Category Archives: Allergy

Gene methylation in newborns is changed by maternal vitamin D supplementation

A randomized controlled study of pregnant women examined 400 IU vitamin D3 vs 3,800 IU from the second trimester through 4-6 weeks postpartum by genome-wide DNA methylation in leukocytes.

At birth, intervention group mothers showed DNA methylation gain and loss at 76 and 89 cytosine- guanine (CpG) dinucleotides, respectively, compared to controls. Postpartum, methylation gain was noted at 200 and loss at 102 CpGs. Associated gene clusters showed strongest biologic relevance for cell migration/ motility and cellular membrane function at birth and cadherin signaling and immune function at postpartum.

It seems that D3 supplementation is generating epigenetic effects in the offspring, something that we predicted already in 2012 as programming of vitamin D sensitivity.

When re-annotating the genes above using biocLite(“mygene”) there are at least 2 interesting genes for gain of methylation are getting to the surface: ZMIZ1  T cell differentiation) and CYP7B1 (first reaction in the cholesterol catabolic pathway of extrahepatic tissues, which converts cholesterol to bile acids). But also methylation loss is interesting with HLA-A (antigen processing).

 

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Framing

As a particular view, framing comprises a set of concepts and theoretical perspectives on how individuals, groups, and societies, organize, perceive, and communicate about reality. I believe it is not an inherent aspect of social sciences but of science in general. Take for an example allergy research: Framing in 1980 was air pollution, in 2000 it was hygiene and in 2018 it is omics while basic research is being largely ignored. So we could rewrite the framing article

Framing involves construction of a scientific reality– by pubmed, congresses, mass media, funding agencies, prize winners, or other scientists and organizations. Participation in a language community necessarily influences an individual scientists’s perception of the meanings attributed to words or phrases. Politically, the language communities of science, advertising, religion, and mass media are highly contested and evolve imperceptibly and organically over cultural time frames.

 

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Esoteric science

“Planetary science” – just esoteric blahblah? Embracing the whole world? Exposome instead of enviromental exposure? The desperate reaction to many unresolved questions?

The importance of the exposome and allostatic load in the planetary health paradigm.
Logan AC, Prescott SL, Haahtela T, Katz DL.
In 1980, Jonas Salk encouraged professionals in anthropology and related disciplines to consider the interconnections between “planetary health,” sociocultural changes associated with technological advances, and the biology of human health. The concept of planetary health emphasizes that human health is intricately connected to the health of natural systems within the Earth’s biosphere; experts in physiological anthropology have illuminated some of the mechanisms by which experiences in natural environments (or the built environment) can promote or detract from health. For example, shinrin-yoku and related research (which first emerged from Japan in the 1990s) helped set in motion international studies that have since examined physiological responses to time spent in natural and/or urban environments. However, in order to advance such findings into planetary health discourse, it will be necessary to further understand how these biological responses (inflammation and the collective of allostatic load) are connected to psychological constructs such as nature relatedness, and pro-social/environmental attitudes and behaviors. The exposome refers to total environmental exposures-detrimental and beneficial-that can help predict biological responses of the organism to environment over time. Advances in “omics” techniques-metagenomics, proteomics, metabolomics-and systems biology are allowing researchers to gain unprecedented insight into the physiological ramifications of human behavior. Objective markers of stress physiology and microbiome research may help illuminate the personal, public, and planetary health consequences of “extinction of experience.” At the same time, planetary health as an emerging multidisciplinary concept will be strengthened by input from the perspectives of physiological anthropology.

 

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How does vitamin D imprinting work?

I have  predicted an epigenetic regulation of vitamin D converting enzymes in 2010 to explain the programming effect of vitamin D supplements on later allergy.
Last week, a first study examining vitamin D supplement effects in newborns has been published. They compare 400IU versus 3800IU while I am already convinced that 400 IU has some measureable effect.

 

table 2 screenshot of selected rows

 

So maybe I was wrong with my prediction of a differential CYP24A1 methylation, as the authors now describe CYP7B1. CYP7B1 encodes for 25-hydroxycholesterol 7-alpha-hydroxylase which is more upstream in the  synthesis of cholesterol.

 

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Where have all the flowers gone?

Here is some background information of my forthcoming talk.

Congress: European Academy of Allergy and Clinical Immunology
Congress: 2018 Munich
Session number: OAS 03
Session title: Pan-omics in respiratory and skin disorders
Session date: Sunday, 27 May 2018
Session time: 10:30 – 12:00
Session room: Hall C
Abstract number: 0012

 

Background: In the pre-GWAS era (1993-2007) numerous association studies have been published in renowned journals including The Lancet, New England Journal of Medicine, Nature, Nature Genetics, Nature Immunology, Science and Human Molecular Genetics. They all showed an association of allergy related traits while these results have not been systematically matched with results from current GWAS studies.
Method: We are now following up several prominent associations by comparing the previously published results with currently deposited data at the NHGRI-EBI Catalog of published genome-wide association studies http://www.ebi.ac.uk/gwas NHGRI-EBI listed phenotypes were only selected if they are not suffering themselves from serious problems like unstandardized outcomes. Also the SNP marker set should have a good coverage of the region of interest.
Results: In total 26 allergy associated genes could be reanalyzed. The initial association could not be confirmed for CD14, ADRB2, TNF, MS4A2, ADAM33, GSTM1, IL10, CTLA4, SPINK5, LTC4S, LTA, NPSR1, NOD1, SCGB1A1, GSTP1, NOS1, CCL5, TBXA2R, and TGFB1. Some genes showed borderline significant results like IL4 and IL4R while only IL13, HLA-DRB1, HLA-DQB1, IL1 cluster and STAT6 were clearly associated also in recent GWAS studies.
Conclusion: Most of the early SNP association studies could not be replicated which has also been described in other disease areas (“non- replication crisis”). Assumed reasons range from insuffficient editorial oversight, poor review, phenotyping or genotyping errors, selective reporting or intentional fraud. In addition there are numerous study inherent problems like population stratification or wrong significance thresholds that may have led to largely irreproducible results.

 

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Refutation of the vitamin D hypothesis?

A new epidemiological study arguments against vitamin D inducing later allergy (Parr et al., Vitamin A and D intake in pregnancy, infant supplementation, and asthma development: the Norwegian Mother and Child Cohort, Am J Clin Nutr 2018;107:789-798). Table 5 in the most recent paper shows no effect when correlating first year of life supplementation and later asthma.

 

But why did they authors not even cite our study from 2004 (Hyppönen et al. Infant Vitamin D Supplementation and Allergic Conditions in Adulthood Northern Finland Birth Cohort 1966.  Ann. N.Y. Acad. Sci. 1037: 84-95) ??

 

Although our interest was more with allergy there have been clear effects on asthma  that have been confirmed now two dozen times.  Why did the authors miss that effect?

  • The cohort consists of 115,000 children but only 55,000 are analyzed. So selection bias is omnipresent.
  • A key issue is the definition of “asthma” as “having ≥2 pharmacy dispensations of asthma medication within a 12-month interval, which is more a “last resort” option than a correct diagnosis. “We cannot rule out some misclassication in our asthma outcome“. I agree.
  • Another issue is the unrecorded vitamin supply by standard baby food in the range of 500-1000 IU/daily. Does it make any sense to test for excess supplements in a population that is already heavily exposed to >90%? “A limitation of this study is that we did not have data on nutrient intake from supplements in infant“. I agree, it makes the study worthless.
  •  The supplementation with cod liver oil, vitamin D and multivitamins is chaotic as been shown in the last row of table 5. In real life or just in this paper? Numbers are contradicting “Vitamin D only, sometimes” and “daily” do not add to the number given for “vitamin D only” in the “combined use” section.
  • Supplementation at  month 6 is even a late event if we believe that the first allergen contact under vitamin D exposure is  being important.

So, still not need to drop the vitamin D hypothesis.

 

CC-BY-NC Science Surf accessed 18.02.2026

Stop public funding of this sort of work

One of my most favorite blogs write

We have absolutely no reason–or, at least, no need–to criticize anything about individual mapping papers. Surely there are false findings, misused statistical tests, and so on, but that is part of the normal life in science, because we don’t know everything and have to make assumptions, etc. Some of the findings will be ephemeral, sample-specific, and so on. That doesn’t make them wrong. Instead, the critique should be aimed at authors who present such work with a straight face as if it is (1) important, (2) novel in any really novel way, and (3) not saying that the paper shows why, by now with so many qualitatively similar results, we should stop public funding of this sort of work.

Maybe I see also good reasons to criticize individual mapping papers.

 

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Loss of IL33 -/- protects against allergy

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!

IL33, FLG, HLA-DQB1
GSDMB, BTN3A2, CCHCR1

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

 

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Any free DNA kits by 23andme? No, bioprospecting

The Atlantic knows

23andMe is best known for selling DNA test kits, but the company’s real value lies in the data of its 5 million customers. The bigger its genetic database, the more insights 23andMe can glean from DNA. That, in turn, means the more it can tell customers about their ancestry and health and the more valuable the data it shares with academic scientists and sells to pharmaceutical companies for research. About 80 percent of 23andMe customers choose to participate in such research.

Bioprospecting are

companies pressured by legal uncertainties and unrealistic expectations of benefit-sharing are exploring alternative technologies rather than using natural products for drug R&D

which is a bit different from a welcome framework for Africa

In human genomics, there has been a push to ensure that research on samples collected in developing countries — particularly in Africa — is anchored in local science and community engagement. One example of this is the Human Heredity and Health in Africa (H3Africa) initiative, which is funded by the US National Institutes of Health and the London-based Wellcome Trust. Since 2012, it has funded genomics projects whose principal investigators are African, with several of the projects being managed locally from Kenya’s capital, Nairobi.

 

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Allergen Immuntherapie

Spam Email

Science Spam nimmt immer mehr zu. Die Abbildung zeigt eine Spam-Email, die ich letzte Woche bekommen habe. Fake Konferenzen. Predatory Journals. Nonsense Papers. Es wird immer schwieriger, den Überblick zu behalten.

Schauen wir uns also auf Wunsch der Firma Stallergenes einen Artikel an: Allergy 2018 Jan;73(1):165-177. Sublingual immunotherapy provides long-term relief in allergic rhinitis and reduces the risk of asthma: A retrospective, real-world database analysis. Zielen S, Devillier P, Heinrich J, Richter H, Wahn U. Continue reading Allergen Immuntherapie

 

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Eosinophils in asthma

There is an update of our eosinophil SNP paper now in the Lancet with 27 new asthma CpG associations. The authors claim 3 overlaps to Cookson’s  36 IgE loci while I see only cpg0177040, maybe there are two more conicidental findings in the supplement? At least the paper says

eosinophil counts were not significantly different between patients with asthma and controls in our discovery cohorts, suggesting that our results reflect the presence of a different subset or activation state of eosinophils, rather than a change in eosinophil counts per se. Although eosinophils are linked to sub-phenotypes of asthma such as the T helper 2-type subset, our study provides unequivocal data supporting their involvement at the epigenetic level in mild-to-moderate asthma in children.

maybe, maybe not – this could be just residual confounding…

Additionally, CpG methylation patterns identified an early-life shift from naive T cell populations towards effector and memory CD8 and natural killer cell subsets, indicating a potentially crucial role for host virus interactions

maybe, maybe not – this could be vaccine effects, some other antigens, allergens or vitamin D

 

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Allergy risk by baby food

A new analysis of the GINI-LISA study published this month in  has an interesting plot showing the eczema incidence in the first 15 years of life. Eczema is a major allergy symptom.

On the right side (FIG1C), we find the untreated group, and on the left (FIG1A) we find the intervention group. Overlying both figures with Photoshop gives an interesting perspective.

When we use the lower opaque double line as reference, all types of baby feeding  give an increased eczema risk. To be more comparable, the opaque upper two lines should be used, which will result in zero effect size.

The question is: Why is breast feeding / breast milk (BF) a risk factor in the interventional (left figure)  but not in the observational arm (right figure)?

  1. In accordance with national and international guidelines full BF was recommended for 4 months in the interventional group. “Only in case of insufficient BF, children were randomized to one of the baby foods”. “Insufficient BF” is not clearly defined and the reasons seem to be complex.
  2. The general pediatric recommendation at the time of the study was that BF is allergy-preventive and that allergic children should be BF as long as possible.
  3. BF in the interventional arm therefore is a self-selected biased group primarily by allergic mothers and children with unclear criteria. The authors acknowledge in the discussion “Even adjustment for the potential confounders does not eliminate the phenomenon of reverse causality. Particular early eczema occurring in the first months of life may influence the mother’s decision regarding full breastfeeding versus formula supplementation.”
  4. BF is a complex chemical mixture that even varies over time – there is is a long-standing controversy on the effect of BF on allergy  with many negative, null and positive associations to allergy. From this discussion we can assume, that there is probably no direct effect of BF on allergy development. More likely BF is a proxy for something else – setting up a further biological argument that the interventional BF group should NOT be used as a  reference.

Children who receive “antiallergic” formula food will not have any benefit which is in accordance with a recent review in the BMJ. Nevertheless Nestlé Beba Pro HA is further advertising as “reducing allergy risk to milk protein”, Hipp HA Combobiotik as “reducing allergy risk by strong protein cleavage”, Nutramigen 1 LGG as “extensively hydrolysed, hypoallergenic formula … suitable for babies with … allergy”.

 

Postscriptum

The revised blog entry has been published as a letter to PAI. Unfortunately it turned out only after submission that there are also some major issues with the number of individuals included when comparing the 2003 with the 2013 and 2018 report.

 

 

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