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Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis.

ABSTRACT: The prediction of response (or non-response) to anti-TNF treatment for rheumatoid arthritis (RA) is a pressing clinical problem. We conducted a genome-wide association study using the Illumina HapMap300 SNP chip on 89 RA patients prospectively followed after beginning anti-TNF therapy as part of Autoimmune Biomarkers Collaborative Network (ABCoN [Autoimmune Bio-markers Collaborative Network]) patient cohort. Response to therapy was determined by the change in Disease Activity Score (DAS28) observed after 14 wks. We used a two-part analysis that treated the change in DAS28 as a continuous trait and then incorporated it into a dichotomous trait of "good responder" and "nonresponder" by European League Against Rheumatism (EULAR) criteria. We corrected for multiple tests by permutation, and adjusted for potential population stratification using EIGENSTRAT. Multiple single nucleotide polymorphism (SNP) markers showed significant associations near or within loci including: the v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene on chromosome 20; the type I interferon gene IFNk on chromosome 9; and in a locus on chromosome 7 that includes the paraoxonase I (PON1) gene. An SNP in the IL10 promoter (rs1800896) that was previously reported as associated with anti-TNF response was weakly associated with response in this cohort. Replications of these results in independent and larger data sets clearly are required. We provide a reference list of candidate SNPs (P < 0.01) that can be investigated in future pharmacogenomic studies.

SUBMITTER: Liu C

PROVIDER: S-EPMC2443997 | biostudies-other | 2008 Sep-Oct

REPOSITORIES: biostudies-other

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Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis.

Project description:The prediction of response (or non-response) to anti-TNF treatment for rheumatoid arthritis (RA) is a pressing clinical problem. We conducted a genome-wide association study using the Illumina HapMap300 SNP chip on 89 RA patients prospectively followed after beginning anti-TNF therapy as part of Autoimmune Biomarkers Collaborative Network (ABCoN [Autoimmune Bio-markers Collaborative Network]) patient cohort. Response to therapy was determined by the change in Disease Activity Score (DAS28) observed after 14 wks. We used a two-part analysis that treated the change in DAS28 as a continuous trait and then incorporated it into a dichotomous trait of "good responder" and "nonresponder" by European League Against Rheumatism (EULAR) criteria. We corrected for multiple tests by permutation, and adjusted for potential population stratification using EIGENSTRAT. Multiple single nucleotide polymorphism (SNP) markers showed significant associations near or within loci including: the v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene on chromosome 20; the type I interferon gene IFNk on chromosome 9; and in a locus on chromosome 7 that includes the paraoxonase I (PON1) gene. An SNP in the IL10 promoter (rs1800896) that was previously reported as associated with anti-TNF response was weakly associated with response in this cohort. Replications of these results in independent and larger data sets clearly are required. We provide a reference list of candidate SNPs (P < 0.01) that can be investigated in future pharmacogenomic studies.

| S-EPMC2276142 | biostudies-literature

Genome-Wide Scan for Runs of Homozygosity Identifies Candidate Genes in Three Pig Breeds.

Project description:Runs of homozygosity (ROH) are contiguous homozygous genotype segments in the genome that are present in an individual since the identical haplotypes are inherited from each parent. The aim of this study was to investigate the frequency and distribution of ROH in the genomes of Landrace, Songliao black and Yorkshire pigs. We calculated two types of genome inbreeding coefficients and their correlation, including the inbreeding coefficient based on ROH (FROH) and the inbreeding coefficient based on the difference between the observed and expected number of homozygous genotypes (FHOM). Furthermore, we identified candidate genes in the genomic region most associated with ROH. We identified 21,312 ROH in total. The average number of ROH per individual was 32.99 ± 0.38 and the average length of ROH was 6.40 ± 0.070 Mb in the three breeds. The FROH results showed that Yorkshire pigs exhibited the highest level of inbreeding (0.092 ± 0.0015) and that Landrace pigs exhibited the lowest level of inbreeding (0.073 ± 0.0047). The average correlation between FROH and FHOM was high (0.94) within three breeds. The length of ROH provides insight into the inbreeding history of these three pig breeds. In this study, Songliao black pigs presented a higher frequency and average length of long ROH (>40 Mb) compared with those of Landrace and Yorkshire pigs, which indicated greater inbreeding in recent times. Genes related to reproductive traits (GATM, SPATA46, HSD17B7, VANGL2, DAXX, CPEB1), meat quality traits (NR1I3, APOA2, USF1) and energy conversion (NDUFS2) were identified within genomic regions with a high frequency of ROH. These genes could be used as target genes for further marker-assisted selection and genome selection.

| S-EPMC6720638 | biostudies-other

Classification of rheumatoid arthritis status with candidate gene and genome-wide single-nucleotide polymorphisms using random forests.

Project description:Using the North American Rheumatoid Arthritis Consortium (NARAC) candidate gene and genome-wide single-nucleotide polymorphism (SNP) data sets, we applied regression methods and tree-based random forests to identify genetic associations with rheumatoid arthritis (RA) and to predict RA disease status. Several genes were consistently identified as weakly associated with RA without a significant interaction or combinatorial effect with other candidate genes. Using random forests, the tested candidate gene SNPs were not sufficient to predict RA patients and normal subjects with high accuracy. However, using the top 500 SNPs, ranked by the importance score, from the genome-wide linkage panel of 5742 SNPs, we were able to accurately predict RA patients and normal subjects with sensitivity of approximately 90% and specificity of approximately 80%, which was confirmed by five-fold cross-validation. However, in a complete training-testing framework, replication of genetic predictors was less satisfactory; thus, further evaluation of existing methodology and development of new methods are warranted.

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A genome-wide association scan for rheumatoid arthritis data by Hotelling's T2 tests.

Project description:We performed a genome-wide association scan on the North American Rheumatoid Arthritis Consortium (NARAC) data using Hotelling's T2 tests, i.e., TH based on allele coding and TG based on genotype coding. The objective was to identify associations between single-nucleotide polymorphisms (SNPs) or markers and rheumatoid arthritis. In specific candidate gene regions, we evaluated the performance of Hotelling's T2 tests. Then Hotelling's T2 tests were used as a tool to identify new regions that contain SNPs showing strong associations with disease. As expected, the strongest association evidence was found in the region of the HLA-DRB1 locus on chromosome 6. In the region of the TRAF1-C5 genes, we identified two SNPs, rs2900180 and rs3761847, with the largest and the second largest TH and TG scores among all SNPs on chromosome 9. We also identified one SNP, rs2476601, in the region of the PTPN22 gene that had the largest TH score and the second largest TG score among all SNPs on chromosome 1. In addition, SNPs with the largest TH score on each chromosome were identified. These SNPs may be located in the regions of genes that have modest effects on rheumatoid arthritis. These regions deserve further investigation.

| S-EPMC2795960 | biostudies-literature

Genome-wide scan for runs of homozygosity identifies candidate genes in Wannan Black pigs.

Project description:ObjectiveRuns of homozygosity (ROH) are contiguous lengths of homozygous genotypes that can reveal inbreeding levels, selection pressure, and mating schemes. In this study, ROHs were evaluated in Wannan Black pigs to assess the inbreeding levels and the genome regions with high ROH frequency.MethodsIn a previous study, we obtained 501.52 GB of raw data from resequencing (10×) of the genome and identified 21,316,754 single-nucleotide variants in 20 Wannan Black pig samples. We investigated the number, length, and frequency of ROH using resequencing data to characterize the homozygosity in Wannan Black pigs and identified genomic regions with high ROH frequencies.ResultsIn this work, 1,813 ROHs (837 ROHs in 100 to 500 kb, 449 ROHs in 500 to 1,000 kb, 527 ROHs in >1,000 kb) were identified in all samples, and the average genomic inbreeding coefficient (FROH) in Wannan Black pigs was 0.5234. Sixty-one regions on chromosomes 2, 3, 7, 8, 13, 15, and 16 harbored ROH islands. In total, 105 genes were identified in 42 ROH islands, among which some genes were related to production traits.ConclusionThis is the first study to identify ROH across the genome of Wannan Black pigs, the Chinese native breed of the Anhui province. Overall, Wannan Black pigs have high levels of inbreeding due to the influence of ancient and recent inbreeding due to the genome. These findings are a reliable resource for future studies and contribute to save and use the germplasm resources of Wannan Black pigs.

| S-EPMC8563231 | biostudies-literature

Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis.

Project description:BACKGROUND:Treatment strategies blocking tumour necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently, there are no means of identifying these patients before treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patients with RA using a genome-wide association approach. METHODS:We conducted a multistage, genome-wide association study with a primary analysis of 2 557 253 single-nucleotide polymorphisms (SNPs) in 882 patients with RA receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with p<10(-3) were selected for replication in 1821 patients from three independent cohorts. Pathway analysis including all SNPs with p<10(-3) was performed using Ingenuity. RESULTS:772 markers showed evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p value in the overall meta-analysis compared with the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four cohorts studied. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology. CONCLUSIONS:Using a multistage strategy, we have identified eight genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections.

| S-EPMC4169706 | biostudies-literature

Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.

Project description:To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 x 10(-8)) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK. We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles.

| S-EPMC4243840 | biostudies-literature

Genome-wide identification of RNA modification-related single nucleotide polymorphisms associated with rheumatoid arthritis.

Project description:BackgroundRNA modification plays important roles in many biological processes, such as gene expression control. The aim of this study was to identify single nucleotide polymorphisms related to RNA modification (RNAm-SNPs) for rheumatoid arthritis (RA) as putative functional variants.MethodsWe examined the association of RNAm-SNPs with RA in summary data from a genome-wide association study of 19,234 RA cases and 61,565 controls. We performed eQTL and pQTL analyses for the RNAm-SNPs to find associated gene expression and protein levels. Furthermore, we examined the associations of gene expression and circulating protein levels with RA using two-sample Mendelian randomization analysis methods.ResultsA total of 160 RNAm-SNPs related to m6A, m1A, A-to-I, m7G, m5C, m5U and m6Am modifications were identified to be significantly associated with RA. These RNAm-SNPs were located in 62 protein-coding genes, which were significantly enriched in immune-related pathways. RNAm-SNPs in important RA susceptibility genes, such as PADI2, SPRED2, PLCL2, HLA-A, HLA-B, HLA-DRB1, HLA-DPB1, TRAF1 and TXNDC11, were identified. Most of these RNAm-SNPs showed eQTL effects, and the expression levels of 26 of the modifiable genes (e.g., PADI2, TRAF1, HLA-A, HLA-DRB1, HLA-DPB1 and HLA-B) in blood cells were associated with RA. Circulating protein levels, such as CFB, GZMA, HLA-DQA2, IL21, LRPAP1 and TFF3, were affected by RNAm-SNPs and were associated with RA.ConclusionThe present study identified RNAm-SNPs in the reported RA susceptibility genes and suggested that RNAm-SNPs may affect RA risk by affecting the expression levels of corresponding genes and proteins.

| S-EPMC10045113 | biostudies-literature

Simultaneous analysis of all single-nucleotide polymorphisms in genome-wide association study of rheumatoid arthritis.

Project description:The availability of very large number of markers by modern technology makes genome-wide association studies very popular. The usual approach is to test single-nucleotide polymorphisms (SNPs) one at a time for association with disease status. However, it may not be possible to detect marginally significant effects by single-SNP analysis. Simultaneous analysis of SNPs enables detection of even those SNPs with small effect by evaluating the collective impact of several neighboring SNPs. Also, false-positive signals may be weakened by the presence of other neighboring SNPs included in the analysis. We analyzed the North American Rheumatoid Arthritis Consortium data of Genetic Analysis Workshop 16 using HLasso, a new method for simultaneous analysis of SNPs. The simultaneous analysis approach has excellent control of type I error, and many of the previously reported results of single-SNP analyses were confirmed by this approach.

| S-EPMC2795881 | biostudies-literature

Transethnic genome-wide scan identifies novel Alzheimer's disease loci.

Project description:IntroductionGenetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.MethodsWe conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.ResultsGenome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10-8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10-6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10-6).DiscussionOur findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

| S-EPMC5496797 | biostudies-literature

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