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Published on: January 17, 2018
WDFY4 polymorphisms in Chinese patients with anti-MDA5 dermatomyositis is associated with rapid progressive
Li Guo1,2, Xueliang Zhang2, Weilin Pu3
1State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China.
Objectives:
Anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+DM), is susceptible to development of rapidly progressive interstitial lung disease (RPILD), which has been predominantly reported in East Asia. A Japanese genome-wide study has identified a WDFY4 variant rs7919656 linkage. We sought to evaluate this genetic marker and exploit its possible clinical relevance in Chinese MDA5+DM.
Methods:
We genotyped and compared the minor allele A frequency of WDFY4 rs7919656 in patients with MDA5+DM (n = 254) including 190 clinically amyopathic dermatomyositis (CADM), MDA5-DM (n = 53), anti-synthetases syndrome (ASyS, n = 72) and healthy controls (n = 192). Association of the WDFY4 variant with clinical phenotype was evaluated using logistic regression.
Results:
Although the minor allele A frequencies of WDFY4 rs7919656 in MDA5+DM and CADM were comparable to that in healthy controls, we observed a significant correlation between the WDFY4 variant (GA+AA genotype) and the incidence of RPILD in MDA5+DM (OR: 2.11; 95% CI: 1.21, 3.69; P = 0.007). Moreover, this variant was an independent risk factor for RPILD in multivariate analysis (OR: 4.98; 95% CI: 1.59, 17.19; P = 0.008), along with other well-recognized risk factors, i.e. forced vital capacity % predicted, diffusing capacity for carbon monoxide % predicted, serum ferritin and prednisolone exposure. In addition, this variant was associated with higher expression of WDFY4 in PBMCs of MDA5+DM, especially those with RPILD. WDFY4 overexpression was also observed in lung biopsy of MDA5+DM-RPILD bearing the variant genotype.
Conclusion:
We found that the WDFY4 variant was associated with an increased risk of RPILD, not with disease susceptibility in Chinese MDA5+DM.
Insights
A specific WDFY4 gene variant (rs7919656) increases the risk of rapidly progressive interstitial lung disease (RPILD) in Chinese patients with anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+DM). This variant is linked to higher WDFY4 expression and RPILD incidence.
Area of Science:
- Genetics
- Immunology
- Pulmonology
Background:
- Anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+DM) is frequently complicated by rapidly progressive interstitial lung disease (RPILD), particularly in East Asian populations.
- A Japanese genome-wide study identified a WDFY4 variant (rs7919656) potentially linked to MDA5+DM.
Purpose of the Study:
- To evaluate the WDFY4 variant rs7919656 as a genetic marker in Chinese patients with MDA5+DM.
- To investigate the clinical relevance of this WDFY4 variant, specifically its association with RPILD.
Main Methods:
- Genotyping of the WDFY4 rs7919656 variant in 254 MDA5+DM patients (including clinically amyopathic dermatomyositis), 53 MDA5-DM patients, 72 anti-synthetases syndrome patients, and 192 healthy controls.
- Comparison of minor allele A frequencies across groups.
- Logistic regression analysis to assess the association between the WDFY4 variant and clinical phenotypes, including RPILD.
Main Results:
- The WDFY4 variant (GA+AA genotype) showed a significant correlation with the incidence of RPILD in MDA5+DM (OR: 2.11; P=0.007).
- The variant was identified as an independent risk factor for RPILD in multivariate analysis (OR: 4.98; P=0.008), alongside other known risk factors.
- Higher WDFY4 expression was observed in peripheral blood mononuclear cells (PBMCs) and lung biopsies of MDA5+DM patients with RPILD carrying the variant genotype.
Conclusions:
- The WDFY4 variant rs7919656 is associated with an increased risk of developing RPILD in Chinese MDA5+DM patients.
- This genetic marker does not appear to influence disease susceptibility but rather the progression to RPILD.
