Assessment of the genetic basis of rosacea by genome-wide association study

Anne Lynn S Chang, Inbar Raber, Jin Xu, Rui Li, Robert Spitale, Julia Chen, Amy K Kiefer, Chao Tian, Nicholas K Eriksson, David A Hinds, Joyce Y Tung, Anne Lynn S Chang, Inbar Raber, Jin Xu, Rui Li, Robert Spitale, Julia Chen, Amy K Kiefer, Chao Tian, Nicholas K Eriksson, David A Hinds, Joyce Y Tung

Abstract

Rosacea is a common, chronic skin disease that is currently incurable. Although environmental factors influence rosacea, the genetic basis of rosacea is not established. In this genome-wide association study, a discovery group of 22,952 individuals (2,618 rosacea cases and 20,334 controls) was analyzed, leading to identification of two significant single-nucleotide polymorphisms (SNPs) associated with rosacea, one of which replicated in a new group of 29,481 individuals (3,205 rosacea cases and 26,262 controls). The confirmed SNP, rs763035 (P=8.0 × 10(-11) discovery group; P=0.00031 replication group), is intergenic between HLA-DRA and BTNL2. Exploratory immunohistochemical analysis of HLA-DRA and BTNL2 expression in papulopustular rosacea lesions from six individuals, including one with the rs763035 variant, revealed staining in the perifollicular inflammatory infiltrate of rosacea for both proteins. In addition, three HLA alleles, all MHC class II proteins, were significantly associated with rosacea in the discovery group and confirmed in the replication group: HLA-DRB1*03:01 (P=1.0 × 10(-8) discovery group; P=4.4 × 10(-6) replication group), HLA-DQB1*02:01 (P=1.3 × 10(-8) discovery group; P=7.2 × 10(-6) replication group), and HLA-DQA1*05:01 (P=1.4 × 10(-8) discovery group; P=7.6 × 10(-6) replication group). Collectively, the gene variants identified in this study support the concept of a genetic component for rosacea, and provide candidate targets for future studies to better understand and treat rosacea.

Figures

Figure 1
Figure 1
Manhattan plot of single-nucleotide polymorphisms in the rosacea genome-wide association study of the discovery group. Single-nucleotide polymorphisms meeting a Bonferroni threshold of significance at P<5 × 10−8 (gray line) were rs763035 and rs111314066; however, only rs763035 was confirmed in the replication group (Table 2). Results are plotted as −log10-transformed P-values from the association test.
Figure 2
Figure 2
Regional association plot for rs763035, the single-nucleotide polymorphism confirmed in the replication group. The y-axis shows negative transformed −log10 of association test P-values, and x-axis shows the adjacent region on the chromosome. Colors indicate the strength of linkage disequilibrium with the index single-nucleotide polymorphism, and plot symbols indicate imputed (+) and genotyped (o) single-nucleotide polymorphisms. The human leukocyte antigen association is supported by numerous genotyped and imputed variants spanning an interval of about 1.5 Mb.
Figure 3
Figure 3
Genes associated with rs763035 are present in rosacea skin. (a) Rosacea skin from an individual of European descent and heterozygous for the minor allele at rs763035 immunostained with human leukocyte antigen-DRA antibody with a strong signal in the perifollicular inflammatory infiltrate (black and white arrow), epidermal Langerhans cells (single black arrow), and endothelial cells (double arrows). (b) Rosacea skin from the same individual as a and b immunostained with BTNL2 antibody showed mild–moderate staining in keratinocytes, perifollicular infiltrate (black and white arrow), and endothelial cells (double arrow). (c) Normal skin from the same individual stains with human leukocyte antigen-DRA antibody but lacks perifollicular infiltrate, numerous epidermal Langerhans cells, and dilated blood vessels seen in rosacea skin. (d) Normal skin from the same individual stained with BTNL2 antibody in keratinocytes but does not contain inflammatory infiltrate or dilated blood vessels. Negative controls were performed for all the tissues above by omitting either human leukocyte antigen-DRA or BTNL2 primary antibodies, and these displayed no staining (data not shown). Scale bar=100 μm.

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