C/T——
SP-A2
Intron 31382C/G——
Intron 31492T/C——
Exon 41649G/C91stAla to Pro
Exon

Discussion

Increased incidence of ABPA in genetically predisposed atopic patients, asthmatic patients, and patients with cystic fibrosis indicates a multifactorial genetic basis for the disease.21, 22 A plausible genetic contribution to ABPA is also suggested by its familial occurrence.23, 24, 25, 26 In recent years, polymorphisms of several candidate genes, such as that for cystic fibrosis transmembrane regulatory protein (CFTR ) and HLA-DR , have been correlated with susceptibility to ABPA.27, 28, 29, 30

Acknowledgements

We thank the Functional Genomics Unit, Institute for Genomics and Integrative Biology, for the sequencing of PCR products. We also thank Dr Deepak, Vallabhbhai Patel Chest Institute, for his help in collection of samples from patients with ABPA.

References (41)

  • TR Korfhagen et al.

    Altered surfactant function and structure in SP-A gene targeted mice

    Proc Natl Acad Sci U S A

    (1996)
  • AM LeVine et al.

    Surfactant protein-A deficient mice are susceptible to group B streptococcal infection

    J Immunol

    (1997)
  • AM LeVine et al.

    Surfactant protein-A enhances respiratory syncytial virus clearance in vivo

    J Clin Invest

    (1999)
  • EC Crouch

    Collectins and pulmonary host defense

    Am J Respir Cell Mol Biol

    (1998)
  • RR Hoover et al.

    Organization of the human SP-A and SP-D loci at 10q22-q23. Physical and radiation hybrid mapping reveal gene order and orientation

    Am J Respir Cell Mol Biol

    (1998)
  • S DiAngelo et al.

    Novel, non-radioactive, simple and multiplex PCRcRFLP methods for genotyping human SP-A and SP-D marker alleles

    Dis Markers

    (1999)
  • G Wang et al.

    The effect of ozone exposure on the ability of human surfactant protein A variants to stimulate cytokine production

    Environ Health Perspect

    (2002)
  • AM Karinch et al.

    Effect of genotype on the levels of surfactant protein A mRNA and on the SP-A2 splice variants in adult humans

    Biochem J

    (1997)
  • P Kala et al.

    Association of pulmonary surfactant protein A (SP-A) gene and respiratory distress syndrome: interaction with SP-B

    Pediatr Res

    (1998)
  • M Ramet et al.

    Human surfactant protein-A gene locus for genetic studies in the Finnish population

    Dis Markers

    (2000)

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    ☆

    Supported by the Institute of Genomics and Integrative Biology (Council of Scientific and Industrial Research). Dr Taruna Madan is a recipient of Young scientist grant of Indian National Science Academy. Ms Shweta Saxena is a recipient of Senior Research Fellowship of Council of Scientific and Industrial Research.

    ☆☆

    Reprint requests: Puranam Usha Sarma, PhD, Molecular Biochemistry and Diagnostics, Institute of Genomics and Integrative Biology, Mall Road, Delhi-110007, India.

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