Screening for Alpha 1 antitrypsin deficiency in Tunisian subjects with obstructive lung disease: a feasibility report

<p>Abstract</p> <p>Background</p> <p>AATD is one of the most common inherited disorders in the World. However, it is generally accepted that AATD in North African populations is not a risk factor for lung and/or liver disease, based on a number of small studies. We therefore planned a screening study for detection of AATD in patients with OLD in a cohort of patients from Kairouan in central Tunisia. Methods: One hundred twenty patients with OLD (asthma, emphysema, COPD) were enrolled in the screening programme. Laboratory diagnosis for AATD was performed according to current diagnostic standards.</p> <p>Results</p> <p>We found that 6/120 OLD patients carried an AAT deficient allele, 1 PI*MZ, 1 PI*MPlowel, 3 PI*MMmalton, 1 PI*MMwurzburg.</p> <p>Conclusion</p> <p>this pilot study demonstrated that alleles related to deficiency of AAT are not absent in the Tunisian population, and that rare AATD variants prevailed over commonest PI*Z variant. These results would support a larger scale screening for AATD in Tunisia.</p

The p400 ATPase regulates nucleosome stability and chromatin ubiquitination during DNA repair

p400 unwinds chromatin from nucleosomes flanking double-strand breaks to facilitate recruitment of the DNA repair components brca1 and 53BP1

Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood appr

Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p(interaction) values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.Peer reviewe

Identification of a novel alpha1-antitrypsin null variant (Q0Cairo)

Alpha1-antitrypsin deficiency (AATD) is a common hereditary disorder associated with high risk of developing pulmonary emphysema early in life and, to a lesser extent, chronic liver disease and cirrhosis. Among Northern Europeans and Northern Americans, more than 95% of individuals with emphysema associated with AATD carry the most frequent AAT deficient gene variants, PI*Z and PI*S. Rare AAT deficient variants account for 2-4% of AATD individuals. We extend the sequence data on AAT by characterizing a novel Null allele detected in 3 subjects: a carrier belonging to an Italian/Egyptian family and 2 members of a family originating from Southern Italy. The mutation raised on a M1 (Ala213) base allele and it is characterized by an A-->T transversion at exon III, nt 218, codon 259 (AAA-->TAA) (GeneBank accession number AY 256958). The transversion results in a premature stop codon (Lys259AAA-->Stop259TAA). The proposed nomenclature of Q0cairo is from the birthplace of the father of first recognized subject. Serum levels and isoelectric focusing of AAT were consistent with the presence of the Null variant

Plasma sRAGE and N-(carboxymethyl) lysine in patients with CHF and/or COPD

BACKGROUND: Professional societies, like many other organizations around the world, have recognized the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the 10th of a series of 14 articles that were prepared to advise guideline developers in respiratory and other diseases. This article deals with how multiple comorbidities (co-existing chronic conditions) may be more effectively integrated into guidelines. METHODS: In this review we addressed the following topics and questions using chronic obstructive pulmonary disease (COPD) as an example. (1) How important are multiple comorbidities for guidelines? (2) How have other organizations involved in the development of guidelines for single chronic disease approached the problem of multiple comorbidities? (3) What are the implications of multiple comorbidities for pharmacological treatment? (4) What are the potential changes induced by multiple comorbidities in guidelines? (5) What are the implications of considering a population of older patients with multiple comorbidities in designing clinical trials? Our conclusions are based on available evidence from the published literature, experience from guideline developers, and workshop discussions. We did not attempt to examine all Clinical Practice Guidelines (CPGs) and relevant literature. Instead, we selected CPGs generated by prominent professional organizations and relevant literature published in widely read journals, which are likely to have a high impact on clinical practice. RESULTS AND CONCLUSIONS: A widening gap exists between the reality of the care of patients with multiple chronic conditions and the practical clinical recommendations driven by CPGs focused on a single disease, such as COPD. Guideline development panels should aim for multidisciplinary representation, especially when contemplating recommendations for individuals aged 65 years or older (who often have multiple comorbidities), and should evaluate the quality of evidence and the strength of recommendations targeted at this population. A priority area for research should be to assess the effect of multiple concomitant medications and assess how their combined effects are altered by genetic, physiological, disease-related, and other factors. One step that should be implemented immediately would be for existing COPD guidelines to add new sections to address the impact of multiple comorbidities on screening, diagnosis, prevention, and management recommendations. Research should focus on the possible interaction of multiple medications. Furthermore, genetic, physiological, disease-related, and other factors that may influence the directness (applicability) of the evidence for the target population in clinical practice guidelines should be examined

Case-finding for alpha1-antitrypsin deficiency in Kazakh patients with COPD

Alpha-1-antitrypsin deficiency (AATD) is an under-diagnosed condition in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to screen for AATD in Kazakh patients with COPD using dried blood spot specimens