Genetic susceptibility loci of idiopathic interstitial pneumonia do not represent risk for systemic sclerosis: a case control study in Caucasian patients

abstract: ...Background 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 also risk loci for SSc overall or severity of ILD in SSc. Methods A 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. Results We 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 (=-2.29, CI 95 % -3.85 to -0.74, p value=0.004) rs17690703 in SPPL2C (=2.04, CI 95 % 0.21 to 3.88, p value=0.029) and rs1981997 in MAPT (=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. Conclusions Our results add new evidence that SSc and SSc-related ILD are genetically distinct from IIP, although they share phenotypic similarities. Electronic supplementary material The online version of this article (doi:10.1186/s13075-016-0923-3) contains supplementary material, which is available to authorized users.

... % -3.85 to -0.74, p value=0.004) rs17690703 in SPPL2C (=2.04, CI 95 % 0.21 to 3.88, p value=0.029) and rs1981997 in MAPT (=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. Conclusions Our results add new evidence that SSc and SSc-related ILD are genetically distinct from IIP, although they share

... , AZGP1 , MUC2 , IVD , DSP , MAPT , DPP9 , LRRC34 , FAM13A , OBFC1 , CSMD1 , ATP11A [ 7 ] and TOLLIP , MDGA2 , SPPL2C [ 8 ]. Given the clinical and radiologic similarities between SSc-ILD and IIP, we examined the association of the 13 SNPs among the listed genes, identified in the above IIP and IPF GWASs [ 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

... ), rs2076295 ( DSP ), rs4727443 ( AZGP1 ), rs7934606 ( MUC2 ), rs2034650 ( IVD ), rs1981997 ( MAPT ), rs12610495 ( DPP9 ), rs6793295 ( LRRC34 ), rs2609255 ( FAM13A ), rs11191865 ( OBFC1 ), rs1278769 ( ATP11A ), rs1379326 ( CSMD1 ) and an additional SNP rs17690703 ( SPPL2C ) [ 8 ], were investigated in the discovery cohort. We also investigated association of 13 SNPs with anti-topoisomerase 1 antibody (ATA) and anti-centromere antibody (ACA) positive subgroup patients. The SNPs reaching a nominal level of

... rs1981997 MAPT A 0.22 0.97 (0.88; 1.08) 0.636 rs12610495 DPP9 G 0.28 1.00 (0.91; 1.10) 0.967 rs6793295 LRRC34 C 0.29 1.14 (1.03; 1.25) 0.009 rs2609255 FAM13A G 0.22 1.01 (0.91; 1.12) 0.851 rs11191865 OBFC1 G 0.52 1.09 (1.00; 1.19) 0.043 rs1278769 ATP11A A 0.24 0.95 (0.86; 1.06) 0.365 rs1379326 CSMD1 G 0.26 0.86 (0.69; 1.08) 0.199 rs17690703 SPPL2C T 0.26 1.03 (0.95; 1.11) 0.546 Gene names: TERT : telomerase reverse transcriptase; DSP : desmoplakin; AZGP1 : alpha-2-glycoprotein 1, zinc-binding; MUC2 : mucin 2; IVD : isovaleryl-CoA dehydrogenase; MAPT : microtubule-associated protein tau; DPP9 : dipeptidyl-peptidase 9; LRRC34 : leucine-rich repeat-containing 34; FAMI3A : family with sequence similarity 13, member A; OBFC1 : oligonucleotide/oligosaccharide-binding fold containing 1; ATP11A : ATPase, class VI, type 11A; CSMD1 : CUB and Sushi multiple domains 1; SPPL2C : signal peptide peptidase-like 2C SSc systemic sclerosis, SNP single nucleotide

...; 1.42) 0.172 1.15 (0.98; 1.35) 0.080 rs2609255 * FAMI3A 1.04 (0.83; 1.30) 0.736 1.00 (0.84; 1.19) 1.000 rs11191865 * OBFC1 1.21 (1.00; 1.45) 0.048 0.99 (0.86; 1.14) 0.898 rs1278769 * ATP11A 1.09 (0.89; 1.35) 0.394 0.96 (0.81; 1.14) 0.650 rs1379326 CSMD1 0.78 (0.46; 1.31) 0.340 0.94 (0.65; 1.36) 0.736 rs17690703 SPPL2C 0.97 (0.76; 1.26) 0.870 1.14 (0.94; 1.38) 0.184 Gene names: TERT : telomerase reverse transcriptase; DSP : desmoplakin; AZGP1 : alpha-2-glycoprotein 1, zinc-binding; MUC2 : mucin 2; IVD : isovaleryl-CoA dehydrogenase; MAPT : microtubule-associated protein tau; DPP9 : dipeptidyl-peptidase 9; LRRC34 : leucine-rich repeat-containing 34; FAMI3A : family with sequence similarity 13, member A; OBFC1 : oligonucleotide/oligosaccharide-binding fold containing 1; ATP11A : ATPase, class VI, type 11A; CSMD1 : CUB and Sushi multiple domains 1; SPPL2C : signal peptide peptidase-like 2C ATA anti-topoisomerase 1 antibody, ACA anti-centromere antibody, SSc systemic

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Gene: SPPL2C - signal peptide peptidase like 2C - (NCBI)

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