Tag Archives: allergy

Farming and allergy

7.08.2023 admin

Hopefully the thread here on “farming and allergy” is now coming to an end. I tried to refute it for many years – last attempt in 2020

the main objection against the farming hypothesis is the interpretation of a negative statistical association as a “protective” effect. Only after thorough exclusion of alternative explanations, this interpretation may be justified.

but unfortunately missed another paper from the literature that had already been published in 2011, sorry for that.

With environmental exposures aside, at least 2 profound differences between farming and nonfarming families could be a threat to the validity of such investigations. One of these is the long-term selection of traits and genes in favor of the demanding living conditions of farmers because the agricultural lifestyle is often handed down within families. Referring to the “healthy worker effect,” we could expect certain disadvantages to be underrepresented in a farming population, giving rise to the concept of a “healthy farmer effect.”

Also the second point of Grabenhenrich has never been assessed

The other area expected to be different when comparing farming and nonfarming families constitutes behavioral patterns, lifestyle, and knowledge. For example, “soft factors,” such as health care use, symptom perception, and labeling, as well as access to and interest in health-related information, are most likely to be distributed dissimilarly. This disparity, in turn, could severely affect the response pattern in studies basing their case definition mainly on questionnaires. A temporal shift of these soft factors toward increased cautiousness and awareness has been assumed to contribute to the worldwide increase in symptoms of allergic diseases and, to a lesser extent, to the increase in clinically apparent disease.10, 11 Why should such a change be uniform in all parts of a population? Particular subgroups might be susceptible to catch up more rapidly. This phenomenon could be studied by identifying outliers in otherwise homogenous populations.

in the hope that journalists and politicians will never find it?

Is this “pioneering epidemiology” as judged by MP Dr. Söder?

Promoting a stolen idea (the original was published in German only) where the source was never cited?

Is it any good science ignoring all objections?

True heroes in epidemiology and public health are Semmelweis, Snow, von Pettenkofer, Doll & Hill, Hesse & Rehn but not a MD who can not even explain an Odds Ratio…

Allergy, Genetics

An update on the asthma exome

12.05.2023 admin

Here is a quick update on some genes of my recent asthma exome paper coming now from the 1 M exome paper published yesterday as a preprint.

loss of function variants IL1RL1. https://rgc-mcps.regeneron.com/gene/IL1RL1, 12 May 2023

Also ClinVar shows that the IL33 receptor is not “essential” making anti IL33 receptor antibodies like etokimab, itepekimab, tozorakimab a safe therapy although not being effective in any LOF mutation carrier.

The most interesting thing in the preprint is in supplemental table 2 with the s-het values for 16,704 genes. From that table I have selected my favorite target IL33 receptor together with TLR1, ALOX15, GSDMA, IL13 and IKZF3 ( BTNL2 could not be found in the list).

asthma exome https://rgc-mcps.regeneron.com/gene/IL1RL1, 12 May 2023

IKZF3 would be dangerous to be touched (see my 2008 commentary) while in the 2022 exome paper I also found only protective variants in the 5′-UTR but not any LOF variant – probably as IKZF3 is the only essential gene in the list.

So what’s next? I am still thinking how to reduce my exome set to the causal variants as half of the mutations are probably LD artefacts. And well, it would be super interesting to examine now two extreme inbred populations for their mutation spectrum, loosing either asthma variants by healthy (Amish) or diseased founders (Tristan da Cunha). Unfortunately there is little hope that this will happen – current science is built more on competition than collaboration.

Allergy, Genetics

Any proof for hygiene hypothesis by lockdown babies?

27.03.2023 admin

It is an interesting question – does social distancing influence later allergy ? Lawler et al. in November 2021

report the impact of COVID‐19 lockdown in 365 Irish babies at 6 months of age enrolled in the CORAL study. These were a subset of 3773 infants born in two participating major maternity hospitals in Dublin between March and May 2020. Unfortunately only 10% of children participated, so families were self-selected. Allergic rhinitis was common in both mothers (36%) and fathers (30%) which is higher than reported by Allergy Ireland (26%) and explained by the authors that parental allergy is “higher than the general population, which may have contributed to parental desire to enrol in this study.”

A follow-up in March 2022 in 344 children consecutively shows higher food allergy (4.7% vs 3.5%, NS) when compared to an earlier cohort (BASELINE 2008). Atopic dermatitis increased of 15.5% in the BASELINE study to 25.3% in CORAL (no P reported) which is not unexpected given the interest of parents in an allergy study.

Maybe a short questionnaire at 2026 school entry would be informative than the current study? Nevertheless the authors needed now to analyze their stool samples sitting in the shelves. This is the content of the March 2023 preprint that has just been published. There may be an association of some bacteria with atopic dermatitis but in the end it is a useless result as the strongest risk factors for atopic dermatitis – parental history and/or FLG mutations – are missing from the presented models

At the end we can safely assume that the 2020 lockdown did not have any influence on allergy prevalence in Ireland.

Allergy

Warum es in der DDR so viel weniger Allergien gab

11.12.2022 admin

Ich hatte direkt nach der Wende in Halle und Leipzig die erste Ost-West Allergiestudie* durchgeführt und dabei die verblüffende Entdeckung gemacht, dass es im Osten nicht mal halb so häufig Allergien gab.

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.149.2.8306030

Der Grund dafür war uns zunächst nicht klar, aber dann stelle sich doch bald heraus, daß es wohl die unterschiedliche Vitamin D Prophylaxe war – im Westen gab es tägliche niedrige Dosen ab der ersten Lebenswoche, im Osten wurde ab dem 2. Monat wenig hohe hohe Einzeldosen verabreicht. Wenn Kinder im Osten krank waren, dann fiel auch immer wieder die eine oder andere Dosis aus, auch wurde das Schema nach meiner Recherche nicht immer komplett durchgezogen. Leider haben wir uns damals aber nur die Impfpässe angesehen, nicht aber die im Nachinein wichtigeren Wiegekarten.

DDR Wiegekarte. Quelle https://www.ddr-museum.de/de/objects/1011262

Westdeutsches Untersuchungsheft U2. Quelle https://www.g-ba.de/downloads/83-691-452/2017-05-11_GBA_Kinderuntersuchungsheft_Web-WZ.pdf

Die Befürchtung der Professoren Mai und Beuren in dem alten SPIEGEL Artikel über Vitamin D Nebenwirkungen haben sich zum Glück nicht bewahrheitet. Dafür aber stellte sich dann aber eine unerwünschte immunologische Wirkung heraus die damals noch nicht bekannt war.

Mit dem aus England bzw Amerika importierten Schema zur Supplementierung stiegen die Allergien an. In der BRD war das ab den frühen 60er Jahren , wie überhaupt die englischsprachigen Länder immer die höchsten Allergiehäufigkeiten hatten, da sie wegen der häufigen Rachitis auch viel konsequenter supplementierten (die Rachitis hiess früher einmal auch “englische Krankheit”).

Mit dem Mauerfall 1989 setzte der Anstieg dann auch in der ex DDR ein und erreichte nach 10, 20 Jahre das Westniveau . Leider wurden unsere Warnungen vor einer zu frühen Supplementierung nicht ernst genommen, der Osten Deutschlands hat – wie so vieles andere auch – das Schema aus dem Westen übernommen und den Preis dafür mit ebenfalls hohen Allergieraten bezahlt.

Der Mechanismus der Allergieentstehung ist dabei nur teilweise aufgeklärt: Vitamin D ist jedenfalls immunsuppressiv mit vielfacher Auswirkung auf B und T Zellen was seit dem Nachweis des Vitamin D Rezeptors auf diesen Immunzellen wissen. Die Supplementierung stört offensichtlich die initiale Klassifikation ob ein Protein harmlos oder allergen ist.

Warum es aber auch schon 1989 Allergien im Osten gab? Nun, es war ja keine Vitamin D freie Zone, offensichtlich sensibilisiert man sich auch noch ausserhalb des überkritischen Intervals in den ersten Lebenswochen.

Allergy, Genetics, Vitamins

Allergy GWAS hits in VDR binding sites

30.11.2022 admin

It seems that I missed an interesting 2017 paper that looked for disease-associated SNPs in canonical DR3 motifs. Only 7 out of 211 traits showed significant hits, one of these was self-reported allergy. When annotating these SNPs, there are only two genes: LINC00299 and TLR1

hg38 position
rs10174949 2:8302018 LINC00299
rs10178845 2:8303773 LINC00299
rs5743566 4:38804221 TLR1
rs2101521 4:38809830 TLR1
rs5743565 4:38804262 TLR1
rs45588337 4:38805607 TLR1
rs55830619 4:38805643 TLR1

So are TLR1 & LINC00299 variant carriers more susceptible to vitamin D induced allergy?

LINC00299 (Long Intergenic Non-Protein Coding RNA 299) is a RNA Gene of largely unknown function, associated so far with allergy only on a genetic level in Framingham, href=”https://pubmed.ncbi.nlm.nih.gov/23817569/”>23andme and other studies. We don’t know so much here, the function of the long non coding RNAs

depends on subcellular localization. Depending on their niche, they specifically interact with DNA, RNA, and proteins and modify chromatin function, regulate transcription at various stages, forms nuclear condensation bodies and nucleolar organization. lncRNAs may also change the stability and translation of cytoplasmic mRNAs and hamper signaling pathways. Thus, lncRNAs affect the physio-pathological states and lead to the development of various disorders, immune responses, and cancer.

The TLR1 genetic association is found by many genetic studies, while the clinical association is probably more by an infectious origin. TLR1 is a pattern recognition receptor with a specificity for gram-positive bacteria and also included in my forthcoming exome paper as a protective factor for asthma/allergy. And we are also close to my earlier review of vitamin D, the microbiome and allergy…

Does any co-infection response during first vitamin D exposure influence allergic sensitisation? There are indeed some hints of an short-lived effect of lung group 2 innate lymphoid cells (ILC2s)

Laboratory mice cohoused for 2 weeks had impaired ILC2 responses and reduced lung eosinophilia to intranasal allergens, whereas these responses were restored in mice cohoused for ≥2 months. … These findings suggest that ILC2s respond dynamically to environmental cues and that microbial exposures do not control long-term desensitization of innate type 2 responses to allergens.

Allergy

Hygiene hypothesis hyperbole

12.08.2022 admin

Having written about the hygiene hypothesis, I missed a PNAS News feature even some years ago.

Again: The hygiene hypothesis was not born by David Strachan and well, there are more cracks of the hygiene hypothesis.

“The trouble is, as soon as you use the words ‘hygiene hypothesis,’ the word hygiene prejudges what the cause is,” says Bloomfield. To the public, “hygiene” is interpreted as personal cleanliness: washing hands, keeping food clean and fresh, sanitizing the home. However, because the hypothesis has been largely uncoupled from infections, the idea that we need to be less hygienic is wrong. Relaxing hygiene standards would not reverse the trend but only serve to increase the risks of infectious disease, says Bloomfield. The term “hygiene hypothesis” also fails to incorporate all of the other factors now linked to the increase in immunoregulatory diseases.

I expect that five years after mandating “super hygiene” during COVID-19 we can finally bury the hygiene hypothesis.

Allergy, Software, Vitamins

Not too bad: Citation Gecko

9.08.2022 admin

Just tried citationgecko.com on a topic that I have been working on for 2 decades. It will find rather quickly the source paper, much faster than reading through all of it. Unfortunately reviews are rated to be more influential than original data as Citation Gecko picks articles with many references.

Allergy

Parental allergy history at farms

26.07.2022 admin

A recent paper on the bias of farming studies did not discuss a healthy worker effect although this is being a reasonable explanation.

So let’s have a more detailed look at farm parents. It can be drilled down to the question if parents are also “protected” or it is more likely that some affected parents just moved away. Here are 13 studies that included information about farm parents. Continue reading Parental allergy history at farms →

Genetics, Philosophy

What is needed is a confrontational approach

1.02.2022 admin

Google showed me today a long forgotten abstract. Although I am not an expert in schizophrenia we collaborated two decades ago on this particular chromosomal region.

What is even more remarkable is the challenging keynote of the Xth World Congress of Psychiatric Genetics in The Palais des Congre ́s Brussels, Belgium October 9 –13, 2002 by Irving Gottesman [+2016], the father of epigenetics in psychiatry. He wrote there

We cannot escape the history of our field and are constantly guided today by the accumulation of facts with either positive or negative valences from our past. But when did the clock start—with the domestication of animals, with Galton’s musings and amoral passion for data collection about individual differences in behavior, or with the initially objective scientizing of Mendelism applied to schizophrenia but ending with a Nazi-tainted albatross around the neck of psychiatric genetics. In regard to the long quest for the distal and genetic (partial) causes of mental diseases, the conclusion that both genetic and environmental factors, none yet known in detail, provide the distal causes of mental disorders—that statement is too general to be of use to making further progress. What is needed is a confrontational approach based on evidence collected from competing ‘schools of thought’, and then reconciliation before some kind of omniscient and impartial Science Court.

I couldn’t agree more. What is needed is a confrontational approach based on evidence collected from competing ‘schools of thought’, and then reconciliation before some kind of omniscient and impartial Science Court.

Allergy, Genetics

How atopic dermatitis is linked to vitamin D and how IL33 splice variants associate to eosinophil numbers

10.12.2021 admin

(first published 12 Dec2020 and revised 10Dec2021)

We had a major discussion right before our 2010 paper where I argued that rare variants should have been included into our asthma/allergy/dermatitis GWAS. Ten years after there is now a nice paper using massive exome sequencing that finally includes them.

It seems that the respiratory tract isn’t so much influenced by rare gene variants but that there is a strong effect in the immune system.

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 … increased sensitivity to ultraviolet B radiation.

So far, I have only assumed an asthma/allergy priming effect of oral vitamin D in the newborn gut. This paper now argues for an increased vitamin D sensitivity also 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 skin and local vitamin D turnover?

-II-

The most prominent IL33 variant carried by over 2,300 people is splice acceptor 9-6250473-G-C followed by 600+ individuals with splice donor 9-6250600-G-T.

There are not too many carriers of this variant by the sheer amount of 177,882 participants. We nevertheless know already something about the seven IL33 splice variants since 2012.

Novel Splice Variants of IL-33: Differential Expression in Normal and Transformed Cells Journal of Investigative Dermatology (2012) 132, 2661–2664; doi:10.1038/jid.2012.180

with updates in 2016

Gordon, Alternative splicing of interleukin-33 and type 2 inflammation in asthma, PNAS 2016

as well as in 2017

Fig 3A Smith et al. A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma, PLoS Genetics 2017 – describes the splice site as NM_001199640:exon7:c.487-1G>C or rs146597587-C

So I did a sequence match to compare the new finding with these older publications.

own sequence match exon7 using data from dbSNP, UCSC GoldenPath and Uniprot – reference is hg19

Indeed, the 2017 paper already described rs146597587 which is probably identical to the splice acceptor 9-6250473-G-C in Astra UK Phewas (genome positions do not match – I used hg19 while I don’t know the Astra reference) . Astra says also c.613-1G>C while rs146597587 is just upfront of my codon 205 (3*205=615) whatever that means.

The Astra UK Phewas at least confirms the Iceland paper above

rs146597587-C associates with lower eosinophil counts (ß= -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids.

So it is basically a rediscovery meaning that we reached saturation.

Allergy, Vitamins

Vitamin D traces in later life

12.11.2021 admin

This is basically an update of my 2017 Allergy paper where I asked about sequelae of early vitamin D supplementation.

Two extensively examined hypotheses are the hygiene hypothesis (lack of protective bacterial exposure which leads to subsequent allergy) and the vitamin D hypothesis (early vitamin D supplementation sensitizes newborns against allergens) … The interesting question is: Are these concepts exclusive? … There is some preliminary evidence that – like many other environmental factors –vitamin D may modify the human microbiome.

Only yesterday a paper popped up during a presentation of Amelie Baud about the influence of social partners and the gut microbiome. This 2018 study tested gut microbial composition from 16S rRNA sequencing during the first year of life and subsequent risk of asthma in 690 participants

1-year-old children with an immature microbial composition have an increased risk of asthma at age 5 year … the microbial composition was not affected by maternal asthma status suggests that only susceptible children, exposed to inappropriate microbial stimulation during the first year of life, may express their inherited asthma risk …. The five most discriminating indicator OTUs for each cluster were identified for PAM cluster 1 as Enterobacteriaceae, Staphylococcus, Streptococcus, Bifidobacterium and Enterococcus, and for PAM cluster 2 as Faecalibacterium, Bacteroides(x3), and Anaerostipes … the risk of developing persistent asthma was increased (adjusted hazard ratio (aHR) 2.87 (1.25−6.55), P = 0.013) if the microbiome remained in PAM cluster 1 at age 1.

IMHO this doesn’t look very much like direct microbiome effects but some colliding factor. The authors discuss cesarean section-birth and antibiotics as relevant factors while I wonder why the last author (who is a known pro vitamin D lobbyist ) doesn’t take into account vitamin D here?

My 2017 review summarized only early results, where there are now many more robust studies like the 2019 Naderpoor study

there was a significant association between community composition and vitamin D supplementation at the genus level. The vitamin D group had a higher abundance of genus Lachnospira, and lower abundance of genus Blautia (linear discriminate analysis >3.0). Moreover, individuals with 25(OH)D >75 nmol/L had a higher abundance of genus Coprococcus and lower abundance of genus Ruminococcus compared to those with 25(OH)D <50 nmol/L.

or the 2020 Singh paper

Vitamin D supplementation significantly increased gut microbial diversity. Specifically, the Bacteroidetes to Firmicutes ratio increased, along with the abundance of the health-promoting probiotic taxa Akkermansia and Bifidobacterium. Significant variations in the two-dominant genera, Bacteroides and Prevotella, indicated a variation in enterotypes following supplementation.

So is the microbiome just an indicator of vitamin D exposure in genetic susceptible children?

Allergy, Password, Software

When a scientific journal is modifying your images

28.08.2021 admin

This content has restricted access, please type the password below and get access.

Allergy

Blaming genes for resistance to environmental stressors

28.12.2019 admin

This something that I always avoided in human research – blaming genes for resistance to environmental stressors.

Nevertheless a Californian group (https://doi.org/10.1371/journal.pgen.1008528) now tested 101 mouse strains for lung resistance with exposure to diesel exhaust particles (DEP). After sensitizing the animals with dust mite and aluminium they could also test metacholine hyperreactivity (AHR).

Strains that exhibited the highest lung resistance after control exposure were not necessarily the same as those with high lung resistance after DEP exposure. It is unclear which strain was used for the consecutive GWAS. Did they put all mice into one cage for that?

The metacholine AHR GWAS results are not very impressive. And there seem to be also errors, as for example the lead SNP on chr 19 (rs51547574, near IL33) is shown with different allele frequencies in text and Fig 2. As the expression quantitative trait locus (eQTL) for Il33 is not in the lung, I think there is nothing to memorize here – IL33 is just a gatekeeper for surface integrity.

In a next step I wouldhave expected a GWAS for resistance change after DEP but FIG 3 only gives the result of Δ AHR_DEP—AHR_PBS data at an abitrary methacholine dose of 10mg/ml. The identifed locus could be interesting but as the LD there is rather high without any corresponding eQTL (I always wondered why there has never been a significance threshold for LD blocks, only for isolated SNPs?), the logic of the paper is broken here. Induction of lung resistance by DEP was significantly blunted in Dapp1^-/- female mice? What about male Gm5105^-/- , Mttp^-/- , and Lamtor3^-/- animals?

Hopefully nobody else will now try to find diesel, ozone, NOx resistance genes in humans as this is not a a scientific but a political issue…

Allergy, Genetics

What is wrong with the 2011 NEJM paper?

16.10.2019 admin

N Engl J Med 2011;364:701-9 is another paper with 1000+ citations that had a lasting impression on some but not all people.

First, I can’t remember of any study with such an enormous selection bias where >94% of individuals have been lost.

Second, we should not forget that farm is not protective per se – farmers may just avoid a known allergy risk factor. PARSIFAL participants in this study included Steiner schools — anthroposophic medicine mostly avoids vitamin D (ref). This is of course a major issue for any cross-sectional study that doesn’t take into account the temporality of events.

Third, in PARSIFAL dust from children’s mattresses were collected by vacuuming — it is not very likely that many helminthic eggs were transported from stable to bedroom. In GABRIELA, only airborne dust samples were collected which again may miss helminth eggs although being certainly present in stable dust.

Fourth, more microbial exposure and more fungal taxa on farms are a trivial finding.

The inverse associations of the diversity scores with asthma were not confounded by status with respect to living on a farm because adjustment did not change the respective point estimates for asthma (Table 2), although the associations became nonsignificant.

Small sample size, borderline p-values even after a long fishing expedition?

What do these strange “probability” plots really show – the probability of asthma or the probability to live on a farm?

N Engl J Med 2011;364:701-9 Figure 3 Does it refute any general effect of diversity?

The plots are misleading if adjustment for farm living does not change the parameter estimates for bacterial/fungal diversity.

Sixth – even many years later, the main findings of this study have not been independently replicated. There is not any single study that shows listeriosis (Listeria) or diphtheria (Corynebacterium) to be protective.

Allergy, Philosophy

medRxiv

24.09.2019 admin

ArXiv is operational since 1991, bioRxiv since 2013 and since 2019 there is now also medrxiv. More details at https://www.bmj.com/content/365/bmj.l2301

The main arguments in favour of sharing work in its preliminary form are, firstly, that science works faster if work is made available sooner after it is completed and, secondly, that articles are improved by feedback from a wider group of readers, alongside formal peer review by a few experts. Simple estimates suggest that halving the delay to sharing a research result can double the speed at which research progresses. Ambitious research funders are now embracing preprints and other measures that aim to accelerate the pace of research.

Although there was a mixed reception in the beginning, see Science back in 2017

MedArXiv will have a hard time attracting preprints if mainstream medical journal editors decide they won’t publish final versions of the papers. Currently, The BMJ and The Lancet are among the few medical journals that have explicitly said that posting a preprint doesn’t preclude publication; Nature and Science, which both occasionally publish medical studies, have the same policy. But at the JAMA Network, which publishes a dozen journals, the issue is hotly debated.

@medRxiv opened on June 6. So far they have only 304 followers on Twitter (and no allergy paper in the archive).

As the current “Allergy” editor and the publisher (John Wiley and Sons A/S) agreed to preprints last week, I have submited now my first preprint paper. Therefore, there are now 305 followers and 1 allergy paper :-)