Sylvia Hofmann

Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis

Sarcoidosis is a complex chronic inflammatory disorder with predominant manifestation in the lung. In the first genome-wide association study (>440,000 SNPs) of this disease, comprising 499 German individuals with sarcoidosis and 490 controls, we detected a series of genetic associations. The strongest association signal maps to the ANXA11 (annexin A11) gene on chromosome 10q22.3. Validation in an independent sample (1,649 cases, 1,832 controls) confirmed the association (SNP rs2789679: P = 3.0 × 10−13, rs7091565: P = 1.0 × 10−5, allele-based test). Extensive fine mapping located the association signal to a region between exon 5 and exon 14 of ANXA11. A common nonsynonymous SNP (rs1049550, C > T, R230C) was found to be strongly associated with sarcoidosis. The GWAS lead SNP and additional risk variants in the region (rs1953600, rs2573346, rs2784773) were in strong linkage disequilibrium with rs1049550. Annexin A11 has complex and essential functions in several biological pathways, including apoptosis and proliferation.

Genome-Wide Association Analysis in Sarcoidosis and Crohn's Disease Unravels a Common Susceptibility Locus on 10p12.2

BACKGROUND & AIMS Crohns disease (CD) and sarcoidosis (SA) are chronic inflammatory barrier diseases that share several clinical and immunological features, including the occurrence of granulomas. METHODS A 100k genome-wide association study with 83,360 single-nucleotide polymorphisms (SNPs) was performed on 382 CD patients, 398 SA patients, and 394 control individuals. The 24 SNPs that were most strongly associated in the combined CD/SA phenotype were selected for verification in an independent sample of 1,317 patients (660 CD and 657 SA) and 1,091 controls. RESULTS The most significant association (Bonferroni corrected P = .036) was obtained at SNP rs1398024 on chromosome 10p12.2, with an odds ratio (OR) for both diseases of 0.81 (95% confidence interval [CI], 0.69-0.96) for carriership of the rarer allele A. The P value in the overall combined sample was 4.24 x 10(-6). During further follow-up, a moderate association (OR, 0.83; 95% CI, 0.72-0.96; P = .015) was observed between rs1398024 and ulcerative colitis (1,080 patients vs 1,091 controls), the second main subphenotype of inflammatory bowel disease in addition to CD. Extensive fine mapping of the 10p12.2 locus points to yet unidentified variants in the C10ORF67 gene region as the most likely underlying risk factors. CONCLUSION Our study demonstrates that the combined analysis of different, albeit clinically related, phenotypes can lead to the identification of common susceptibility loci.

Genetics of Sarcoidosis

Sarcoidosis is a multigenic and multifactorial disease. Predisposing genes have been identified and fast progress in molecular technologies including systematic genome-wide association studies and large-scale resequencing will aid the discovery of further risk loci and variants. The exploration of the molecular epidemiology of genetic variants in the pathogenesis of sarcoidosis will allow an assessment of their prognostic usefulness. To this end, different granulomatous disorders of known and unknown etiology should be investigated jointly by genetic, immunobiological, and proteomic approaches. The definition of individual genetic risk profiles in sarcoidosis and other chronic inflammatory disorders seems achievable and a useful route for clinical translation.

A genome-wide association study reveals evidence of association with sarcoidosis at 6p12.1

Sarcoidosis is a complex systemic inflammatory disease of unknown aetiology that is influenced by a variety of genetic and environmental factors. To identify further susceptibility loci for sarcoidosis, a genome-wide association study (GWAS) was conducted in 381 patients and 392 control individuals based on Affymetrix 100k GeneChip data. The top 25 single-nucleotide polymorphisms (SNPs) were selected for validation in an independent study panel (1,582 patients versus 1,783 controls). Variant rs10484410 on chromosome 6p12.1 was significantly associated, with a Bonferroni-corrected p-value of 2.90×10−2 in the validation sample and a nominal p-value of 2.64×10−4 in the GWAS. Extensive fine mapping of the novel locus narrowed down the signal to a region comprising the genes BAG2, C6orf65, KIAA1586, ZNF451 and RAB23. Verification of the sarcoidosis-associated nonsynonymous SNP rs1040461 in a further independent case–control sample and quantitative mRNA expression studies point to the RAB23 gene as the most likely risk factor. RAB23 is proposed to be involved in antibacterial defence processes and regulation of the sonic hedgehog signalling pathway. The identified association of the 6p12.1 locus with sarcoidosis implicates this locus as a further susceptibility factor and RAB23 as a potential signalling component that may open up new perspectives in the pathophysiology of sarcoidosis.

Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry

Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry

Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk

RATIONALE Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far. OBJECTIVES To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci. METHODS Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms. MEASUREMENTS AND MAIN RESULTS Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3. CONCLUSIONS Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics.

A Novel Sarcoidosis Risk Locus for Europeans on Chromosome 11q13.1

RATIONALE Sarcoidosis is a complex inflammatory disease with a heterogeneous clinical picture. Among others, an acute and chronic clinical course can be distinguished, for which specific genetic risk factors are known. OBJECTIVES To identify additional risk loci for sarcoidosis and its acute and chronic subforms, we analyzed imputed data from a genome-wide association scan for these phenotypes. METHODS After quality control, the genome-wide association scan comprised nearly 1.3 million imputed single-nucleotide polymorphisms based on an Affymetrix 6.0 Gene Chip dataset of 564 German sarcoidosis cases, including 176 acute and 354 chronic cases and 1,575 control subjects. MEASUREMENTS AND MAIN RESULTS We identified chromosome 11q13.1 (rs479777) as a novel locus influencing susceptibility to sarcoidosis with genome-wide significance. The marker was significantly associated in three distinct German case-control populations and in an additional German family sample with odds ratios ranging from 0.67 to 0.77. This finding was further replicated in two independent European case-control populations from the Czech Republic (odds ratio, 0.75) and from Sweden (odds ratio, 0.79). In a meta-analysis of the included European case-control samples the marker yielded a P value of 2.68 × 10(-18). The locus was previously reported to be associated with Crohn disease, psoriasis, alopecia areata, and leprosy. For sarcoidosis, fine-mapping and expression analysis suggest KCNK4, PRDX5, PCLB3, and most promising CCDC88B as candidates for the underlying risk gene in the associated region. CONCLUSIONS This study provides striking evidence for association of chromosome 11q13.1 with sarcoidosis in Europeans, and thus identified a further genetic risk locus shared by sarcoidosis, Crohn disease and psoriasis.

Association of inflammatory bowel disease risk loci with sarcoidosis, and its acute and chronic subphenotypes

Sarcoidosis is a complex granulomatous inflammatory disorder that shares several clinical and pathogenic features with inflammatory bowel disease (IBD). Postulating a common genetic basis of inflammatory diseases, we tested 106 single-nucleotide polymorphisms (SNPs) that are known or have been suggested to be associated with IBD for a potential association with sarcoidosis and its acute and chronic subphenotypes. We genotyped 1,996 German sarcoidosis patients, comprising 648 acutely and 1,161 chronically affected individuals, 2,622 control subjects, and 342 German trios with affected offspring using SNPlex™ technology. The nonsynonymous SNP rs11209026 (Arg381Gln) in the interleukin (IL)-23 receptor (IL23R) gene was associated with chronic sarcoidosis (OR 0.63; p = 5.58×10−5), which was supported by the result of a transmission disequilibrium test analysis in the independent family sample (OR 0.50; p = 0.031). Marker rs12035082 located at chromosome 1q24.3 was found to be associated with the acute subphenotype (OR 1.36; p = 6.80×10−7) and rs916977 (HERC2 locus; OR 1.30; p = 4.49×10−5) was associated with sarcoidosis. Our results highlight the potential importance of the IL-23 signalling pathway for the development of chronic sarcoidosis. The finding links sarcoidosis pathogenesis to other inflammatory conditions and may contribute to new hypotheses on disease mechanisms.

Male Reproductive Success and Intrasexual Selection in the Common Lizard Determined by DNA-microsatellites

Abstract The common lizard (Lacerta vivipara) is a small, nonterritorial, live-bearing lacertid that is sexually dimorphic in several morphological traits (e.g., tail length, snout–vent length, head size). Using microsatellites, we examined paternity in a wild population and investigated whether sexual dimorphism could be the result of intra- or intersexual selection. We found multiple paternity in 65.4% of 26 clutches. There was no evidence of assortative mating. Successfully reproducing males were larger and heavier and had longer tail regenerates or intact tails compared to those that did not reproduce. Tail length and body condition of males were related to the number of offspring sired. However, we found no evidence that head width was related to male reproductive success. We conclude that (1) males with higher body condition index might be more successful in male-male interactions or might be able to search more effectively for females, (2) sex divergence in relative tail length in common lizards reflects the action of sexual selection for male reproductive success, and (3) intersexual dietary divergence could be an alternative hypothesis for head size difference between sexes rather than intrasexual selection.

Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis

Sarcoidosis is a systemic inflammatory disease of unknown aetiology, influenced by genetic and environmental factors. However, the loci so far identified for sarcoidosis explain only a part of its assumed heritability. To identify further susceptibility loci, we performed a genome-wide association analysis using the Affymetrix 6.0 Human GeneChip followed by validation and replication stages. After quality control, 637 cases, 1233 controls and 677 619 single-nucleotide polymorphisms (SNPs) were available for an initial screening. 99 SNPs were selected for validation in an independent study panel (1664 patients, 2932 controls). SNP rs1050045 was significantly associated with sarcoidosis (corrected p=0.0215) in the validation panel and yielded a p-value of 9.22×10−8 (OR 1.24) in the meta-analysis of the screening and validation stage. A meta-analysis of three populations from Germany, the Czech Republic and Sweden confirmed this finding (p=0.024; OR 1.14). Fine-mapping and mRNA expression studies pointed to osteosarcoma amplified 9 (OS9) as the most likely candidate for the underlying risk factor. The OS9 protein plays an important role in endoplasmic reticulum-associated protein degradation and acts during Toll-like receptor induced activation of myeloid cells. Expression analyses of OS9 mRNA provide evidence for a functional mechanism underlying the detected association signal.