Limits...
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.

Show MeSH

Related in: MedlinePlus

Manhattan Plot for association study finding from Immunochip genotyped cases and controls.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Manhattan Plot for association study finding from Immunochip genotyped cases and controls.

Mentions: We detected suggestive associations in the Immunochip data (uncorrected P <10–4.5) at eight loci (Table 1), five of which showed association in the replication cohort (HLA-DRB1, DNASE1L3, STAT4, TNPO3-IRF5, and VCAM1) (Table 1, Manhattan plot Figure 1). There was also evidence of association at the previously reported genome-wide significant CD247 SNP [9] (rs2056626, OR = 0.76, P = 1.1 × 10−4), but no evidence of association at the genome-wide significant TNIP1 locus [27] (rs2233287, P = 0.94). The overlap between previously reported genome-wide significant SSc loci (outside the MHC) and our data, at an unadjusted P <0.01, is shown in Table 2. Not all previously associated SSc loci could be investigated owing to the limitations of markers available on the array.Table 1


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)

Manhattan Plot for association study finding from Immunochip genotyped cases and controls.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Manhattan Plot for association study finding from Immunochip genotyped cases and controls.
Mentions: We detected suggestive associations in the Immunochip data (uncorrected P <10–4.5) at eight loci (Table 1), five of which showed association in the replication cohort (HLA-DRB1, DNASE1L3, STAT4, TNPO3-IRF5, and VCAM1) (Table 1, Manhattan plot Figure 1). There was also evidence of association at the previously reported genome-wide significant CD247 SNP [9] (rs2056626, OR = 0.76, P = 1.1 × 10−4), but no evidence of association at the genome-wide significant TNIP1 locus [27] (rs2233287, P = 0.94). The overlap between previously reported genome-wide significant SSc loci (outside the MHC) and our data, at an unadjusted P <0.01, is shown in Table 2. Not all previously associated SSc loci could be investigated owing to the limitations of markers available on the array.Table 1

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