A polymorphism in the 5’ UTR of the <i>DEFB1</i> gene is associated with the lung phenotype in F508del homozygous Italian cystic fibrosis patients

Crovella, Sérgio; Segat, Ludovica; Amato, Annalisa; Athanasakis, Emmanouil; Bezzerri, Valentino; Braggion, C.; Casciaro, R.; Castaldo, Giuseppe; Colombo, Carla; Covone, A. E.; Rose, Virginia De; Gagliardini, R.; Lanzara, Carmela; Minicucci, L.; Morgutti, Marcello; Nicolis, Elena; Pardo, Francesca; Quattrucci, Serena; Raia, Valeria; Ravazzolo, Roberto; Seia, Manuela; Stanzial, Valentino; Termini, Lisa; Zazzeron, L.; Cabrini, Giulio; Gasparini, Paolo

doi:10.1515/cclm.2011.023

Cited by 12 publications

(6 citation statements)

References 23 publications

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“…There are three classes of defensins, but only the β-defensins are specifically expressed in epithelial cells, including those lining the respiratory tract. Genetic studies have implicated the β-defensin genes on chromosome 8p23 in lung function in patients with asthma 58 , chronic obstructive pulmonary disease (COPD) 59 and with cystic fibrosis (CF) 60 . In particular, DEFB1 mRNA in bronchial epithelial cell biopsies was significantly elevated in COPD patients compared to controls and significantly associated with both reduced FEV 1 and the FEV 1 /FVC ratio in COPD patients and controls 59 .…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of lung function phenotypes in a founder population

Yao

Han

et al. 2014

Journal of Allergy and Clinical Immunology

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Background Lung function is a long-term predictor of mortality and morbidity. Objective We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. Methods We performed a genome-wide association study (GWAS) of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC in 1,144 Hutterites aged 6–89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation (LASSO) regression to select the minimum set of SNPs that best predict FEV1/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs. Results Our GWAS identified significant associations between FEV1/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7x10−8 ~ 3.4x10−9). Nine SNPs at or near four additional loci had P-values < 10−5 with FEV1/FVC. There were only two SNPs with P-values < 10−5 for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, six loci were identified that had a significant degree of functional connectivity (GRAIL P < 0.05), including three clusters of β-defensin genes, two chemokine genes (CCL18 and CXCL12), and TNFRSF13B. Conclusion This study identifies genome-wide significant associations and replicates results of previous GWAS. Multimarker modeling implicated for the first time common variation in genes involved in anti-microbial immunity in airway mucosa influences lung function.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association study of lung function phenotypes in a founder population

Yao

Han

et al. 2014

Journal of Allergy and Clinical Immunology

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“…Some suggested that polymorphisms in the defensin gene cluster modulate the phenotype of cystic fibrosis (CF) airway disease, including an association with chronic P. aeruginosa infection (25)(26)(27). In addition, a genetic variant in the promoter region of a defensin gene cluster was associated with reduced hBD-1 and hBD-3 transcript levels and a higher risk of persistent S. aureus nasal colonization in a cohort of healthy individuals (28).…”

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confidence: 99%

pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37

Alaiwa¹,

Reznikov²,

Gansemer³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

181

162

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The pulmonary airways are continuously exposed to bacteria. As a first line of defense against infection, the airway surface liquid (ASL) contains a complex mixture of antimicrobial factors that kill inhaled and aspirated bacteria. The composition of ASL is critical for antimicrobial effectiveness. For example, in cystic fibrosis an abnormally acidic ASL inhibits antimicrobial activity. Here, we tested the effect of pH on the activity of an ASL defensin, human β-defensin-3 (hBD-3), and the cathelicidin-related peptide, LL-37. We found that reducing pH from 8.0 to 6.8 reduced the ability of both peptides to kill Staphylococcus aureus. An acidic pH also attenuated LL-37 killing of Pseudomonas aeruginosa. In addition, we discovered synergism between hBD-3 and LL-37 in killing S. aureus. LL-37 and lysozyme were also synergistic. Importantly, an acidic pH reduced the synergistic effects of combinations of ASL antibacterials. These results indicate that an acidic pH reduces the activity of individual ASL antimicrobials, impairs synergism between them, and thus may disrupt an important airway host defense mechanism.

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“…Thirdly, haplotype analysis revealed a higher prevalence of ACG block in BD than in patient groups (OR= 0.55; 95% CI= 0.34-0.89), which might mean a decrease in the risk of HIV-1 infection. This beneficial effect found in this population is opposed to deleterious effects observed in other phenotypes [36,40]. Furthermore, the frequency of ACA haplotype was significantly higher in patients group than in BD and SW groups (OR= 5.82; 95% CI= 2.33-16.43 and OR= 2.18; 95% CI= 1.07-4.46, respectively).…”

Section: Discussionmentioning

confidence: 55%

“…Regarding haplotype frequency, ACG, GCA and GGG blocks were the most common in healthy blood donors, likewise in Italy, African American, Brazilian, German and Chinese populations [28,29,[36][37][38][39].…”

Section: Discussionmentioning

confidence: 97%

DEFB1 5'UTR Polymorphisms Modulate the Risk of HIV-1 Infection in Mexican Women

Estrada-Aguirre¹,

Osuna‐Ramírez²,

de³

et al. 2014

CHR

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olved in HIV-1/AIDS pathogenesis. Defensins are key molecules in d/or development of infection and disease. Using PCR-RFLPs, we d human β-defensin 1 (DEFB1) 5'UTR -52 G/A (rs1799946), -44 sms in three groups of women from the state of Sinaloa, located in s; ii) sex-workers; and iii) HIV-1 patients. The -52GG genotype (p= 0.023; Odds Ratio, OR= 0.49; 95% CI= 0.25-0.95), whereas thes (p= 0.013; OR= 2.03; 95% CI= 1.11−3.79, statistical power SP= = 0.017; OR= 1.60; 95% CI= 1.06−2.40), -20AA genotype (p= 0.047; otype with respect to healthy blood donors (p= 0.000012; OR= 5.82; rs (p= 0.019; OR= 2.18; 95% CI= 1.07-4.46). Conversely, the ACG patients (p= 0.009; OR= 0.55; 95% CI= 0.34-0.89). In addition, the viral load (p= 0.015), whereas AGA, AGG and GGA haplotypes were s (p= 0.004, 0.046, and 0.029, respectively). These findings associate Mexican women for the first time.HIV-1 resistance, AIDS, sex-workers. tion d is gly, to nce lthally 220 Abstract: Immunologic and genetic factors are involved in HIV-1/AIDS pathogenesis. Defensins are key molecules in innate immunity that participate in the control and/or development of infection and disease. Using PCR-RFLPs, we determined the association between HIV-1/AIDS and human β-defensin 1 (DEFB1) 5'UTR -52 G/A (rs1799946), -44 C/G (rs1800972), and -20 G/A (rs11362) polymorphisms in three groups of women from the state of Sinaloa, located in the Northwest region of Mexico: i) healthy blood donors; ii) sex-workers; and iii) HIV-1 patients. The -52GG genotype was more frequent in blood donors than in patients (p= 0.023; Odds Ratio, OR= 0.49; 95% CI= 0.25-0.95), whereas the -52GA genotype was significantly higher in patients (p= 0.013; OR= 2.03; 95% CI= 1.11−3.79, statistical power SP= 98.8%), as well as the frequencies of -20A allele (p= 0.017; OR= 1.60; 95% CI= 1.06−2.40), -20AA genotype (p= 0.047; OR = 2.02; 95% CI= 0.93−4.33) and the ACA haplotype with respect to healthy blood donors (p= 0.000012; OR= 5.82; 95% CI= 2.33-16.43, SP= 99.89%) and sex-workers (p= 0.019; OR= 2.18; 95% CI= 1. 07-4.46). Conversely, the ACG haplotype was higher in healthy blood donors than in patients (p= 0.009; OR= 0.55; 95% CI= 0.34-0.89). In addition, the -44CC genotype was associated with a low plasma viral load (p= 0.015), whereas AGA, AGG and GGA haplotypes were more prevalent in individuals with high CD4 counts (p= 0.004, 0.046, and 0.029, respectively). These findings associate DEFB1 5'UTR polymorphisms with HIV-1/AIDS in Mexican women for the first time.

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A polymorphism in the 5’ UTR of the DEFB1 gene is associated with the lung phenotype in F508del homozygous Italian cystic fibrosis patients

Abstract: Our results, although necessary to be confirmed in larger and multiethnic populations, reinforce DEFB1 as a candidate modifier gene of the CF pulmonary phenotype.

Cited by 12 publications

References 23 publications

Genome-wide association study of lung function phenotypes in a founder population

Genome-wide association study of lung function phenotypes in a founder population

pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37

DEFB1 5'UTR Polymorphisms Modulate the Risk of HIV-1 Infection in Mexican Women

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A polymorphism in the 5’ UTR of the DEFB1 gene is associated with the lung phenotype in F508del homozygous Italian cystic fibrosis patients

Abstract: Our results, although necessary to be confirmed in larger and multiethnic populations, reinforce DEFB1 as a candidate modifier gene of the CF pulmonary phenotype.

Cited by 12 publications

References 23 publications

Genome-wide association study of lung function phenotypes in a founder population

Genome-wide association study of lung function phenotypes in a founder population

pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37

DEFB1 5&#39;UTR Polymorphisms Modulate the Risk of HIV-1 Infection in Mexican Women

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DEFB1 5'UTR Polymorphisms Modulate the Risk of HIV-1 Infection in Mexican Women