Abstract
BackgroundSystemic sclerosis (SSc)-related interstitial lung disease (ILD) has phenotypic similarities to lung involvement in idiopathic interstitial pneumonia (IIP). We aimed to assess whether genetic susceptibility loci recently identified in the large IIP genome-wide association studies (GWASs) were also risk loci for SSc overall or severity of ILD in SSc.MethodsA total of 2571 SSc patients and 4500 healthy controls were investigated from the US discovery GWAS and additional US replication cohorts. Thirteen IIP-related selected single nucleotide polymorphisms (SNPs) were genotyped and analyzed for their association with SSc.ResultsWe found an association of SSc with the SNP rs6793295 in the LRRC34 gene (OR = 1.14, CI 95 % 1.03 to 1.25, p value = 0.009) and rs11191865 in the OBFC1 gene (OR = 1.09, CI 95 % 1.00 to 1.19, p value = 0.043) in the discovery cohort. Additionally, rs7934606 in MUC2 (OR = 1.24, CI 95 % 1.01 to 1.52, p value = 0.037) was associated with SSc-ILD defined by imaging. However, these associations failed to replicate in the validation cohort. Furthermore, SNPs rs2076295 in DSP (β = -2.29, CI 95 % -3.85 to -0.74, p value = 0.004) rs17690703 in SPPL2C (β = 2.04, CI 95 % 0.21 to 3.88, p value = 0.029) and rs1981997 in MAPT (β = 2.26, CI 95 % 0.35 to 4.17, p value = 0.02) were associated with percent predicted forced vital capacity (FVC%) even after adjusting for the anti-topoisomerase (ATA)-positive subset. However, these associations also did not replicate in the validation cohort.ConclusionsOur results add new evidence that SSc and SSc-related ILD are genetically distinct from IIP, although they share phenotypic similarities.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-0923-3) contains supplementary material, which is available to authorized users.
Highlights
Systemic sclerosis (SSc)-related interstitial lung disease (ILD) has phenotypic similarities to lung involvement in idiopathic interstitial pneumonia (IIP)
Given the clinical and radiologic similarities between SSc-associated interstitial lung disease (SSc-ILD) and IIP, we examined the association of the 13 Single nucleotide polymorphisms (SNP) among the listed genes, identified in the above IIP and idiopathic pulmonary fibrosis (IPF) Genome-wide association study (GWAS) [7, 8] (TOLLIP and MDGA2 genes were excluded because the related SNPs were not present on the Illumina BeadChip utilized in SSc GWAS) with SSc as a single disease entity, with SSc-ILD by imaging, or SSc-ILD severity (as determined by percent predicted forced vital capacity (FVC%)) in two large SSc patient samples
Discovery cohort We first investigated whether the 13 IIP-associated polymorphisms were associated with risk of SSc overall or with SSc-ILD
Summary
Systemic sclerosis (SSc)-related interstitial lung disease (ILD) has phenotypic similarities to lung involvement in idiopathic interstitial pneumonia (IIP). We aimed to assess whether genetic susceptibility loci recently identified in the large IIP genome-wide association studies (GWASs) were risk loci for SSc overall or severity of ILD in SSc. Systemic sclerosis or scleroderma (SSc) is a complex autoimmune disease characterized by vasculopathy, autoantibody production and fibrosis in the skin and internal organs. SSc-ILD has clinical and radiologic similarities to idiopathic interstitial pneumonia (IIP). A polymorphism in the MUC5B promoter region was strongly associated with familial and idiopathic pulmonary fibrosis (IPF; the most common IIP type) [3], but it has not been found to be a susceptibility locus for SSc or SSc-associated interstitial lung disease (SSc-ILD) [4,5,6]
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