Validation of potential beef tenderness markers and interpretation of their biological functions

Human and Animal Development Regulatory Mechanisms Session 12 : Experimental epileptology and neurodegenerationabsen

Peak allelic associations within genomic regions of sarcoidosis ancestry linkage with Scadding stage IV disease.

<p>Abbreviations: f_CEU: frequency of modeled allele in HapMap Northern and Western European ancestry population; f_AFR: frequency of modeled allele in HapMap Yoruban African ancestry population; f_AFF: frequency of modeled allele in sarcoidosis-affected individuals; f_UNF: frequency of modeled allele in unaffected individuals; OR: odds ratio; 95%CI: 95% confidence interval; P: p-value; MIX: MIXSCORE test.</p>1<p>Minor allele in African Americans is bolded; modeled by generalized estimating equations adjusting for percent global West African ancestry and sex.</p>2<p>Accuracy of imputation was assessed for SNPs with p-values <10⁻⁵ in a sub-sample; agreements overall and by genotype are reported in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092646#pone.0092646.s004" target="_blank">Table S2</a>. Overall imputation accuracy was 96.0% (rs6547087), 99.2% (rs906233), and 99.3% (rs12919626).</p>3<p>For rs145044562, conditional on rs12919626; for rs1077963, conditional on rs145044562 and rs12919626;</p>4<p>No carriers of the A allele of rs145044562 exist within HapMap or 1000 Genomes Project European populations.</p

Heritability of sarcoidosis risk attributable to difference in local ancestry overall and by radiographic phenotypes.

<p>Note: Number of controls (n = 859) is the same across case analysis strata.</p><p>Abbreviations: N: number of cases; : proportion of additive genetic variance due the common variants (minor allele frequency ≥1%); :the proportion of the additive genetic variance due to local West African ancestry; SE: standard error of ; P: p-value from a one-degree-of-freedom likelihood ratio test of the additive genetic variance component.</p>1<p>For these analyses, the corresponding admixture locus was removed to estimate the effect on the heritability estimate.</p>2<p>These analyses were restricted to the subset of cases with a minimum of two years of follow-up.</p

Genevar results suggest SNP rs6502976* is an eQTL for <i>XAF1</i>.

<p>Abbreviations: r²: linkage disequilibrium r² measure; OR: odds ratio; 95%CI: 95% confidence interval; P: p-value; Correlation: Pearson correlation coefficient.</p>1<p>Linkage disequilibrium r² measure with rs6502976 in 250 unrelated African American controls from this study; SNP rs6502976 was not genotyped in either study.</p>2<p>Minor allele in African Americans bolded; modeled by generalized estimating equations adjusting for percent global West African ancestry and sex.</p>3<p>Pearson correlation values for genotype by <i>XAF1</i> expression level (Illumina probe identifier ILMN_2370573); the direction of the correlation corresponds to an increasing numbers of the minor allele in African Americans, which is the allele that is associated with sarcoidosis risk reduction.</p>4<p>Nica et al 2011. Correlation results reported for twin 1; results were consistent for twin 2.</p>5<p>Dimas et al 2009. SNP rs9891567 was not genotyped as part of this study.</p

Representative pictures of XAF1 and XIAP staining of sarcoidosis-affected tissues.

<p>Panels A–D depict XAF-1 staining; panels E–H depict XIAP staining. Panels A and B are bronchial mucosa; E and F are lung tissue; C and G are liver tissue; and D and H are skin tissue. In general, XAF1 staining is negative in sarcoidosis-affected areas and limited to epithelial cells at the periphery (white arrows). XIAP staining was positive, with greater intensity observed in non-caseating granulomas.</p

Genome-Wide Association Study of African and European Americans Implicates Multiple Shared and Ethnic Specific Loci in Sarcoidosis Susceptibility

<div><p>Sarcoidosis is a systemic inflammatory disease characterized by the formation of granulomas in affected organs. Genome-wide association studies (GWASs) of this disease have been conducted only in European population. We present the first sarcoidosis GWAS in African Americans (AAs, 818 cases and 1,088 related controls) followed by replication in independent sets of AAs (455 cases and 557 controls) and European Americans (EAs, 442 cases and 2,284 controls). We evaluated >6 million SNPs either genotyped using the Illumina Omni1-Quad array or imputed from the 1000 Genomes Project data. We identified a novel sarcoidosis-associated locus, <em>NOTCH4</em>, that reached genome-wide significance in the combined AA samples (rs715299, <em>P</em>_AA-meta = 6.51×10⁻¹⁰) and demonstrated the independence of this locus from others in the MHC region in the same sample. We replicated previous European GWAS associations within <em>HLA-DRA, HLA-DRB5, HLA-DRB1</em>, <em>BTNL2,</em> and <em>ANXA11</em> in both our AA and EA datasets. We also confirmed significant associations to the previously reported <em>HLA-C</em> and <em>HLA-B</em> regions in the EA but not AA samples. We further identified suggestive associations with several other genes previously reported in lung or inflammatory diseases.</p> </div

Sample summary before and after quality control (QC).

a<p>Taken from the Illumina YRI-ASW iControlDB;</p>b<p>175 Caucasian healthy controls from the Illumina iControlDB, 1047 controls from the dbGaP GENEVA Melanoma study, and 1986 controls from the dbGAP CIDR: NGRC Parkinson’s Disease Study.</p

Replication of previously reported SNPs associated with sarcoidosis [9], [11], [25], [27].

1<p>Major/minor allele of AAs as the reference;</p>2<p>Minor allele frequency;</p>3<p>The odds ratio (OR) was calculated with respect to the minor allele of AAs.</p

Regions of association meeting genome-wide significance and their most significant SNPs grouped by sample.

1<p>Major/minor allele of AAs as the reference;</p>2<p>Minor allele frequency;</p>3<p>The odds ratio (OR) was calculated with respect to the minor allele of AAs.</p>a<p>Previously reported sarcoidosis loci meeting genome-wide significance in the AA discovery set.</p>b<p>Potentially novel region meeting genome-wide significance after the meta-analysis of AA datasets.</p>c<p>Previously reported sarcoidosis loci meeting genome-wide significance in the EA dataset.</p><p>Note that stepwise conditional analysis results to identify independent signals within the MHC region can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0043907#pone.0043907.s006" target="_blank">Tables S3</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0043907#pone.0043907.s007" target="_blank">S4</a>.</p

Functional characterizations of <i>OAS1</i> isoforms.

<p>(A) Protein expression of OAS1 isoforms was evaluated in EBV-transformed B cells from SS patients (four independent samples from each genotype group) using anti-OAS1 antibody targeting the shared epitope of all the isoforms. The stimulated cells were treated with universal type I IFN (1500U/ml) for 24hrs. The p44 isoform was not detectable using western-blot due to its low expression. The right panel shows quantified band intensity normalized to the GAPDH in each sample. (B) The transcript levels of each <i>OAS1</i> isoform from the same sets of cells described above were determined using real-time PCR. Consistent with the RNA-seq results, the SS-associated risk allele A of rs10774671 was correlated with decreased levels of p46 and increased expression of the p42, p48, and p44 isoforms (significance levels are shown at the bottom). The transcript levels of all the isoforms significantly increased after IFN stimulation (two-tailed <i>t</i> test); however, only p46 had increased protein production after IFN stimulation. (Significance level: ** <i>P</i><0.01; *** <i>P</i><0.001) (C) Individual isoforms of <i>OAS1</i> tagged with Xpress epitope were cloned and transfected into HEK 293T cells for 48hrs. The p48 and p44 isoforms had impaired protein expression compared to p46 and p42, although their transcript levels were equivalent as determined by real-time PCR (n = 4; normalized to <i>HMBS</i>). (D) The full-length and truncated <i>OAS1</i> p48 and p44 isoforms were cloned into HEK 293T cells. Western-blot indicated the lack of expression of the full-length p48 and p44 isoforms, whereas the truncation of both isoform transcripts (T2 and T4) was able to restore protein expression. (E) The 3' alternatively spliced terminus of different <i>OAS1</i> isoforms were linked to the 3'-end of GFP to observe their influence on GFP protein expression in HEK 293T cells. The 3'-terminus from the p48 and p44 isoforms resulted in decreased expression of GFP.</p