Fine-mapping in African Americans women confirms the importance of the 10p12 locus to sarcoidosis

abstract: ...Sarcoidosis is a chronic granulomatous disease with a wide spectrum of symptoms. Genome-wide association studies in European populations have reported significant associations between sarcoidosis and single nucleotide polymorphisms (SNPs) located in the inter-genic region between the C10ORF67 and OTUD1 genes on chromosome 10p12, and the ANXA11 gene (chromosome 10q22). We carried out fine-mapping at 10p12 and 10q22 to assess associations of genetic variants in those regions with sarcoidosis risk in African American women, based on 486 sarcoidosis cases and 943 age- and geography-matched controls in a nested case-control study within the Black Womens Health Study. There were no significant associations with variants of the ANXA11 gene (P=0.17). Haplotypic analyses of the C10ORF67-OTUD1 inter-genic region revealed a strong inverse association of the variants rs1398024 and rs11013452 with sarcoidosis (OR=0.52; P=0.01). Both SNPs are located inside a ~300 kb low recombination region of chromosome 10p12, suggesting that both SNPs are tagging the same causal variant. Our top SNP (rs11013452) is located inside a smaller LD block in HapMap YRI, further narrowing the position of the causal SNP to a region of ~ 8kb on chromosome 10p12. The present findings confirm the potential importance of the 10p12 locus in the etiology of sarcoidosis.

... documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms Sarcoidosis is a chronic granulomatous disease with a wide spectrum of symptoms. Genome-wide association studies in European populations have reported significant associations between sarcoidosis and single nucleotide polymorphisms (SNPs) located in the inter-genic region between the C10ORF67 and OTUD1 genes on chromosome 10p12, and the ANXA11 gene (chromosome 10q22). We carried out fine-mapping at 10p12 and 10q22 to assess associations of genetic variants in those regions with sarcoidosis risk in African American women, based on 486 sarcoidosis cases and 943 age- and geography-matched controls in a nested case-control study within the Black Womens Health Study. There were no significant associations with variants of the ANXA11 gene (P=0.17). Haplotypic analyses of the C10ORF67-OTUD1 inter-genic region revealed a strong inverse

... sarcoidosis or Crohns disease reported a significant association with the rs1398024 SNP (chromosome 10p12), which is located in the inter-genic region between the C10ORF67 and OTUD1 genes. 5 A second GWAS, in the same population but with >440k SNPs, 6 identified several SNPs in strong linkage disequilibrium (LD) in the annexin ( ANXA11) gene (chromosome 10q22): the leading rs2789679 SNP located in the 3 UTR and a common nonsynonymous SNP (rs1049550, C>T, Arg230Cys) were associated with sarcoidosis risk. 6

...-up study of U.S. black women. RESULTS The present analysis included 486 sarcoidosis cases and 972 controls. The mean age of cases and controls was 43. Twenty-seven percent lived in the Northeast, 31% in the South, 26% in the Midwest, and 15% in the West. The median % African ancestry was 82% (range: 33% 97%). Mean % African ancestry was 81% in cases and 80% in controls. C10ORF67-OTUD1 intergenic region Fine-mapping revealed an 8% nonsignficiant reduction in sarcoidosis risk associated with the A

... measures of disease severity We assessed whether the C10ORF67-OTUD1 or ANXA11 SNPs were associated with disease severity as determined by self-reported symptoms ( Table 3 ). The association of the C10ORF67-OTUD1 rs11013452 SNP with sarcoidosis risk did not vary consistentely from the overall risk in the various categories considered. The ORs were similar to the overall estimate among women who reported 4 symptoms at diagnosis, current fair/poor health, or severe fatigue, while there was a significant

... considerable clinical overlap between the two diseases 10 , 13 including manifestation of both disorders in a single patient. 14 Franke et al. conducted a combined GWAS of 393 Crohns disease and 400 sarcoidosis patients and 399 controls in a German population, hypothesizing that any common susceptibility loci, if present, would demonstrate a stronger association peak. 5 Their analysis identified a common SNP, rs1398024, located in the inter-genic region between the C10ORF67 and OTUD1 genes on chromosome 10p12 that was associated with both sarcoidosis and Crohns disease. They estimated a 19% reduction in disease risk in association with the A allele of rs1398024. We failed to replicate this association in our data, but did observe a non-significant 20% risk reduction associated with each A-allele of the top BWHS SNP: rs11013452. Further, haplotypic analyses of the rs1398024 and rs11013452 SNPs in the C10ORF67-OTUD1 inter-genic region on chromosome 10p12 revealed a strong inverse association with

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Gene: OTUD1 - OTU deubiquitinase 1 - (NCBI)

Protein : 4bop

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