Genetic Variation in the Defensin Gene Cluster

β-defensins are cationic antimicrobial and immunoregulatory peptides that are expressed in epithelia. Their genes have been mapped to chromosome 8p22-p23, which has been shown to be a site of complex genetic variation. DEFB1 (encodes hBD-1) is constitutively expressed and has 2 copies per diploid genome (PDG) whereas DEFB4 (encodes hBD-2) and DEFB103A (encodes hBD-3) are inducible and have multiple copies that range from 2-12 PDG. Ethnic diversity exists in SNP frequency and subsequent haplotypes. We have shown in previous studies that a specific haplotype in DEFB1 is associated with protection against fungi infection, while its peptide, hBD-1 has limited antifungal efficacy when compared to hBD-2 or 3. Objectives: To test if the specific haplotype in DEFB1, which is linked to protection, is associated with high copy numbers in both DEFB4 and DEFB103A genes. Methods: We genotyped 50 ethnically diverse, healthy individuals and 69 genomic DNA samples from the Coriell ethnic diversity panel. High throughput SNP assays were developed using a multiplex ligase detection reaction assay (MLDR), for DEFB1 haplotype determination. Quantitative real time PCR assays (QPCR) were performed for copy number determination in the DEFB4 and DEFB103A genes. Results: A positive correlation exists with the specific haplotype comprised of three SNPs (-52, -44 and -20) in the 5'UTR of DEFB1 with increased copy number in the DEFB4 and DEFB103A genes. Conclusion: These results suggest the likelihood of linkage between the 2 copy per genome DEFB1 gene haplotype and the muticopy variants of DEFB4 and DEFB103A. Interpersonal variability in copy number polymorphism may contribute to variability in predisposition to mucosal infections. Supported by NIH/NIDCR 1 K23 DE016110-01A1