Association of defensin β-1 gene polymorphisms with asthma

Hara Levy*, Benjamin A. Raby, Stephen Lake, Kelan G. Tantisira, David Kwiatkowski, Ross Lazarus, Edwin K. Silverman, Brent Richter, Walter T. Klimecki, Donata Vercelli, Fernando D. Martinez, Scott T. Weiss

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

Background: Defensins are antimicrobial peptides that may take part in airway inflammation and hyperresponsiveness. We characterized the genetic diversity in the defensin β-1 (DEFB1) locus and tested for an association between common genetic variants and asthma diagnosis. Methods: To identify single nucleotide polymorphisms (SNPs), we resequenced this gene in 23 self-defined European Americans and 24 African Americans. To test whether DEFB1 genetic variants are associated with asthma, we genotyped 4 haplotype-tag SNPs in 517 asthmatic and 519 control samples from the Nurses' Health Study (NHS) and performed a case-control association analysis. To replicate these findings, we evaluated the DEFB1 polymorphisms in a second cohort from the Childhood Asthma Management Program. Results: Within the NHS, single SNP testing suggested an association between asthma diagnosis and a 5′ genomic SNP (g.-1816 T>C; P = .025) and intronic SNP (IVS+692 G>A; P = .054). A significant association between haplotype (Adenine, Cytosine, Thymine, Adenine [ACTA]) and asthma (P = .024) was also identified. Associations between asthma diagnosis and both DEFB1 polymorphisms were observed in Childhood Asthma Management Program, a second cohort: g.-1816 T>C and IVS+692 G>A demonstrated significant transmission distortion (P = .05 and .007, respectively). Transmission distortion was not observed in male subjects. The rare alleles (-1816C and +692A) were undertransmitted to offspring with asthma, suggesting a protective effect, contrary to the findings in the NHS cohort. Similar effects were evident at the haplotype level: ACTA was undertransmitted (P = .04) and was more prominent in female subjects (P = .007). Conclusion: Variation in DEFB1 contributes to asthma diagnosis, with apparent gender-specific effects.

Original languageEnglish (US)
Pages (from-to)252-258
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Volume115
Issue number2
DOIs
StatePublished - Feb 2005

Funding

We acknowledge the assistance of the NHS and its participants, particularly Dr Frank E. Speizer and Dr Carlos A. Camargo, who obtained asthma diagnosis information in this cohort. We thank all of the CAMP families for their enthusiastic participation. We also acknowledge the CAMP investigators and research team, supported by the National Heart, Lung and Blood Institute, for collection of CAMP Genetics Ancillary Study data. We are grateful for the helpful comments of Dr Gerald Pier and Dr Carl R. Crawford. Soma Datta, Carrie Beck, Jody Senter Sylvia, Allison Brown, Michael Hagar, and Maura Regan provided technical expertise and support. CAMP was supported by contracts N01-HR-16044, 16045, 16046, 16047, 16048, 16049, 16050, 16051, and 16052 from the National Heart, Lung and Blood Institute. The CAMP Genetics Ancillary Study was supported by P01 HL67664 (Dr Weiss) from the National Heart, Lung and Blood Institute. In addition, this work was supported by research grants and contracts K23HL074202-01 (Dr Levy) and 1 U01 HL66795 21 (Dr Weiss) from the National Heart, Lung and Blood Institute.

Keywords

  • Association studies
  • Asthma
  • Asthma genetics
  • Defensin

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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