Schlagwort-Archive: asthma

Update on asthma and allergy genes

Even the most recent attempt by Open Targets integrating basically everything

GWAS Catalog and UK Biobank) with transcriptomic, proteomic and epigenomic data, including systematic disease–disease and disease–molecular trait colocalization results across 92 cell types and tissues … trained a machine-learning model … to distinguish causal genes from neighboring genes, outperforming a naive distance-based model

ended up with nothing new

I am glad to see, however, that my criticism of the ORMDL3 hype has been taken up by other authors as well

In the first report of the association of the 17q21 locus with asthma, Moffatt et al. suggested ORMDL3 as a promising candidate on the basis of gene expression studies in EBV-transformed lymphoblastoid cell lines 5. However, the function of ORMDL3 remains to be fully elucidated and it is possible that other genes in this region, or more distant genes, contain the true causal variants.

while ORMDL3 isn’t appearing at all in the above analysis. So ORMDL3 seems to suffer the same fate as FcER1b/MS4A2 identified by the same group.

Vitamin D Kids Asthma Study – Criticism is not justified

On Aug 12,  Science magazine published a strange journalistic article of an ongoing vitamin D asthma study.  I responded on the next day

while now also the former editor-in-chief of Science Jeremy Berg noted

 

Science printed the rebuttal of Berg

Piller minimizes the rationale used to select the placebo-controlled trial design and suggests that there is agreement that such a design is unethical… The News story notes that the majority of children in the trial were Black and states that this constitutes overrepresentation… Rather than being criticized, this trial should be commended for inclusion of appropriate trial participants…. Piller writes that participants were at increased risk of fractures and that the nine bone fractures experienced by study participants were more than anticipated, without specifying the magnitude of any increased risk or the anticipated number of fractures. However, there is no consensus that any increased risk exists…
as well as that of Celedon in the same issue
Piller misrepresents the Vitamin D Kids Asthma Study (“Vit-D-Kids” or “VDKA”) . He reports concerns about the study’s design, participant safety and selection, consent forms, and report trans-parency. These doubts are unfounded. VDKA ethically investigated a potentially important treatment for childhood asthma.

Unfortunately the response of the news editor Tim Appenzeller is so weak that I would recommend to search now not only for a new correspondent but also a new editor.

A new hypothesis why atopic dermatitis and asthma may be linked by vitamin D

We had a major discussion before our 2010 paper where I argued that rare variants should have been included. Ten years after there is a nice paper using massive exome sequencing that finally includes them. The respiratory tract isn’t so much influenced by rare variants but there is a strong effect in  the immune system.

Qanli Wang https://www.biorxiv.org/content/10.1101/2020.12.13.422582v1, posted December 13, 2020.

And there is another interesting fact.

Surveying the contribution of rare variants to the genetic architecture of human disease through exome sequencing of 177,882 UK Biobank participants …if we look at the …. European population who are carriers of a filaggrin (FLG) PTV, we find those carriers have significantly higher risk for well-known associations, such as dermatitis  … and asthma … Concomitant increases in vitamin D levels suggest risk of melanoma and basal cell carcinoma in FLG PTV carriers could be attributable to increased sensitivity to ultraviolet B radiation.

So far, I have only assumed some asthma/allergy priming effect of oral vitamin D in the newborn gut.

This paper now argues for an increased vitamin D sensitivity in the skin of  FLG dermatitis patients which is interesting given the largely contradictory data of serum vitamin D and atopic dermatitis. Maybe dermatologists should focus their research more on local vitamin D turnover?

Missing heritability

It is always nice if you are being cited after some years ;-)
There is an important article that I have been reading this morning “Missing heritability of complex diseases: case solved?Emmanuelle Génin is correct by questioning the statistical models underlying our heritability measures.

It is therefore possible to directly quantify the contribution of these genetic variants to phenotypic variance and measure what is called “genomic heritability”. Briefly, the idea is to infer the proportion of variance that can be explained by a linear regression on a set of markers used as explanatory variables.

This genomic heritability seems to be in fact a poor mathematical representation of a biological trait. >1000 hits in >500.000 individuals, does that make any sense at all in terms of biology?

More recently, it was proposed that rather than polygenic, the genetic architecture of common diseases could in fact be “omnigenic” with mainly all active genes affecting every complex traits.

which is fatalistic but justified IMHO. But there could be solutions. We proposed undetected rare variants

When adding these rare and low-frequency variants to the common variants associated with height, 27.4% of the variation can be explained.

while the results are not impressive. We proposed also structural variants (CNVs), but again no convincing effect so far. Allele dosage? Disappointing . GxE, interaction with genome background? Difficult, highly complex. Epigenetic environmental influences ? Sure but where to start?

The “GIGO (Garbage-In Garbage-Out) syndrome in genetics” as coined by Emmanuelle Génin is one of the main reasons why I mostly dropped out of the field.

We believe that the “missing heritability problem” is an ill-posed problem. Solving it by refining over and over again statistical models derived under the “polygenic paradigm” or using more and more sophisticated sequencing machines will not answer the fundamental and biological question of why that individual is affected by the disease and that other individual is not.

My last sentence would be: Phenotypic correlations between relatives determine heritability. So we should go back to family studies if we want to explain heritability.

History of allergy research In Germany

Using data described in Science Magazine (basically 4% of all published books) I constructed a plot showing an update to the 100 year old mystery why we get allergic to certain substances.

There seems to be a good chance for 2011 if the line will further increase…

The largest study so far on serum cytokines

We just published the largest study so far of human serum cytokines providing for the first time reference values.

In this study we investigated serum samples from 944 individuals of 218 asthma-affected families by a multiplex, microsphere based system detecting at high sensitivity eleven asthma associated mediators: eotaxin (CCL11), granulocyte macrophage stimulating factor (GM-CSF), interferon gamma (IFNγ), interleukin-4 (IL-4), IL-5, IL-8, IL-10, IL-12 (p40), IL-13, IL-17 and tumor necrosis factor alpha (TNFα). The largest study so far on serum cytokines weiterlesen

The asthma and glaucoma island

Dr. Zamel, one of the PIs of the Tristan da Cunha study pointed me today to the interesting 30 min BBC documentation online at Allergy Canada

Allergy Island is an exclusive documentary on the history of asthma in Tristan da Cunha and the discovery of the gene related to asthma in that highly inbred community by the expedition that I did in 1993. I went in May 2008 to Tristan da Cunha with the BBC crew to film both parts for the entire month.

So many advertisers

It’s a pleasant experience to write something that is being translated afterwards into so many languages afterwards. It is, however, irritating that this dissemination is irrespective of what I (and all second and third hand journalists and translators) understand of this curious world.

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Münchhausen Trilemma

A scintillatingly witty reply to one of my recent letters say that Münchhausen Trilemma weiterlesen

ORMDL3 – more inconsistencies in the Nature paper

It seems that CEA just published my rather critical view of the recent ORMDL3 association paper. My letter had been first submitted to “Nature” but rejected after review.
A rebuttal seemed to be necessary as the authors repeatedly highlight ORMDL3 as a new asthma gene – in the printed Nature paper, in the Nature podcast and in the accompanying press releases. They even continue with reviews saying that

Completion of the human genome sequence and the advent of genome-wide association studies have resulted in the identification of two novel asthma susceptibility genes, ORMDL3 and CHI3L1, in the past year.

ORMDL3 – more inconsistencies in the Nature paper weiterlesen

Not all that wheezes is asthma

A new abstract at the recent ATS congress now clears the 2007 controversy between the Camargo and Gale studies on the effect of vitamin D: Wheezing is not asthma (as the atopy component is missing?). Not all that wheezes is asthma weiterlesen

CD 14 now also on the vitamin+allergy list

Just for curiosity I am collecting a list of allergy genes that are vitamin D dependent. The list is already rather long but now there is a prominent addition: CD14. Known as asthma gene for many years the vitamin D dependency isn’t such clear. A clever analysis, however, now shows that there is an intermediate step involved CD 14 now also on the vitamin+allergy list weiterlesen