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An Immunochip-based interrogation of scleroderma susceptibility variants identifies a novel association at DNASE1L3.

Zochling J, Newell F, Charlesworth JC, Leo P, Stankovich J, Cortes A, Zhou Y, Stevens W, Sahhar J, Roddy J, Nash P, Tymms K, Rischmueller M, Lester S, Proudman S, Brown MA - Arthritis Res. Ther. (2014)

Bottom Line: Controls were taken from the 1958 British Birth Cohort.A total of eight loci with suggestive association (P <10-4.5) were identified, of which five showed significant association in the replication cohort (HLA-DRB1, DNASE1L3, STAT4, TNP03-IRF5 and VCAM1).The most notable findings were at the DNASE1L3 locus, previously associated with systemic lupus erythematosus, and VCAM1, a locus not previously associated with human disease.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: The aim of the study was to interrogate the genetic architecture and autoimmune pleiotropy of scleroderma susceptibility in the Australian population.

Methods: We genotyped individuals from a well-characterized cohort of Australian scleroderma patients with the Immunochip, a custom array enriched for single nucleotide polymorphisms (SNPs) at immune loci. Controls were taken from the 1958 British Birth Cohort. After data cleaning and adjusting for population stratification the final dataset consisted of 486 cases, 4,458 controls and 146,525 SNPs. Association analyses were conducted using logistic regression in PLINK. A replication study was performed using 833 cases and 1,938 controls.

Results: A total of eight loci with suggestive association (P <10-4.5) were identified, of which five showed significant association in the replication cohort (HLA-DRB1, DNASE1L3, STAT4, TNP03-IRF5 and VCAM1). The most notable findings were at the DNASE1L3 locus, previously associated with systemic lupus erythematosus, and VCAM1, a locus not previously associated with human disease. This study identified a likely functional variant influencing scleroderma susceptibility at the DNASE1L3 locus; a missense polymorphism rs35677470 in DNASE1L3, with an odds ratio of 2.35 (P = 2.3 × 10(-10)) in anti-centromere antibody (ACA) positive cases.

Conclusions: This pilot study has confirmed previously reported scleroderma associations, revealed further genetic overlap between scleroderma and systemic lupus erythematosus, and identified a putative novel scleroderma susceptibility locus.

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Locus zoom plot of chromosome 3p14 region associated with scleroderma.
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Fig2: Locus zoom plot of chromosome 3p14 region associated with scleroderma.

Mentions: Association was observed and replicated at chromosome 3p14, spanning DNASE1L3 to AXOX2 (including PXK; Figure 2), a region that has previously been associated with both SLE [29] and SSc [7]. While the peak association with SLE was originally identified at an intronic SNP rs6445975 in PXK (a PX domain containing serine/threonine kinase), the strongest association with SSc on the Immunochip was at a missense SNP rs35677470 (R206C) in DNASE1L3 (deoxyribonuclease I-like 3); 187 kb distal of rs6445975. Linkage disequilibrium between the two SNPs is modest (r2 = 0.13), and there is weak evidence of a secondary association with rs6445975 in our data after conditioning on rs35677470 (OR = 1.19, P = 0.03). No other associations at this locus are significant after correction for multiple testing. The association with rs35677470 is confined to ACA-positive cases (estimated OR 2.36, P = 2.3 × 10−10), with no association in ACA-negative cases (P = 0.76). rs35677470 also showed association in the replication set (P =0.027), and in the combined analysis (P = 1.2 × 10−6). As in the Immunochip analysis, in the replication set association was much stronger in the ACA-positive group (P = 3.0 × 10−4), and overall (P = 8.71 × 10−13). Association was particularly significant in limited scleroderma (P = 3.36 × 10−9 in overall dataset) compared with diffuse scleroderma (P = 0.57), consistent with the association of ACA antibody status with limited disease. The non-synonymous DNASE1L3 variant is predicted to be deleterious to the protein product using in silico functional prediction tools including both SIFT [30] and PolyPhen [31]. Apart from the DNASE1L3 locus, no other associations showed evidence of heterogeneity by antibody status, or between limited and diffuse SSc.Figure 2


An Immunochip-based interrogation of scleroderma susceptibility variants identifies a novel association at DNASE1L3.

Zochling J, Newell F, Charlesworth JC, Leo P, Stankovich J, Cortes A, Zhou Y, Stevens W, Sahhar J, Roddy J, Nash P, Tymms K, Rischmueller M, Lester S, Proudman S, Brown MA - Arthritis Res. Ther. (2014)

Locus zoom plot of chromosome 3p14 region associated with scleroderma.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4230517&req=5

Fig2: Locus zoom plot of chromosome 3p14 region associated with scleroderma.
Mentions: Association was observed and replicated at chromosome 3p14, spanning DNASE1L3 to AXOX2 (including PXK; Figure 2), a region that has previously been associated with both SLE [29] and SSc [7]. While the peak association with SLE was originally identified at an intronic SNP rs6445975 in PXK (a PX domain containing serine/threonine kinase), the strongest association with SSc on the Immunochip was at a missense SNP rs35677470 (R206C) in DNASE1L3 (deoxyribonuclease I-like 3); 187 kb distal of rs6445975. Linkage disequilibrium between the two SNPs is modest (r2 = 0.13), and there is weak evidence of a secondary association with rs6445975 in our data after conditioning on rs35677470 (OR = 1.19, P = 0.03). No other associations at this locus are significant after correction for multiple testing. The association with rs35677470 is confined to ACA-positive cases (estimated OR 2.36, P = 2.3 × 10−10), with no association in ACA-negative cases (P = 0.76). rs35677470 also showed association in the replication set (P =0.027), and in the combined analysis (P = 1.2 × 10−6). As in the Immunochip analysis, in the replication set association was much stronger in the ACA-positive group (P = 3.0 × 10−4), and overall (P = 8.71 × 10−13). Association was particularly significant in limited scleroderma (P = 3.36 × 10−9 in overall dataset) compared with diffuse scleroderma (P = 0.57), consistent with the association of ACA antibody status with limited disease. The non-synonymous DNASE1L3 variant is predicted to be deleterious to the protein product using in silico functional prediction tools including both SIFT [30] and PolyPhen [31]. Apart from the DNASE1L3 locus, no other associations showed evidence of heterogeneity by antibody status, or between limited and diffuse SSc.Figure 2

Bottom Line: Controls were taken from the 1958 British Birth Cohort.A total of eight loci with suggestive association (P <10-4.5) were identified, of which five showed significant association in the replication cohort (HLA-DRB1, DNASE1L3, STAT4, TNP03-IRF5 and VCAM1).The most notable findings were at the DNASE1L3 locus, previously associated with systemic lupus erythematosus, and VCAM1, a locus not previously associated with human disease.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: The aim of the study was to interrogate the genetic architecture and autoimmune pleiotropy of scleroderma susceptibility in the Australian population.

Methods: We genotyped individuals from a well-characterized cohort of Australian scleroderma patients with the Immunochip, a custom array enriched for single nucleotide polymorphisms (SNPs) at immune loci. Controls were taken from the 1958 British Birth Cohort. After data cleaning and adjusting for population stratification the final dataset consisted of 486 cases, 4,458 controls and 146,525 SNPs. Association analyses were conducted using logistic regression in PLINK. A replication study was performed using 833 cases and 1,938 controls.

Results: A total of eight loci with suggestive association (P <10-4.5) were identified, of which five showed significant association in the replication cohort (HLA-DRB1, DNASE1L3, STAT4, TNP03-IRF5 and VCAM1). The most notable findings were at the DNASE1L3 locus, previously associated with systemic lupus erythematosus, and VCAM1, a locus not previously associated with human disease. This study identified a likely functional variant influencing scleroderma susceptibility at the DNASE1L3 locus; a missense polymorphism rs35677470 in DNASE1L3, with an odds ratio of 2.35 (P = 2.3 × 10(-10)) in anti-centromere antibody (ACA) positive cases.

Conclusions: This pilot study has confirmed previously reported scleroderma associations, revealed further genetic overlap between scleroderma and systemic lupus erythematosus, and identified a putative novel scleroderma susceptibility locus.

Show MeSH
Related in: MedlinePlus