Association of defensin beta-1 gene polymorphisms with asthma.
BACKGROUND
Defensins are antimicrobial peptides that may take part in airway inflammation and hyperresponsiveness.


OBJECTIVE
We characterized the genetic diversity in the defensin beta-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).


CONCLUSIONS
Variation in DEFB1 contributes to asthma diagnosis, with apparent gender-specific effects.
Levy
Hara
H
Children's Hospital, Division of Pulmonary Medicine, Boston, MA, USA. Hara.levy@childrens.harvard.edu
Raby
Benjamin A
BA
Lake
Stephen
S
Tantisira
Kelan G
KG
Kwiatkowski
David
D
Lazarus
Ross
R
Silverman
Edwin K
EK
Richter
Brent
B
Klimecki
Walter T
WT
Vercelli
Donata
D
Martinez
Fernando D
FD
Weiss
Scott T
ST
D001249:Asthma / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D015337:Multicenter Studies as Topic; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D016032:Randomized Controlled Trials as Topic; D012737:Sex Factors; D023083:beta-Defensins / Q000235:genetics*
C406407:DEFB1 protein, human; D023083:beta-Defensins