A new paper in Nat Comm shows the power of natural human gene knockouts. Maybe the finding is not really novel but it finally proves the candidate genes – the most important asthma/allergy paper in the last 2 years!

This is even a nice addition to the most recent review of primary atopic disorders although IL33 is only depicted there in Fig 1.

Response to oral vitamin D seems to be different in humans . How do we buffer (artificial) vitamin D intake?

Vitamin binding protein or group specific component GC is a good candidate.  GC regulates the bioavailability of 25(OH)D3, acting as the main transporterint he blood stream from liver to kidney.  As described earlier GC binds with high affinity to 25(OH)D3, leaving less than 1% of circulating 25(OH)D3 free. In contrast to 25(OH)D3, which has a half-life of several weeks, GC  has a short half-life of 3 days only, suggesting that the protein and its ligand are independently regulated. Also the free binding capacity  of GC is variable. In addition there are GC variants that have different binding characteristics. Depending on these isoforms, serum levels increased between 97% and 307% after receiving 600 or 4000 IU/d vitamin D3 for one year. Taken together GC is assumed to be a buffer of vitamin D effects (and side effects) whenever transport in the blood stream is being involved.

The most recent GWAS study now shows again skyrocking p-values of GC variants and serum 25(OH)D3.

It is long known, that two missense variants of GC locate in exon 11. rs7041 encodes Asp432Glu pr D432E and rs4588 encodes Thr436Lys or T436K. These amino acid exchanges are leading to electrophoretically distinguishable proteins Gc1F/Gc1S and Gc2 respectively.  We are  moving the following gene plot bottom up to match the orientation.

Unfortunately LD is extremely high at GC. The GWAS peaks are therefore in the first intron, at exon 11 and intron 12. Lets’ s get closer to exon 11 where the two most important SNPs reside.

Although both variants are listed at many SNP chips I  can find only results for rs7041 with p=10^-222 in the new dataset.

rs7041 is listed as a A->C SNP there but according to Fu 2009 it is definitely a G->T variant. Also SNPedia has numerous articles for rs7041 being  a G->T exchange, for example Suaini 2014

This is also confirmed by dbsnp.  The GAT -> GAG exchange  is equivalent to D -> E, so the online results report a wrong strand orientation. Unfortunately we are stuck here, as one of the main effect SNP seems to have an unclear allele assignment and the second most important SNP is missing from the meta-analysis.

What would be nice is  a conditional analysis based on rs7041/rs4588 haplotypes. I predict there are further unknown functional variants in GC.  Maybe in intron 1 that often contains regulatory elements at the 5′-site of the intron. As the strongest signal is in the last intron and even beyond the 3′- end, further studies of 3′-UTR would be interesting, looking for binding sites of regulatory proteins, some miRNA or AU rich elements that affect the stability or decay rate of the transcript.

More than 7 years ago, I wrote a blog post that there is nothing new under the sun predicting the next asthma genetics study for 2020 to include 100K asthmatics.

Ok, I am wrong the paper appeared already a week ago with 360K  asthmatics while basically doubling the number to 136 independent risk variants. It’s not an asthma only study as the authors had a rather loose definition of asthma or rhinitis or eczema – is is more about the allergy/atopy complex.

It will be a long time reading and replicating the data while my first interest was to examine the affected gene list as shown in table ST15. Using the online Enrichr database I get the following result from the GO ontology

The highest combined score is with a negative regulation of IL-2. What does that mean? A genetically disturbed pathway predicted by a gene ontology network?

IL2 was discovered in 1976 by Robert Gallo by growing T-cells in culture for more than nine months by stimulating lymphocytes with phytohemagglutinin. ((IL1 was described back in 1972 by Charles Dinarello). Gallo identified T-cell growth factor (TCFG), now known as interleukin-2 (IL-2) as being absolutely important for a protective immune responses (Science 1976).

The next important paper was also published  in Science 1984 showing the following figure

So we have in allergy 2 hits on IL2: by genetics (as show in the new study) and by early vitamin D supplementation (as I reviewed earlier). Maybe we need more clinical studies like the Zhang 2016 study:

In a general population-derived birth cohort, we found that in infants who developed food allergy, cord blood displayed a higher monocyte to CD4(+) T cell ratio and a lower proportion of natural regulatory T cell (nT(reg)) in relation to duration of labor. CD14(+) monocytes of food-allergic infants secreted higher amounts of inflammatory cytokines (IL-1β, IL-6, and tumor necrosis factor-α) in response to lipopolysaccharide. In the presence of the mucosal cytokine transforming growth factor-β, these inflammatory cytokines suppressed IL-2 expression by CD4(+) T cells. In the absence of IL-2, inflammatory cytokines decreased the number of activated nT(reg) and diverted the differentiation of both nT(reg) and naïve CD4(+) T cells toward an IL-4-expressing nonclassical TH2 phenotype.

Suppressed IL2 is a key for allergy development shown also in experiments by Bonnet 2016:

We previously demonstrated that Tregs can be selectively expanded and activated by low doses of IL-2 (ld-IL-2) inducing immunoregulation without immunosuppression and established its protective effect in autoimmune diseases. In this study, we evaluated the ability of ld-IL-2 to control allergy in an experimental model of food allergy. Ld-IL-2 induced Treg expansion and activation that elicited protection against clinical manifestations of food allergy in two mouse models with OVA and peanut. This clinical effect was lost in Treg-depleted mice, demonstrating the major contribution of Tregs in ld-IL-2 efficacy. Mechanistic studies further indicated that protection from allergy could be explained by a Treg-dependent local modification of the Th1/Th2 balance and an inhibition of mast cell recruitment and activation. Preventive and therapeutic effects of ld-IL-2 were observed over a 7-mo-period, highlighting its long-term efficacy. This study demonstrated that ld-IL-2 is efficient to prevent and to treat allergic immune responses, and thus represents a promising therapeutic strategy for managing allergic diseases.

What we do need now for allergy prevention is a trials of newborns with low dose IL2 and also more trials refining the IL2 antagonist application of vitamin D.