One of the few conditions where the genetics led straight to the medicine. The pathways the 2009 scan implicated — IL-23 and NF-κB — are the pathways the drugs that changed psoriasis treatment now block.
Psoriasis is an immune-mediated disease of the skin, nails and joints: the immune system attacks tissue that is not infected, and skin cells are pushed to the surface far faster than they should be.
Most genome-wide findings point at biology nobody knows what to do with yet. Psoriasis is the exception worth knowing about.
A 2009 scan of 438,670 positions in 1,409 patients and 1,436 controls, followed up in 5,048 patients and 5,041 controls, gave strong support to two pathways: IL-23 and NF-κB.
Drugs that block IL-23 are now among the most effective treatments for psoriasis there are. The genetics did not invent them, but it pointed at the pathway and gave the confidence to pursue it — which is what people mean when they say a genome-wide study "worked".
The HLA region encodes the molecules that present fragments of protein to the immune system so it can decide what is foreign. When a disease's strongest signal is in HLA — as it is here, and in coeliac disease, type 1 diabetes and several others — that is a statement about what the disease is: an immune system making a decision about self.
It is also the region where a single common variant carries more risk than almost anywhere else in the genome, which is why HLA associations look so unlike the rest of a GWAS.
Psoriasis is diagnosed by looking at skin, not at DNA. Most people carrying these variants never develop it, and people without them do. Onset involves triggers — infection, injury to the skin, stress, some medicines — that no genotype predicts.
And no guideline chooses a psoriasis treatment from a genotype, including HLA-C*06:02, although whether it should is an open research question rather than a settled no.
The source. Nair et al. (Nat Genet 2009) genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry, following up 21 promising SNPs in 5,048 cases and 5,041 controls. The results provided strong support for the involvement of the IL-23 and NF-κB pathways.
The variants recorded here. rs12191877 tags the HLA-C region; the risk allele of HLA-C*06:02 is the strongest known genetic determinant of psoriasis susceptibility and is more strongly associated with early-onset, type I disease. rs17728338 lies near TNIP1, whose product binds A20 (TNFAIP3) in the negative regulation of NF-κB signalling.
Therapeutic relevance of the pathways. IL-23 and the IL-23/Th17 axis implicated by this and contemporaneous scans are the targets of the IL-23p19 and IL-12/23p40 inhibitors now used in moderate-to-severe psoriasis. This is among the clearest instances of genome-wide association findings converging with successful drug development, though the drugs were not derived from these results.
Clinical boundary. Psoriasis is a clinical diagnosis. Genotype is not used diagnostically, prognostically or to select therapy; HLA-C*06:02 status has been studied as a predictor of response to particular biologics but is not incorporated into any guideline.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Psoriasis comes down to these specific, well-studied positions — not a diagnosis.
Not directly, but it did something rarer than usual: it pointed at IL-23 and NF-κB, and drugs blocking IL-23 are now among the most effective treatments there are. Most genome-wide findings point at biology nobody yet knows what to do with; this is the counter-example.
Because HLA molecules present protein fragments to the immune system so it can decide what is foreign. When a disease’s strongest signal is there, that is a statement about what the disease is — an immune system making a decision about self. Coeliac disease and type 1 diabetes look the same way.
Not yet in practice. HLA-C*06:02 has been studied as a predictor of response to some biologics and the results are interesting, but no guideline uses it. That is an open question rather than a settled no.
Most people who carry them do not, and people without them do. Onset involves triggers — infection, skin injury, stress, certain medicines — that no genotype predicts, and the diagnosis is made by looking at skin.
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