Genomewide association study identifies GALC as susceptibility gene for mucous membrane pemphigoid

Abstract

Mucous membrane pemphigoid (MMP) is a rare, chronic and often aggressive subepidermal autoimmune blistering disease potentially affecting several mucous membranes with blisters and secondary erosions and scars. The pathogenesis of MMP is poorly understood, and the contribution of genetic predispositions, other than HLA class II allele variants to MMP, is unknown. The objective of this study is to identify susceptibility genes for MMP in a British cohort of MMP patients. A GWAS was conducted in a British cohort of 106 MMP patients. Publicly available genotypes of 2900 blood donors of the UK Blood Service and of 6740 individuals of the 1958 British Birth Cohort served as control. Subsequently, putative susceptibility genes were independently replicated in a German cohort of 42 MMP patients. The GWAS found 38 SNPs in 28 haploblocks with an odds ratio >2 reaching genomewide significance (P < 5.7 × 10 ). Replication confirmed an association of MMP with SNPs in rs17203398 (OR: 3.9), located intronically in the β-galactocerebrosidase gene (GALC) on chromosome 14 and with recessive polymorphisms in rs9936045 (OR: 3.1) in the intergenic region between CASC16 and CHD9 on chromosome 16. The risk of developing MMP is partially genetically determined. SNPs in GALC enhance the risk for MMP, indicating that β-galactocerebrosidase may be involved in the pathogenesis of MMP. Likewise, impacts of polymorphisms in the intergenic region between CASC16 and CHD9 on the activity of neighbouring genes may facilitate the emergence of MMP. The putative role of both polymorphisms requires functional studies in the future.

European guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology – Part I

“… 123 , 124 , 125 , 126 A genome‐wide association study found 38 single‐nucleotide polymorphisms associated with MMP; these polymorphisms need functional validation. 126 In a few cases, drug‐induction of MMP has been described. 127 , 128 , 129 Dipeptidyl peptidase‐4 inhibitors may be associated with the induction of MMP.…”

Indirect immunofluorescence in mucous membrane pemphigoid: which substrate should be used?

“…A different genetic basis may conceivably explain the different results achieved by these studies. Genetic factors determine the targeted autoantigens or epitopes of MMP, but they may also regulate their different expression between the skin and mucous membranes …”

New insights into pemphigoid diseases

“…Previous studies have reported an association of pemphigus and pemphigoid disease susceptibility with certain HLA alleles, the association of bullous pemphigoid with several polymorphisms with the Fc gamma receptor locus, ST18 in pemphigus, and mitochondrial alterations in bullous pemphigoid patients . In this FTI, a genomewide association study with 106 MMP patients and over 8,000 controls identified 38 single nucleotide polymorphisms (SNP) . Of these, in addition to the HLA locus, an association of mucous membrane pemphigoid (MMP) with rs17203398, located intronically in the β‐galactocerebrosidase gene ( GALC ), was replicated and confirmed in an independent cohort.…”