Psoriasis is associated with increased beta-defensin genomic copy number.
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ABSTRACT:
SUBMITTER: Hollox EJ
PROVIDER: S-EPMC2447885 | biostudies-literature | 2008 Jan
REPOSITORIES: biostudies-literature
Publications
Psoriasis is associated with increased beta-defensin genomic copy number.
Hollox Edward J EJ Huffmeier Ulrike U Zeeuwen Patrick L J M PL Palla Raquel R Lascorz Jesús J Rodijk-Olthuis Diana D van de Kerkhof Peter C M PC Traupe Heiko H de Jongh Gys G den Heijer Martin M Reis André A Armour John A L JA Schalkwijk Joost J
Nature genetics 20071202 1
Psoriasis is a common inflammatory skin disease with a strong genetic component. We analyzed the genomic copy number polymorphism of the beta-defensin region on human chromosome 8 in 179 Dutch individuals with psoriasis and 272 controls and in 319 German individuals with psoriasis and 305 controls. Comparisons in both cohorts showed a significant association between higher genomic copy number for beta-defensin genes and risk of psoriasis. ...[more]
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Project description:A single previous study has demonstrated significant association of psoriasis with copy number of β-defensin genes, using DNA from psoriasis cases and controls from Nijmegen and Erlangen. In this study, we attempted to replicate that finding in larger new cohorts from Erlangen (N=2,017) and Michigan (N=5,412), using improved methods for β-defensin copy number determination based on the paralog ratio test, and enhanced methods of analysis and association testing implemented in the CNVtools resource. We demonstrate that the association with psoriasis found in the discovery sample is maintained after applying improved typing and analysis methods (P=5.5 × 10(-4), odds ratio (OR)=1.25). We also find that the association is replicated in 2,616 cases and 2,526 controls from Michigan, although at reduced significance (P=0.014), but not in new samples from Erlangen (1,396 cases and 621 controls, P=0.38). Meta-analysis across all cohorts suggests a nominally significant association (P=6.6 × 10(-3)/2 × 10(-4)) with an effect size (OR=1.081) much lower than found in the discovery study (OR=1.32). This reduced effect size and significance on replication is consistent with a genuine but weak association.
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Project description:Human beta-defensin 2 (DEFB4, also known as DEFB2 or hBD-2) is a salt-sensitive antimicrobial protein that is expressed in lung epithelia. Previous work has shown that it is encoded in a cluster of beta-defensin genes at 8p23.1, which varies in copy number between 2 and 12 in different individuals. We determined the copy number of this locus in 355 patients with cystic fibrosis (CF), and tested for correlation between beta-defensin cluster genomic copy number and lung disease associated with CF. No significant association was found.
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Project description:Using a combination of multiplex amplifiable probe hybridization and semiquantitative fluorescence in situ hybridization (SQ-FISH), we analyzed DNA copy number variation across chromosome band 8p23.1, a region that is frequently involved in chromosomal rearrangements. We show that a cluster of at least three antimicrobial beta-defensin genes (DEFB4, DEFB103, and DEFB104) at 8p23.1 are polymorphic in copy number, with a repeat unit >/=240 kb long. Individuals have 2-12 copies of this repeat per diploid genome. By segregation, microsatellite dosage, and SQ-FISH chromosomal signal intensity ratio analyses, we deduce that individual chromosomes can have one to eight copies of this repeat unit. Chromosomes with seven or eight copies of this repeat unit are identifiable by cytogenetic analysis as a previously described 8p23.1 euchromatic variant. Analysis of RNA from different individuals by semiquantitative reverse-transcriptase polymerase chain reaction shows a significant correlation between genomic copy number of DEFB4 and levels of its messenger RNA (mRNA) transcript. The peptides encoded by these genes are potent antimicrobial agents, especially effective against clinically important pathogens, such as Pseudomonas aeruginosa and Staphylococcus aureus, and DEFB4 has been shown to act as a cytokine linking the innate and adaptive immune responses. Therefore, a copy number polymorphism involving these genes, which is reflected in mRNA expression levels, is likely to have important consequences for immune system function.
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Project description:Pregnancy rates for elite bulls used in artificial insemination (AI) can vary significantly and therefore the identification of molecular markers for bull fertility and targets to improve bull selection is important. β-defensins are peptides with diverse regulatory roles in sperm function across multiple species. To explore the functional impact of DEFB103 CNV on the uterine response in vivo, 18 heifers were inseminated with sperm from bulls categorized by low, intermediate, and high CN levels. Transcriptomic analysis of uterine tissue collected 12 hours after insemination revealed significant differential expression of 58 genes (FDR<0.1) related to sperm migration, immune signaling, and chemotaxis. These findings highlight the significant role of DEFB103 CN in both sperm function and the uterine response to bull sperm, suggesting its potential influence on pregnancy outcomes in cattle.
2024-09-15 | E-MTAB-14398 | biostudies-arrayexpress