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.
A scintillatingly witty reply to one of my recent letters say that Continue reading Münchhausen Trilemma
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.
Continue reading ORMDL3 – more inconsistencies in the Nature paper
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?). Continue reading Not all that wheezes is asthma
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 Continue reading CD 14 now also on the vitamin+allergy list
A new paper – the second bioinfomatics approach following the groundbreaking work by Perez-Iratxeta – is now coming up with some interesting remarks beyond IL-13 and TGF-ß1 Continue reading Where is the asthma gene?
What do these guys offer here? Continue reading Para asma, bronquios y catarros
The J Int Med has a symposium series about the “origins of the developmental origins theory” scienceblog:doi:10.1111/j.1365-2796.2007.01809.x or the so called “Barker hypothesis” Continue reading Why we didn´t find the asthma gene
Waiting to exhale was a book in 1992 (“Right now I am supposed to be all geeked up”). Waiting to exhale then was a movie in 1995 (“Friends are the people who let you be yourself… and never let you forget it”). And finally Waiting to exhale was the title of a meeting report 1995 Continue reading Waiting to exhale
I have just found our most recent PLOS paper about asthma in Africa being published online
As of the 1980s, there was an overall conviction that asthma had an anthropogenic origin with indoor and outdoor air pollution as the main culprits. Following some overinterpreted epidemiological findings of the “hygienic†phase, there is now evidence accumulating that the asthma epidemic might have an iatrogenic origin. There might not only be indirect effects of improved living standards and better medical care, there are even direct effects under discussion, for example by oestrogens, vitamin D, antibiotics, and paracetamol. Infant formula (which contains vitamin D) has already entered the food chain in Africa; paracetamol is the most common drug bought over the counter in Ghana. Do African countries offer any unique observations where singular effects of these drugs can be delineated?
An independent review (that I did not know at time of writing) arrived at similar conclusions. We all, however, forgot to mention sensational news as Gambian president Yahya Jammeh can heal asthma click – click – a more serious appraisal click.
My childhood favorites
A new series of pro- and con editorials in the Am J Res Crit Care Med discusses the question why in some instances mouse models have “misdirected resources and thinking”. You may have noticed that I have only rarely used animals for research; the authors of this editorial have collected empirical data on the exploding use of murine models. Despite their attractiveness from a technological point, they are often useless because
I am sure there are even more arguments – I suggest that the authors deserve the Felix-Wankel price.
15 Dec 2006: The BMJ has 6 more examples about the discordance between animal and human studies: steroids in acute head injury, antifibrinolytics in haemorrhage, thrombolysis or tirilazad treatment in acure ischaemic stroke, antenatal steroids to prevent RDS and biphosphonate to treat osteoporosis.
19 Dec 2006: Another pitfall paper
31 Dec 2006: A blog on animal welfare
25 Apr 2007: Call for better mouse models
15 Jul 2018: Of Mice, Dirty Mice, and Men: Using Mice to Understand Human Immunology
7 Jan 2023: A review concluding that The vitamin D system in humans and mice: Similar but not the same
Just found at the HUM MOLGEN bulletin board a link to Fable, a new automated literature extraction system. Fable is pretty fast and can output gene lists. Sure, the screenshot below shows only those genes that I mentioned in the abstract, but this is not so bad as the most important genes wil be placed there.
BTW, the number of reviews on asthma genetics have been falling to less than 50% after closing the Asthma Gene Database. Maybe this new service will help to re-establish the former output of reviews ;-) yea, yea.
I am detailing in a forthcoming paper in “Allergy”, that the contradicting results found with ADAM33 (the first positionally cloned asthma gene) probably results from a rather poor design of all follow-up studies.
It does not make so much sense to repeat over and over the same few SNP marker; instead a full resquencing of the linkage region would be necessary. From the analysis of public LD maps it is even possible that neighboring genes may be responsible for the observed associations.
I have also doubts if the SNP-centric view is always leading to success. BTW there is a new database of over 400,000 non-reduandt indels of which 280,000 are validated by comparison with other human or chimpanzee genomes (see Mills et al., the indels are available in dbSNP under the “Devine_lab” handle).
Microchimerism is an interesting phenomenon that describes the hosting of foreign cells in an individuum – the prefix micro relates to the rather low counts of foreign cells (see the self discussion).
It is believed (but unproven) that most cases of microchimerism relate to the persistence of fetal cells in the maternal organism. The background of microchimerism is extremely complicated as highlighted in a recent review about the immunology of placentation in mammals. This paper has some nice cartoons about the types of placentation (epitheliochorial, endothelichorial and haemochorial) where the invasive potential of fetal trophoblast cells is the culprit of reciprocal (?) cell traffic between mother and fetus. The highest risk is found in women with induced abortion; cell count is ranging from 0 to 21 male cells per 100,000 female cells in peripheral blood; transfer may occur from mother <-> child, twin <-> twin, or sib <-> mother <-> sib.
Microchimerism has been examined in transplantation medicine (where the recipient replaces the outer donor organ epithelium), in blood transfusion and HCT, as well as in some autoimmune diseases (systemic sclerosis, SLE, thyroiditis, PBC). A clinical review reports that fetal cells have been found to persist for many years, probably for a lifetime.
I have doubts if that is true as I am not aware of any quantitative long-term study. Nearly all studies identified only male cells in women although now genomic studies of single cells are possible allowing a much better identification of foreign cells. If you are looking for a PhD thesis, microchimerism could be your field!
I already wondered if microchimerism could lead to genotyping errors, a question that can now easily be tested on the garbage of genotyping labs: We usually have genotyping errors in the 1-10 o/oo range; sometimes we see also triallelic SNPs. As far as I can renember, microchimerism has never been analyzed in the allergy field, although allergy can transplanted as well as asthma. Yea, yea.
What makes the difference between genetic linkage and association studies? Simply speaking, for linkage you need to inherit a particular marker allele from your parents where it does not matter if a child in another family inherits another allele (pending it shares it with its affected sibling). With association studies this matters.
As we found with the much relaxed linkage strategy so many minor diverse loci, I assume a rather heterogeneous origin of complex diseases. There is no doubt about the importance of genes, but about the sharing of the same genetic abnormality. An (anonymous) position paper on basic Asthma Research Strategy II in Clin Exp All 2006; 36: 1326 says
The average size of effect on asthma and related traits from common SNPs is small. For instance, seven common SNPs in the IL13 gene jointly accounted for only 0,5% of the variance of total IgE … With a heritability of circa 60% for total IgE this implies that hundreds of genes, each with small effects, may be involved in IgE regulation.
Families presenting with a complex system disease will all have unique patterns how they arrive at the same clinical endpoint. Alpha-delta-gamma asthma, theta-kappa-jota schizophrenia or $%&# diabetes – are they combining lets say 3000 variations in 300 genes of 30 metabolic-signalling pathways to 1 disease of variable onset, severity and prognosis? Yea, yea.