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  • 1
    Publication Date: 2011-11-15
    Description: So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds. Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log of odds (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266855/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266855/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yokoyama, Satoru -- Woods, Susan L -- Boyle, Glen M -- Aoude, Lauren G -- MacGregor, Stuart -- Zismann, Victoria -- Gartside, Michael -- Cust, Anne E -- Haq, Rizwan -- Harland, Mark -- Taylor, John C -- Duffy, David L -- Holohan, Kelly -- Dutton-Regester, Ken -- Palmer, Jane M -- Bonazzi, Vanessa -- Stark, Mitchell S -- Symmons, Judith -- Law, Matthew H -- Schmidt, Christopher -- Lanagan, Cathy -- O'Connor, Linda -- Holland, Elizabeth A -- Schmid, Helen -- Maskiell, Judith A -- Jetann, Jodie -- Ferguson, Megan -- Jenkins, Mark A -- Kefford, Richard F -- Giles, Graham G -- Armstrong, Bruce K -- Aitken, Joanne F -- Hopper, John L -- Whiteman, David C -- Pharoah, Paul D -- Easton, Douglas F -- Dunning, Alison M -- Newton-Bishop, Julia A -- Montgomery, Grant W -- Martin, Nicholas G -- Mann, Graham J -- Bishop, D Timothy -- Tsao, Hensin -- Trent, Jeffrey M -- Fisher, David E -- Hayward, Nicholas K -- Brown, Kevin M -- 10118/Cancer Research UK/United Kingdom -- 10589/Cancer Research UK/United Kingdom -- AR043369-14/AR/NIAMS NIH HHS/ -- C490/A11021/Cancer Research UK/United Kingdom -- C588/A10589/Cancer Research UK/United Kingdom -- C588/A4994/Cancer Research UK/United Kingdom -- C8197/A10123/Cancer Research UK/United Kingdom -- C8216/A6129/Cancer Research UK/United Kingdom -- CA88363/CA/NCI NIH HHS/ -- K24CA149202/CA/NCI NIH HHS/ -- P50CA9368/CA/NCI NIH HHS/ -- R01 AR043369/AR/NIAMS NIH HHS/ -- R01 CA-83115-01A2/CA/NCI NIH HHS/ -- R01 CA088363/CA/NCI NIH HHS/ -- R01 CA088363-09/CA/NCI NIH HHS/ -- R01 CA83115/CA/NCI NIH HHS/ -- England -- Nature. 2011 Nov 13;480(7375):99-103. doi: 10.1038/nature10630.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22080950" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Aged, 80 and over ; Female ; Gene Expression Regulation, Neoplastic ; *Genetic Predisposition to Disease ; Humans ; Male ; Melanoma/*genetics ; Microphthalmia-Associated Transcription Factor/*genetics ; Middle Aged ; *Mutation ; Sumoylation/genetics ; Young Adult
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We have examined the relationship between month of birth and episodes of wheezing, productive cough, eczema and hayfever, and also standardized maximum midexpiratory flow (FEF25–75) in a representative sample of 4549 Australian primary schoolchildren (mean age 10.1 years). Children experiencing frequent wheezing (one or more episodes per month) were more likely to be born in spring and summer (odds ratio =1.6, 95% confidence interval = 1.1–2.4), but this was not seen for less severe disease. No effect of season or birth month was seen for the other illnesses examined or for lung function.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background IL-16 is an immunomodulatory cytokine whose expression is increased in the bronchial mucosa, bronchoalveolar lavage fluid and induced sputum of asthmatic patients. It has been suggested that IL-16 has a regulatory role in the pathophysiology of asthma. A single-nucleotide polymorphism (T−295C) has been described in the promoter region of the gene and it has been hypothesized that this polymorphism may be associated with altered levels of IL-16 expression, and account for the increased levels of IL-16 seen in the asthmatic airway.Objective To determine the association between the T−295C promoter polymorphism and asthma, disease severity and atopy in a large Australian Caucasian population.Methods We used PCR and restriction fragment length polymorphism analysis to establish the allele frequency of the T−295C promoter polymorphism in a random Australian Caucasian population (n=176) and to characterize the polymorphism in a large Australian Caucasian population of mild (n=273), moderate (n=230) and severe (n=77) asthmatic patients, and non-asthmatic controls (n=455). Genotype association analyses were performed using χ2 tests.Results The polymorphic C allele was present in 19% of the asthmatic population and 21% of the non-asthmatic population. There was no association between the polymorphism and asthma (P=0.153) nor with asthma severity (P=0.417) or atopy (P=0.157) in this population.Conclusion Although it has been hypothesized that the T−295C promoter polymorphism may be associated with increased IL-16 gene expression, it is not associated with asthma, disease severity or atopy in this Australian population.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background Cyclooxygenase (COX)-2 is a key inducible enzyme that regulates the production of anti-inflammatory prostaglandin E2. A single-nucleotide polymorphism, −765G〉C, located within a stimulatory protein-1 binding site in the COX-2 promoter region, has been shown to have significantly lower promoter activity in vitro compared with the wild-type and was associated with decreased plasma levels of C-reactive protein after coronary artery bypass surgery. We hypothesized that this polymorphism, which may result in decreased COX-2 transcription, could be associated with more severe asthma, and/or aspirin-intolerant asthma (AIA).Objective To determine the association between the −765G〉C COX-2 polymorphism and asthma, disease severity and AIA in a large, well-phenotyped Australian population.Methods PCR and restriction fragment length polymorphism analysis was used to characterize the polymorphism in an Australian Caucasian population of patients with mild (n=322), moderate (n=254) or severe (n=88) asthma and in non-asthmatic control subjects (n=512), as well as in patients with AIA (n=58). Genotype and allele association analyses were performed using χ2 tests.Results The polymorphic −765C allele was present in approximately 30% of asthmatic patients and non-asthmatic controls. There was no association between the −765G〉C polymorphism and asthma (P=0.920), disease severity (P=0.840), atopy (P=0.655) or AIA (P=0.841) in this population.Conclusion Although the −765G〉C polymorphism may have lower promoter activity and result in decreased COX-2 expression, it is not associated with asthma, disease severity, AIA or atopy in this Australian population.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background The fungus Alternaria alternata contains potent allergens, and sensitization to these allergens is associated with a high risk of respiratory disease. The influence of genetic regulation on sensitization to Alternaria is unknown.Objective To determine the influence of genetic factors on IgE responses to specific allergens of Alternaria.Methods The concordance of skin prick test (SPT), radioallergosorbent test (RAST) and IgE-binding profiles of sera were examined from a large cohort of monozygotic and dizygotic twins.Results Casewise concordance for a positive SPT response was monozygous (MZ) 66%: dizygous (DZ) 40% (P = 0.002). Logistic regression confirmed that casewise concordance was significantly stronger between MZ than DZ pairs. Immunoblotting against an Alternaria extract revealed 19 allergenic bands. The differences in concordance between the different bands were not significant for either the MZ (P = 0.97) or DZ (P = 0.84) groups. The pooled MZ : DZ difference in concordance was just significant (P = 0.049), suggesting an overall genetic effect on the response to Alternaria. This was reinforced by the comparison of the MZ and DZ correlations for total number of bands recognized (MZ r = 0.65; DZ r = 0.37, P = 0.015). Overall, there was a moderate correlation between the individual SPT weal size and RAST score (r2 = 0.41) and a substantial correlation between the number of immunoblotted bands and RAST scores (r2 = 0.79).Conclusion There is a strong genetic influence on IgE response to the mixture of Alternaria allergens and a lesser effect on IgE response to individual allergens.
    Type of Medium: Electronic Resource
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