Genome-wide meta-analysis implicates mediators of hair follicle development and morphogenesis in risk for severe acne

Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin for which five genetic risk loci have so far been identified. Here, we perform a genome-wide association study of 3823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identify 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease. Likely causal variants disrupt the coding region of WNT10A and a P63 transcription factor binding site in SEMA4B. Risk alleles at the 1q25 locus are associated with increased expression of LAMC2, in which biallelic loss-of-function mutations cause the blistering skin disease epidermolysis bullosa. These findings indicate that variation affecting the structure and maintenance of the skin, in particular the pilosebaceous unit, is a critical aspect of the genetic predisposition to severe acne

IL-17/Th17 Pathway Is Activated in Acne Lesions

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Memorial Ball Park, Summerland, B.C., ca. 1948

Image of the Living Memorial Baseball Park at the north of town, opened May 24, 1948

Expression at the mRNA level of proinflammatory mediators in the German acne cohort determined by Affymetrix microarray technology.

<p>Expression at the mRNA level of proinflammatory mediators in the German acne cohort determined by Affymetrix microarray technology.</p

Clinical characteristics of acne patient group from Germany.

<p>Clinical characteristics of acne patient group from Germany.</p

The expression of proinflammatory mediators in Finnish patient cohort examined by RT-PCR.

<p>The expression of <b>a</b>) toll-like receptors TLR2 and TLR4, <b>b</b>) proinflammatory cytokine TNF-α and neutrophil chemotactic factor IL-8 were significantly up-regulated in lesional acne. <b>c</b>) IL-20 mRNA were increased in acne and psoriasis lesions. It is known that IL-20 can stimulate epidermal hyperplasia in model systems and is upregulated in psoriasis. *P<0.05, **P<0.01, ***P<0.001; bars represent mean ±SEM.</p

2-components NMF (Non Negative Matrix Factorization) model.

<p>The heatmap of 904 regulated genes on subjects-corrected log2-expressions (legend color blue for low expression and red for high expression).</p

Expression at the protein level of markers and cytokines characterizing the Th17 cell subtype in the German acne cohort.

<p>Expression at the protein level of markers and cytokines characterizing the Th17 cell subtype in the German acne cohort.</p

Top 20 up-regulated genes in the German acne patient group based on Affymetrix microarray technology.

<p>Top 20 up-regulated genes in the German acne patient group based on Affymetrix microarray technology.</p

The effect of IL-17 on keratinocytes.

<p>Th17-cells are defined to secrete IL-17 cytokines. Also some other cells can secrete IL-17 cytokines when properly activated. IL-17A and IL-17F regulate genes on keratinocytes, that are involved in innate immune defence, such as antimicrobial peptides (beta-defensins, S100 proteins A7/9, cathelicidin, LCN2) and a range of chemokines G-CSF, CXCLs and CCL20 which regulate neutrophil and lymphocyte trafficking. IL-17A and IL-17F stimulate keratinocytes leading to keratinocyte proliferation. Also vascular inflammation is activated.</p