Mucin Variable Number Tandem Repeat Polymorphisms and Severity of Cystic Fibrosis Lung Disease: Significant Association with MUC5AC
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{"title"=>"Mucin variable number tandem repeat polymorphisms and severity of cystic fibrosis lung disease: Significant association with MUC5AC", "type"=>"journal", "authors"=>[{"first_name"=>"Xue Liang", "last_name"=>"Guo", "scopus_author_id"=>"53881195400"}, {"first_name"=>"Rhonda G.", "last_name"=>"Pace", "scopus_author_id"=>"8934686100"}, {"first_name"=>"Jaclyn R.", "last_name"=>"Stonebraker", "scopus_author_id"=>"6603113391"}, {"first_name"=>"Clayton W.", "last_name"=>"Commander", "scopus_author_id"=>"22133986900"}, {"first_name"=>"Anthony T.", "last_name"=>"Dang", "scopus_author_id"=>"53881204500"}, {"first_name"=>"Mitchell L.", "last_name"=>"Drumm", "scopus_author_id"=>"7006422406"}, {"first_name"=>"Ann", "last_name"=>"Harris", "scopus_author_id"=>"36105900000"}, {"first_name"=>"Fei", "last_name"=>"Zou", "scopus_author_id"=>"35294423500"}, {"first_name"=>"Dallas M.", "last_name"=>"Swallow", "scopus_author_id"=>"7006425537"}, {"first_name"=>"Fred A.", "last_name"=>"Wright", "scopus_author_id"=>"37024767900"}, {"first_name"=>"Wanda K.", "last_name"=>"O'Neal", "scopus_author_id"=>"7003320585"}, {"first_name"=>"Michael R.", "last_name"=>"Knowles", "scopus_author_id"=>"7101801977"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"362707318", "isbn"=>"1932-6203", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0025452", "scopus"=>"2-s2.0-80053604911", "pmid"=>"21998660", "sgr"=>"80053604911"}, "id"=>"8592fc35-4400-3040-8a68-6ca26683c072", "abstract"=>"Variability in cystic fibrosis (CF) lung disease is partially due to non-CFTR genetic modifiers. Mucin genes are very polymorphic, and mucins play a key role in the pathogenesis of CF lung disease; therefore, mucin genes are strong candidates as genetic modifiers. DNA from CF patients recruited for extremes of lung phenotype was analyzed by Southern blot or PCR to define variable number tandem repeat (VNTR) length polymorphisms for MUC1, MUC2, MUC5AC, and MUC7. VNTR length polymorphisms were tested for association with lung disease severity and for linkage disequilibrium (LD) with flanking single nucleotide polymorphisms (SNPs). No strong associations were found for MUC1, MUC2, or MUC7. A significant association was found between the overall distribution of MUC5AC VNTR length and CF lung disease severity (p = 0.025; n = 468 patients); plus, there was robust association of the specific 6.4 kb HinfI VNTR fragment with severity of lung disease (p = 6.2 x 10(-4) after Bonferroni correction). There was strong LD between MUC5AC VNTR length modes and flanking SNPs. The severity-associated 6.4 kb VNTR allele of MUC5AC was confirmed to be genetically distinct from the 6.3 kb allele, as it showed significantly stronger association with nearby SNPs. These data provide detailed respiratory mucin gene VNTR allele distributions in CF patients. Our data also show a novel link between the MUC5AC 6.4 kb VNTR allele and severity of CF lung disease. The LD pattern with surrounding SNPs suggests that the 6.4 kb allele contains, or is linked to, important functional genetic variation.", "link"=>"http://www.mendeley.com/research/mucin-variable-number-tandem-repeat-polymorphisms-severity-cystic-fibrosis-lung-disease-significant-3", "reader_count"=>1, "reader_count_by_academic_status"=>{"Student > Doctoral Student"=>1}, "reader_count_by_user_role"=>{"Student > Doctoral Student"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "reader_count_by_subdiscipline"=>{"Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/726918"], "description"=>"<p>Distributions of VNTR allele sizes by lung severity status for (A) <i>MUC1</i>, (B) <i>MUC2</i>, (C) <i>MUC5AC</i>, and (D) <i>MUC7</i> are shown. The number of chromosomes (alleles) representing each phenotype category for each mucin is given (n), as is the Wilcoxon rank-sum test p value.</p>", "links"=>[], "tags"=>["vntr", "allele", "sizes", "severity"], "article_id"=>397256, "categories"=>["Medicine", "Genetics"], "users"=>["XueLiang Guo", "Rhonda G. Pace", "Jaclyn R. Stonebraker", "Clayton W. Commander", "Anthony T. Dang", "Mitchell L. Drumm", "Ann Harris", "Fei Zou", "Dallas M. Swallow", "Fred A. Wright", "Wanda K. O'Neal", "Michael R. Knowles"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025452.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Distributions_of_VNTR_allele_sizes_by_lung_severity_status_/397256", "title"=>"Distributions of VNTR allele sizes by lung severity status.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-06 02:00:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/727154"], "description"=>"<p>P values represent evidence of an improved fit to the LD patterns between SNPs and the VNTR when 6.3/6.4 are treated as separate VNTR alleles (three-allele system) instead of being collapsed into a single allele (two-allele system). The p values represent a direct test of the hypothesis that the 6.3 kb and 6.4 kb alleles follow distinct LD patterns with the surrounding SNPs. Non-significant p values, e.g., those 5′ to <i>MUC5AC</i>, indicate that the two alleles share the same LD structure with the SNPs, while significant p values indicate that the LD pattern between the two alleles is different, e.g., at rs28514396. Approximate location of <i>Hinf</i>I fragment in <i>MUC5AC</i> shown in gray.</p>", "links"=>[], "tags"=>["differential", "linkage", "disequilibrium", "kb", "alleles"], "article_id"=>397493, "categories"=>["Medicine", "Genetics"], "users"=>["XueLiang Guo", "Rhonda G. Pace", "Jaclyn R. Stonebraker", "Clayton W. Commander", "Anthony T. Dang", "Mitchell L. Drumm", "Ann Harris", "Fei Zou", "Dallas M. Swallow", "Fred A. Wright", "Wanda K. O'Neal", "Michael R. Knowles"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025452.g004", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Analysis_of_differential_linkage_disequilibrium_between_MUC5AC_6_3_and_6_4_kb_alleles_versus_nearby_SNPs_/397493", "title"=>"Analysis of differential linkage disequilibrium between <i>MUC5AC</i> 6.3 and 6.4 kb alleles versus nearby SNPs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-06 02:04:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/727032"], "description"=>"<p>The LD structure is shown for (A) <i>MUC1</i> (n = 514 patients; human genome build 19) and (B) <i>MUC5AC</i> genes (n = 468 patients; human genome build 18 was used due to incomplete build information in this region in build 19). The location of the SNPs (minor allele frequency >9%) that have been evaluated are shown, along with their relative chromosome position. The LD structure is shown, considering cut-points to assign genotypes for <i>MUC1</i> (cut-point 4.9 kb; short≤4.9 kbMUC5<i>AC</i> (cut-point 6.7 kb; short<6.7 kb≤long). The plot was constructed with the Haploview program and the pairwise <i>r</i><sup>2</sup> (×100) values are depicted in the diamonds. The dark diamonds have higher <i>r</i><sup>2</sup> ((×100) values, and the diamonds in lighter shade of color have lower <i>r</i><sup>2</sup> ((×100) values. The colored boxes above the LD map represent the p value from chi-square tests to evaluate the significance of the SNP genotype to the VNTR allele genotypes. Color coding: white (<i>p</i>>0.1), light blue (10<sup>−5</sup>−10−5); dark blue (10<sup>−50</sup>−10) and red (p≤10<sup>−50</sup>).</p>", "links"=>[], "tags"=>["representations", "ld"], "article_id"=>397381, "categories"=>["Medicine", "Genetics"], "users"=>["XueLiang Guo", "Rhonda G. Pace", "Jaclyn R. Stonebraker", "Clayton W. Commander", "Anthony T. Dang", "Mitchell L. Drumm", "Ann Harris", "Fei Zou", "Dallas M. Swallow", "Fred A. Wright", "Wanda K. O'Neal", "Michael R. Knowles"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025452.g003", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_representations_of_MUC1_and_MUC5AC_LD_structure_/397381", "title"=>"Schematic representations of <i>MUC1</i> and <i>MUC5AC</i> LD structure.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-06 02:03:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/367637", "https://ndownloader.figshare.com/files/367688", "https://ndownloader.figshare.com/files/367744", "https://ndownloader.figshare.com/files/367826", "https://ndownloader.figshare.com/files/367916", "https://ndownloader.figshare.com/files/367950", "https://ndownloader.figshare.com/files/367993", "https://ndownloader.figshare.com/files/368036"], "description"=>"<div><p>Variability in cystic fibrosis (CF) lung disease is partially due to non-<em>CFTR</em> genetic modifiers. Mucin genes are very polymorphic, and mucins play a key role in the pathogenesis of CF lung disease; therefore, mucin genes are strong candidates as genetic modifiers. DNA from CF patients recruited for extremes of lung phenotype was analyzed by Southern blot or PCR to define variable number tandem repeat (VNTR) length polymorphisms for <em>MUC1</em>, <em>MUC2</em>, <em>MUC5AC</em>, and <em>MUC7.</em> VNTR length polymorphisms were tested for association with lung disease severity and for linkage disequilibrium (LD) with flanking single nucleotide polymorphisms (SNPs). No strong associations were found for <em>MUC1</em>, <em>MUC2</em>, or <em>MUC7</em>. A significant association was found between the overall distribution of <em>MUC5AC</em> VNTR length and CF lung disease severity (p = 0.025; n = 468 patients); plus, there was robust association of the specific 6.4 kb <em>Hinf</em>I VNTR fragment with severity of lung disease (p = 6.2×10<sup>−4</sup> after Bonferroni correction). There was strong LD between <em>MUC5AC</em> VNTR length modes and flanking SNPs. The severity-associated 6.4 kb VNTR allele of <em>MUC5AC</em> was confirmed to be genetically distinct from the 6.3 kb allele, as it showed significantly stronger association with nearby SNPs. These data provide detailed respiratory mucin gene VNTR allele distributions in CF patients. Our data also show a novel link between the <em>MUC5AC</em> 6.4 kb VNTR allele and severity of CF lung disease. The LD pattern with surrounding SNPs suggests that the 6.4 kb allele contains, or is linked to, important functional genetic variation.</p> </div>", "links"=>[], "tags"=>["mucin", "tandem", "polymorphisms", "severity", "cystic", "fibrosis"], "article_id"=>132630, "categories"=>["Medicine", "Genetics"], "users"=>["XueLiang Guo", "Rhonda G. Pace", "Jaclyn R. Stonebraker", "Clayton W. Commander", "Anthony T. Dang", "Mitchell L. Drumm", "Ann Harris", "Fei Zou", "Dallas M. Swallow", "Fred A. Wright", "Wanda K. O'Neal", "Michael R. Knowles"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0025452.s001", "https://dx.doi.org/10.1371/journal.pone.0025452.s002", "https://dx.doi.org/10.1371/journal.pone.0025452.s003", "https://dx.doi.org/10.1371/journal.pone.0025452.s004", "https://dx.doi.org/10.1371/journal.pone.0025452.s005", "https://dx.doi.org/10.1371/journal.pone.0025452.s006", "https://dx.doi.org/10.1371/journal.pone.0025452.s007", "https://dx.doi.org/10.1371/journal.pone.0025452.s008"], "stats"=>{"downloads"=>25, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Mucin_Variable_Number_Tandem_Repeat_Polymorphisms_and_Severity_of_Cystic_Fibrosis_Lung_Disease_Significant_Association_with_MUC5AC_/132630", "title"=>"Mucin Variable Number Tandem Repeat Polymorphisms and Severity of Cystic Fibrosis Lung Disease: Significant Association with <em>MUC5AC</em>", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-10-06 00:43:50"}
  • {"files"=>["https://ndownloader.figshare.com/files/726823"], "description"=>"<p>Distributions of VNTR allele sizes as determined by Southern blot analysis of <i>Hinf</i>I-digested genomic DNA are shown for (A) <i>MUC1</i>, (B) <i>MUC2</i>, (C) <i>MUC5AC,</i> and by polymerase chain reaction for (D) <i>MUC7</i>.</p>", "links"=>[], "tags"=>["vntr", "allele"], "article_id"=>397171, "categories"=>["Medicine", "Genetics"], "users"=>["XueLiang Guo", "Rhonda G. Pace", "Jaclyn R. Stonebraker", "Clayton W. Commander", "Anthony T. Dang", "Mitchell L. Drumm", "Ann Harris", "Fei Zou", "Dallas M. Swallow", "Fred A. Wright", "Wanda K. O'Neal", "Michael R. Knowles"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025452.g001", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Distributions_of_VNTR_allele_sizes_/397171", "title"=>"Distributions of VNTR allele sizes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-06 01:59:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/727224"], "description"=>"<p>For each test, a specific size is denoted the “Designated” allele (allele D), and is compared to all other alleles (non-D). The number of patients (n = 468; Severe = 194; Mild = 274) with each genotype (D, D; D, non-D; and non-D, non-D) is given for each test.</p>†<p>Analyzed only for allele sizes that were present in ≥ 4% of the population.</p>‡<p>6.35 kb (and 6.30 kb) allele tends to associate with “mild” disease, but is not significant after Bonferroni correction.</p><p>*6.4 kb allele associates with “severe” lung disease; Bonferroni corrected p value for the tests indicated in this Table (8 tests total), p = 1.1×10<sup>−4</sup>; corrected p value for the tests in this Table, plus the original tests for association with lung disease severity shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025452#pone-0025452-g002\" target=\"_blank\">Figure 2</a> (12 tests total), p = 1.7×10<sup>−4</sup>; corrected p value for all tests directly above, plus the additional tests utilizing the cut-point analysis in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025452#pone.0025452.s003\" target=\"_blank\">Figure S3</a> (15 tests total), p = 2.1×10<sup>−4</sup>; corrected p value for all tests directly above, plus the <i>MUC1</i> and <i>MUC2</i> VNTR allele size tests for association (data not shown; 29 tests total), p = 4.1×10<sup>−4</sup>; corrected p value for all tests directly above, plus SNPs in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025452#pone.0025452.s007\" target=\"_blank\">Table S3</a> (44 tests total), p = 6.2×10<sup>−4</sup>.</p>", "links"=>[], "tags"=>["vntr", "allele", "sizes", "severity"], "article_id"=>397567, "categories"=>["Medicine", "Genetics"], "users"=>["XueLiang Guo", "Rhonda G. Pace", "Jaclyn R. Stonebraker", "Clayton W. Commander", "Anthony T. Dang", "Mitchell L. Drumm", "Ann Harris", "Fei Zou", "Dallas M. Swallow", "Fred A. Wright", "Wanda K. O'Neal", "Michael R. Knowles"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025452.t001", "stats"=>{"downloads"=>2, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Association_of_MUC5AC_VNTR_allele_sizes_with_lung_disease_severity_Severe_versus_Mild_8224_/397567", "title"=>"Association of <i>MUC5AC</i> VNTR allele sizes with lung disease severity (“Severe” versus “Mild”)<sup>†</sup>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-10-06 02:06:07"}

PMC Usage Stats | Further Information

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Relative Metric

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