Tag Archives: vitamin-D

Allergy, Genetics, Vitamins

5% of methylated sites escape reprogramming – a new allergy research direction

New Scientist Health has a short report how parents’ lives could change children’s DNA.

Azim Surani at Cambridge University and colleagues have demonstrated that some genes in the developing fetus escape the cleaning mechanism. Surani’s team analysed methylation patterns in a type of fetal cell that later forms a fetus’s own sperm or eggs. We would expect these cells to have been wiped clean when the fetus’s epigenome was reset at the early embryo stage. “However, about 2 to 5 per cent of methylation across the genome escaped this reprogramming,” says Surani.

The current wave of interest stems from three new papers: “The Transcriptome and DNA Methylome Landscapes of Human Primordial Germ Cells” by Guo demonstrates

The transcriptome of human primordial germ cells from the migrating stage to the gonadal stage reveals that both pluripotency genes and germline-specific genes are simultaneously expressed within the same individual cells. The global erasure of DNA methylation creates a super-hypomethylated germline genome.

So at week 10 after gestation, all analyzed 233 primordial germ cells lost their parental methylation marks except of 6% of the male and 8% of the female genome (which is a bit larger) . Unfortunately I did not find a list of genes there that have their parental methylation status transmitted.

Tang from a British consortium “A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development” writes

A unique transcriptome drives extensive epigenome resetting in human primordial germ cells for establishment of totipotency. Some loci associated with metabolic and neurological disorders exhibit resistance to reprogramming and are candidates for transgenerational epigenetic inheritance.

Here evolutionarily young and potentially hazardous retroelements, like SVA, remain methylated ( the number of embryos being examined is not given). Evolutionarily young and potentially hazardous retroelements, like SVA, remain methylated. When testing for resistant loci, they found that H3K9me3 marked escaping ; resistant regions were also enriched for KAP1 (alias TRIM28) binding sites of ESCs. But still no gene list there.

Sofia Gkountela “DNA Demethylation Dynamics in the Human Prenatal Germline” from the US

performed whole-genome bisulfite sequencing (WGBS) and RNA-sequencing (RNA-seq) of human prenatal germline cells from 53 to 137 days of development. We discovered that the transcriptome and methylome of human germ-line is distinct from both human PSCs and the inner cell mass (ICM) of human blastocysts … Gene expression do not correlate with global changes in DNA methylation.

In this paper finally there is the gene list, I was looking for — basically not demethylated, parentally inherited genes. Persistent methylated regions (also termed DMR, differential methylated regions) in advanced germline cells (AGCs) were seen in 500+ genes as given in table S4:

AADACL2-AS1, ABCA7, ABCC5, ABHD12, ABR, AC093375.1, ACSL4, ACSM1, ACVR1C, ACYP1, ADAMTSL3, ADARB2, ADK, AGBL4, AGK, AGPS, AIG1, AKAP9, AKR1B15, ALPK2, ANK1, ANKHD1, ANKHD1-EIF4EBP3, ANKRD11, ANKRD12, ANKRD19P, ANKRD20A9P, ANKRD24, ANKRD26, ANKRD26P1, ANKRD30BL, ANKRD31, AP2A2, AP3D1, AP4E1, ARAP2, ARHGAP26, ARHGAP39, ARHGAP44, ARHGEF18, ARHGEF4, ARHGEF7, ARID3A, ARL13B, ASB3, ASH1L, ASTN2, ASZ1, ATAD3A, ATF1, ATP11A, ATP13A1, ATP2C1, ATP8A2, ATP9B, AUH, AVEN, BAGE, BAGE2, BAGE3, BAGE4, BAGE5, BASP1P1, BAZ1A, BBS9, BCAS3, BCO2, BCYRN1, BEND3, BEND7, BRE, BRSK2, C14orf159, C15orf37, C1GALT1, C1orf159, C20orf196, C22orf34, C2orf61, C3orf67, C3orf67-AS1, C7orf50, C7orf60, C9orf3, CACNA1B, CACNG4, CALN1, CAMK1D, CARF, CARS2, CC2D2A, CCBL2, CCDC101, CCDC130, CCDC148, CCDC149, CCDC57, CCDC88C, CCDC97, CCNY, CCSER1, CD163, CD2AP, CD46, CDH12, CDH4, CDKAL1, CELF2, CEP70, CERK, CERS4, CFH, CHD2, CHD6, CHODL, CHRM5, CHRNA10, CHRNA4, CLEC16A, CLIC5, CLIC6, CNOT2, CNTN6, CNTNAP2, COG2, COL15A1, COL18A1, COL24A1, COL6A4P2, COLEC11, CORO2B, CPVL, CRTC3, CSMD1, CSMD2, CSNK1D, CTB-7E3.1, CTDP1, CTIF, CTNNA2, CTNNA3, CUBN, CXCR2, CXorf49, CXorf49B, CYCS, CYP3A5, DAPK2, DCDC2C, DDA1, DENND1A, DENND5A, DGUOK-AS1, DIP2C, DLG1, DLK1, DNAH6, DNAH8, DNAJC1, DNER, DOC2GP, DOCK1, DOCK7, DPP10, DSTN, DTNB, DYX1C1, DYX1C1-CCPG1, EBF3, ECHDC2, EDIL3, EEPD1, EFCAB10, EFCAB4B, EFTUD1, EHBP1, EIF2B3, ELMO1, EP400NL, EPHA6, EPPK1, ERC1, ERCC8, ERICH1-AS1, ERP44, ETFA, EVC2, EXD3, EXOC2, EYS, F11-AS1, FAAH, FAM172A, FAM174A, FAM207A, FAM209A, FAM86FP, FANCC, FBN3, FBXO39, FGD4, FGF14, FHIT, FIG4, FLJ30403, FNBP4, FOXN3, FREM3, FZR1, GABRA2, GAS6, GBP2, GCNT7, GDA, GGCX, GLCCI1, GLRA1, GLRA2, GMDS, GNAI1, GOLIM4, GPR75-ASB3, GRIK2, GRM7, GTF3C6, GTPBP10, GUSBP1, H6PD, HCCAT3, HCN4, HDAC4, HECTD4, HEG1, HPGD, HRNR, HS6ST3, HTR7, IFNAR1, IGF2BP3, IGSF11, IGSF22, IGSF9B, IL1RAPL2, IL31RA, IMMP2L, IMPG2, INF2, INTS1, INVS, IPO7, IQCF3, IQCG, IRAK1BP1, ISOC2, ISPD, ITFG1, ITGB1BP2, ITGBL1, JAM3, JAZF1, JMJD1C, KALRN, KATNBL1, KDM3B, KDM4C, KIAA0825, KIAA1328, KIF4A, KIF5B, KLHL20, KLHL3, LANCL3, LDB2, LDLRAD3, LHCGR, LINC00239, LINC00408, LINC00469, LINC00670, LINC00871, LINC00922, LINC01193, LINC01194, LINGO2, LMF1, LOC100128505, LOC100133669, LOC100188947, LOC100289333, LOC101927069, LOC101927280, LOC101927286, LOC101929064, LOC101929387, LOC102723742, LOC145837, LOC283683, LOC285768, LOC286083, LOC442132, LPA, LPPR1, LRP1B, LRRC4C, LTBP1, LUZP2, MAD1L1, MAGT1, MAML3, MAOA, MAP3K15, MAP4K5, MAPK10, MAPK8, MAPK8IP3, MAST2, MCTP1, MCU, MEF2A, MEI4, MELK, METTL15, METTL9, MFHAS1, MIR1273H, MIR518B, MIR518F, MIR520B, MIR548H2, MIR548O2, MIR6130, MIR6744, MOB3B, MOCOS, MTG1, MTMR7, MUC2, MUC5B, MUM1L1, MYO10, MYO5A, MYO9A, MYT1, MYT1L, NAA20, NAALADL2, NAT1, NAV2, NBPF10, NBPF20, NCALD, NCOA2, NEBL, NFATC3, NIFK-AS1, NIPA1, NKAIN2, NKAIN3, NLRP4, NME7, NOC4L, NONO, NPHP4, NQO2, NRXN3, NSUN6, NTSR1, NUBPL, NXN, OGG1, OR8S1, OSBP2, OSBPL6, OSMR, PACS2, PARK2, PARL, PAWR, PCBP3, PCDH19, PCDH9, PCNT, PCNXL2, PCSK6, PDAP1, PDE11A, PDE4D, PGAM1P5, PGAM5, PHKB, PHRF1, PIK3C2A, PIK3CA, PIP5K1B, PKD2L1, PKHD1, PKIB, PLCD1, PLCH1, PLEC, PLOD2, POLR1A, POMK, PPARA, PPARGC1B, PPP2R5C, PRH1, PRH1-PRR4, PRICKLE1, PRKAR1B, PRKCZ, PROSER2, PROSER2-AS1, PRR26, PRUNE2, PTCD3, PTDSS2, PTGFRN, PTPN21, PTPRD, PTPRN2, PYGB, RAB28, RAB3D, RAB3GAP2, RAB3IP, RABGAP1L, RAPGEF6, RBFOX1, RC3H2, RFX7, RGS6, RGS7, RNF115, RNH1, RNU6-52P, RNU6-81P, RPH3AL, RPIA, RPL35A, RPS6KC1, RSPH1, RYR1, S100Z, SCAPER, SCCPDH, SCEL, SCFD2, SCHLAP1, SCMH1, SDHAP3, SDK1, SEC14L1, SEC24D, SEL1L, SEMA3C, SERPINB3, SESN2, SESTD1, SETD1A, SETDB1, SHANK2, SHC2, SIL1, SIN3B, SLC12A3, SLC22A15, SLC24A2, SLC38A10, SLC44A5, SLC6A1, SLC8A1-AS1, SNORD115-1, SNORD115-2, SNTB2, SNTG2, SNX29, SORCS2, SOX5, SPATA5, SPIDR, SPIRE1, SPTB, SPTBN2, SPTLC3, SRD5A1, SRRM4, ST20, ST20-MTHFS, ST6GAL1, STARD9, STIM1, STK31, STK38, STON1-GTF2A1L, STXBP5-AS1, SUPT3H, SYN3, TAF1L, TAS2R19, TENM2, TENM3, THRB, THSD7B, TIMM23B, TJP2, TLK1, TMCC1, TMED1, TMEM132D, TMEM218, TMEM66, TMTC2, TNRC6B, TPST1, TPTE, TRAPPC9, TRIO, TRPC4AP, TRPM2, TRRAP, TSNARE1, TSPAN15, TSPEAR, TSSC1, TTC28, TTC40, TULP4, TYRO3P, TYSND1, TYW1B, UGGT2, UHRF1, ULK4, UNC5D, UNC79, UNC93A, USP13, USP15, USP34, USP50, VGLL4, VPRBP, VPS53, WDPCP, WDR1, WDR19, WDR36, WDR60, WWOX, XAF1, ZBTB20, ZCWPW2, ZFPM2, ZFYVE9, ZKSCAN5, ZMAT1, ZMYM4, ZNF135, ZNF14, ZNF317, ZNF32, ZNF32-AS1, ZNF32-AS2, ZNF32-AS3, ZNF335, ZNF341, ZNF350, ZNF382, ZNF415, ZNF556, ZNF595, ZNF664-FAM101A, ZNF670, ZNF670-ZNF695, ZNF7, ZNF717, ZNF718, ZNF767P, ZNF808, ZNF845, ZNRF1, ZSWIM5

(I dropped two genes as they are only date-formatted numbers in the supplied Excel sheet).

The interesting question for me is if there is an interaction with genes identified earlier in asthma and allergy research. According to the GWAS catalog there are 190 associated genes that match only 9 on the list above: AS1, CLEC16A, CTNNA3, EDIL3, PDE4D, PGAM1P5, SDK1, WDR36. Nothing exciting, in particular no HLA association. WDR36 is the only gene, we published some years ago. I find also only one match (COL15A1) of the 73 low methylation IgE loci published earlier.

Possibly, any of these persistent methylated genes can even stand on its own feet with just one silenced / activated gene being responsible for the pathology in a pedigree. I cannot identify so many signals in the list above, maybe some IL1 related stuff (IL1RAPL2, IL31RA, IRAK1BP1). CD46 at least is a good candidate as it is known that enhanced CD46-induced regulatory T cells will suppress allergic inflammation after allergen specific immunotherapy.

Unexpectedly, there are also no vitamin D related genes, no VDR, no cytochrome P450 enzymes. Nevertheless I recognize a whole bunch of calcium related genes: STIM1 (transmembrane protein that mediates Ca2+ influx), ATP11A + ATP2C1 (ATP dependent Ca2+ transporter), TRPM2 ( another Ca2+ channel), TRPC4AP + RYR1 (sarcoplasmic reticulum calcium channels) and NCALD (a cytosolic calcium transporter).

So would be definitely interesting to test the methylation status of these genes along with vitamin D levels in allergic parents and their kids.

 

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Vitamins

No wonder pill

"In the case of religion, we put our faith in gods. And in nutrition, we have vitamins," writes journalist Catherine Price in Vitamania, in which she traces vitamin crazes from the 1920s to the present.

Harvard Magazine reports about a new cancer vitamin D study. It includes more than 1,000 patients with metastatic colorectal cancer but going into the details it is a phase 3 clinical trial of chemotherapy and NOT a clinical trial of vitamin D. Vitamin D serum levels are used for posthoc stratification only although we know that these kind of studies are always misleading. At least HM quotes VITAL research Manson with

Clinical enthusiasm for supplemental vitamin D has outpaced available evidence on its effectiveness

I wish the VDAART chairs at Brigham and Women’s Hospital would have a similar realistic assessment. Their results are overdue with June 2014 ending of data collection for the primary outcome. Is it just the simple fact that vitamin D is not a wonder pill?

 

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Allergy, Vitamins

A jubilee – today we have 1000 papers on allergy and vitamin D

It is a long time period from our first paper in July 1999 in Allergy, but more than 15 years later there is now a huge list of papers.

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When looking for potential paradigm shift in research, however, vitamin D is still largely ignored.

    • Professional organizations that give legitimacy to the paradigm: NONE
    • Dynamic leaders who introduce and purport the paradigm: FEW
    • Journals and editors who write about the system of thought: FEW
    • Government agencies who give credence to the paradigm: NONE
    • Educators who propagate the paradigm’s ideas by teaching it to students: NONE
    • Conferences conducted that are devoted to discussing ideas central to the paradigm: YES
    • Media coverage: MINOR
    • Lay groups, or groups based around the concerns of lay persons, that embrace the beliefs central to the paradigm: FEW
    • Sources of funding to further research on the paradigm: NONE

 

 

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Vitamins

A large inter-individual variation for the efficiency of vitamin D3 supplementation

I believe this already since my first step into the vitamin D field but only now a review shows that

The integration of all these genome-wide data facilitates the identification of the most important VDR binding sites and associated primary 1,25(OH)2D3 target genes. Expression changes of these key genes can serve as biomarkers for the actions of vitamin D3 and its metabolites in different tissues and cell types of human individuals. Analysis of primary tissues obtained from vitamin D3 intervention studies using such markers indicated a large inter-individual variation for the efficiency of vitamin D3 supplementation.

It is a continuous medical malpractice to supplement newborn children with vitamin D without taking into account variation of the inter-individual response, body weight, or any co-medication.

 

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Genetics, Joke, Vitamins

Cycling is good for you (and vitamin D is an activity marker)

Vitamin D level is an activity or lifestyle marker, although this has been largely neglected in the medical literature, maybe except Gannage 2000, Hyppönen 2007, Sohl 2013 and Choi 213. A new paper by de Rui in PLoS now shows that

serum 25OHD levels were significantly higher in individuals who engaged in outdoor pastimes … compared to those who did not. In particular, subjects regularly practicing gardening or cycling had higher serum 25OHD levels than those who did not, whereas 25OHD levels differed little between subjects who did or did not undertake indoor activities.

While these are good news for older cyclists Continue reading Cycling is good for you (and vitamin D is an activity marker) →

 

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Philosophy, Vitamins

Reference values should be based on reference populations and not on politics

For a long time this has been a general rule. Just take the mean and substract two standard deviations and you get some useful reference values. Or whatever algorithm you like. This changed considerably where commercial or any other personal interests come into play. The cholesterin discussion settled only by studies showing that people with a history of cardiovascular disease may derive benefit from statins irrespective of their cholesterol levels.
I see some analogy in the vitamin D field. There is a German dermatologist who believes that 60% of all Germans are vitamin D deficient (the comments following the interview highlight this as an epiphany “totale Erleuchtung”). And a more recent paper showed that “89.9%” of all healthy newborns being insufficient. Really looks like a mix-up of some basic concepts in clinical medicine, yea, yea.

 

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Allergy, Vitamins

The first proven risk factor for allergy

After more than a century of research, the first successful clinical trial of an allergy risk factor has been performed. It looks like the authors even did not anticipate such an effect (known as triple blind design). But read what the Pubmed article about the Norizoe et al. paper says

To elucidate whether maternal vitamin D supplementation during lactation improves infantile eczema and other subsequent allergic disorders, a randomized, double-blind, placebo-controlled trial was performed.
Mothers (n=164) of infants with facial eczema at one-month checkup were randomly assigned to receive vitamin D3 supplements (n=82; 800 IU/day) or placebo (n=82) for 6 weeks from May 2009 to January 2011. The primary outcome was infantile eczema quantified by Scoring Atopic Dermatitis (SCORAD) index at the three-month checkup, and the secondary outcomes were atopic dermatitis, food allergy, and wheeze diagnosed by doctors up to 2 years of age.
There was no significant difference in SCORAD at 3-month checkup between two comparative groups. Doctor-diagnosed food allergy was significantly more common up to age 2 years in vitamin D group (10/39: 25.7%) than in placebo group (3/40: 7.5%; RR=3.42, 95%CI=1.02 to 11.77, P=0.030). Moreover, at least one secondary outcome was also significantly more common in vitamin D group (17/39: 43.6%) than in placebo group (7/40: 17.5%; RR=2.49, 95%CI=1.16 to 5.34, P=0.012).
These results suggest that vitamin D supplementation may not decrease the severity of infantile eczema at three months of age, but may rather increase the risk of later food allergy up to two years of age. Because a large number of subjects was lost to follow-up, further study is needed to confirm the findings.

Of course, there may be some weakness in the study design, a large loss to follow-up and the way how food allergy was diagnosed will be critized. I think, however, that this is a major breakthrough that raises the hope that we will finally understand how allergy develops.

Addendum Dec 23th, 2013

I should have added “true” risk factor, as there are positive trials on probiotics and atopic dermatitis. The meta-analysis by Lee immediately lead to a rebuttal

Their review fails to meet published standards for the quality of systematic reviews on several criteria, and this has led to inappropriate conclusions. […] These defects in methodologic rigor have led to an exaggeration of the clinical benefits of probiotics for eczema prevention.

The Cochrane Summaries are also negativ

There is not enough evidence to recommend using probiotics for the treatment of eczema.

Same situation with asthma

We found no evidence to support a protective association between perinatal use of probiotics and doctor diagnosed asthma or childhood wheeze

 

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Allergy, Vitamins

Handout text 2011 AAAAI Seminar San Francisco Vitamin D deficiency

2011 AAAAI Annual Meeting Handout

Session Number: 3523
Session Title: Vitamin D: Vitamin D Deficiency Causes Asthma -> CON
Session Start: 3/20/2011 12:45 AM
Matthias Wjst, Munich

Welcome to the third major symposium on vitamin D and asthma at the AAAAI. Continue reading Handout text 2011 AAAAI Seminar San Francisco Vitamin D deficiency →

 

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Allergy, Vitamins

Once more: Calcium and IgE

Here comes the most striking connection between calcium and IgE that updates some earlier posts here

The fact that the regulation of intracellular Ca2+ concentration is different in various T-cell effectors may offer the opportunity to target key intermediates … to inhibit specifically the functions of one given T-cell subset. Continue reading Once more: Calcium and IgE →

 

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Allergy, Vitamins

Why FFQs don’t predict vitamin D status

Two recent studies used food frequency questionnaires to predict vitamin D status and later allergy (Devereux 2007 and Camargo 2007) probably the only two studies that seem to contradict the vitamin D hypothesis.
New research now reported at the ATS congress [Poster Board # A84] “Measurement of Vitamin D Levels Utilizing Laboratory and Dietary Recall Information from the Tennessee Children’s Respiratory Initiative” and published in Am J Respir Crit Care Med 181;2010:A1890 shows that FFQs don’t predict vitamin D status Continue reading Why FFQs don’t predict vitamin D status →

 

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Allergy, Vitamins

When will they ever learn?

A new abstract shows

Perinatal data for singleton children who were prescribed anti-asthmatic medication (n = 61 256) were compared with corresponding data for all singleton children born in Sweden … (n = 1 338 319). … Being the first-born child, maternal age above 44 yr, involuntary childlessness for more than 1 yr, maternal smoking during pregnancy, maternal diabetes mellitus of any kind, pre-eclampsia, caesarean section, and instrumental vaginal delivery were all associated with an increased prescription of anti-asthmatic medication during childhood. Continue reading When will they ever learn? →

 

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Allergy, Genetics, Vitamins

rs4711, uh rs7041

The first GWAS of human vitamin serum D level finds the most important SNPs:

In a genome-wide association study (GWAS) of 4,501 persons of European ancestry drawn from five cohorts, we identified single nucleotide polymorphisms (SNPs) in the gene encoding group-specific component (vitamin D binding) protein, GC, on chromosome 4q12-13 that were associated with 25(OH)D concentrations: rs2282679 (P=2.0 x 10â€"30), in LD with rs7041, a nonsynonymous SNP (D432E; P=4.1 x 10-22), and rs1155563 (P = 3.8 x 10â€"25).

Funny, rs7041 is the same variant Continue reading rs4711, uh rs7041 →

 

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