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
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 â€œhygienicâ€ 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.
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 useless because
- mice do not have asthma as even the most hyperresponsive strain does not show spontaneous symptoms
- mice do not have allergy – although sensitization can be manipulated by high intraperitoneal allergen/adjuvant injection, this does not involve immediate and late airway obstruction.
- immune reaction in mice is quite different – the interfering of some substances like vitamin D cannot be reliable tested, there is no pure Th1 and Th2 reaction in human and less stronger IL-13 response
- mice typically can not be challenged with the complex (and interacting) human exposure – oxidant stress, viral infection, obesity, diet, smoke, pollutants, ….
- time course is difficult to mimicking in the mouse, there is no longterm model
- structure of mouse airways is different – there are fewer airway generations, much less hypertrophy of smooth muscle
- inflammation in mouse is parenchymal rather than restricted
- humans are outbred, mice are inbred
- many promising interventions of mice pathways failed in humans (VLA-4, IL4, IL5, bradykinine, PAF,…)
I am sure there are even more arguments – I suggest that the authors have deserved the Felix-Wankel price.
15 Dec 06: 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 06: Another pitfall paper
31 Dec 06: A blog on animal welfare
25 Apr 07: Call for better mouse models
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.