Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway
© Wjst et al. 2006
Received: 23 December 2005
Accepted: 06 April 2006
Published: 06 April 2006
The vitamin D prophylaxis of rickets in pregnant women and newborns may play a role in early allergic sensitization. We now asked if an already diseased population may have inherited genetic variants in the vitamin D turnover or signalling pathway.
Serum levels of calcidiol (25-OH-D3) and calcitriol (1,25-(OH)2-D3) were retrospectively assessed in 872 partipants of the German Asthma Family Study. 96 DNA single base variants in 13 different genes were genotyped with MALDI-TOF and a bead array system. At least one positive SNP with a TDT of p < 0.05 for asthma or total IgE and calcidiol or calcitriol was seen in IL10, GC, IL12B, CYP2R1, IL4R, and CYP24A1. Consistent strong genotypic association could not be observed. Haplotype association were found only for CYP24A1, the main calcidiol degrading enzyme, where a frequent 5-point-haplotype was associated with asthma (p = 0,00063), total IgE (p = 0,0014), calcidiol (p = 0,0043) and calcitriol (p = 0,0046).
Genetic analysis of biological pathways seem to be a promising approach where this may be a first entry point into effects of a polygenic inherited vitamin D sensitivity that may affect also other metabolic, immunological and cancerous diseases.
Asthma is a chronic inflammatory condition of the airways, variable airway obstruction and elevated serum IgE levels of unclear pathogenesis . A hypothesis relating early vitamin D supplementation and induction of later allergy has initially been postulated as the main cholecalciferol metabolite calcitriol may suppresses dendritic cell maturation and consecutive development of Th1 cells  which is now supported by in vitro, animal and human studies [3, 4].
The German Asthma Family Study collected affected sib pairs in 26 paediatric centres in Germany and Sweden for a two-stage genome-wide linkage scan [7, 8]. In these families at least two children were required with confirmed clinical asthma, while prematurity or low birth weight of the children were excluded, along with any other severe pulmonary disease. All affected children over age 3 had a history of at least 3 years of recurrent wheezing and with no other airway disease diagnosed. Unaffected siblings were also sampled if they were at least 6 years old and eligible for pulmonary function testing. Each study participant signed a consent form. All study methods were approved by the ethics commission of "Ärztekammer Nordrhein-Westfalen".
A complete pedigree of the family was drawn and information collected in a questionnaire. Participants were examined for several closely associated phenotypes. Pulmonary function tests were performed by forced flow volume tests and bronchial challenge was done by methacholine (discontinued in the second stage of the study) as reported earlier [7, 8].
Total IgE was determined with an ELISA (Pharmacia Diagnostics, Uppsala, Sweden). 25-OH-D3 was determined with an enzymatic immunoassay (OCTEIA 25-Hydroxy Vitamin D kit, Immunodiagnostic Systems IDS, Frankfurt, Germany) that has a working range of 6–360 nmol/L, an intra-assay of 8% and inter-assay variation of 10% with a 100% specificity for 25-OH-D3 and 75% specificity for 25-OH-D2 according to the manufacturer. 1,25-OH2-D3 was determined by immunoextraction followed by an enzyme-immunoassay (OCTEIA 1,25-Hydroxy Vitamin D kit, Immunodiagnostic Systems IDS, Frankfurt, Germany) that has a working range of 6–500 pmol/L, a 100% specificity for 1,25-OH2-D3 and 0,009% specificity for 25-OH-D2. 25-OH-D3 values reported are the mean of a duplicate analysis while due to limited serum availability only single assays have been performed for 1,25-OH2-D3.
191 anonymized DNAs were selected randomly from the ECRHS II study  to fill in remaining slots on the genotyping plates. These DNA samples served as population-based controls to test if the parents of the famillies had different allele spectrum.
DNA preparation and genotyping
DNA was isolated from peripheral white blood cells using Qiamp (Qiagen, Germany) or Puregene isolation kits (Gentra Systems, Minneapolis, MN, USA).
Genes were selected as coding either for key enzymes in the vitamin D conversion pathway or being regulated by vitamin D metabolites . SNPs were being picked more or less randomly either for tagging haplotypes or being functional relevant . Most SNPs were genotyped using MALDI-TOF mass spectrometry of allele-specific primer extension products generated from amplified DNA sequences (MassARRAY, SEQUENOM Inc., San Diego, CA, USA). A few SNPs were also genotyped at Illumina (San Diego CA, USA) by use of the Sentrix bead arrays. VDR  and IL4R  SNP results have been published earlier and are reanalysed here for the vitamin D levels. The following SNPs were analyzed (genotyping details upon request): rs3024498 (IL10), rs3024493 (IL10), rs1518111 (IL10), rs10000076 (IL10), rs1800872 (IL10), Il10-571CA (IL10), rs1800895 (IL10), rs1800894 (IL10), rs1800896 (IL10), rs1800893 (IL10), rs705120 (GC), rs222040 (GC), rs7041 (GC), rs4752 (GC), rs222011 (GC), rs221999 (GC), rs6811536 (SPP1), rs4754 (SPP1), rs1042714 (ADRB2), rs1800888 (ADRB2), rs1368439 (IL12B), rs3212227 (IL12B), rs2853697 (IL12B), rs3213119 (IL12B), rs2853696 (IL12B), rs2853694 (IL12B), rs2288831 (IL12B), rs3213096 (IL12B), rs2569254 (IL12B), rs3181216 (IL12B), rs3212220 (IL12B), rs3212218 (IL12B), rs1433048 (IL12B), rs2546890 (IL12B), rs3132299 (RXRA), rs877954 (RXRA), rs1045570 (RXRA), rs10500804 (CYP2R1), rs1562902 (CYP2R1), rs10766197 (CYP2R1), rs2853563 (VDR), rs731236 (VDR), rs7975232 (VDR), rs1544410 (VDR), rs2239185 (VDR), rs987849 (VDR), rs1540339 (VDR), rs3819545 (VDR), rs3782905 (VDR), rs2239186 (VDR), rs2228570 (VDR), rs1989969 (VDR), rs2853564 (VDR), hCV2880804 (VDR), rs238532 (CYP27B1), rs2072052 (CYP27B1), rs1048691 (CYP27B1), rs4646537 (CYP27B1), rs4646536 (CYP27B1), rs8176345 (CYP24A1), rs703842 (CYP27B1), I50V (IL4R), rs2234897 (IL4R), rs1805011 (IL4R), C406R (IL4R), rs1805015 (IL4R), Q551R (IL4R), rs1805016 (IL4R), rs10000306 (CARD15), rs2076753 (CARD15), rs2066842 (CARD15), rs2066843 (CARD15), rs2076756 (CARD15), rs10000331 (CARD15), rs3135499 (CARD15), rs3135500 (CARD15), rs375947 (IL12RB1), rs447009 (IL12RB1), rs436857 (IL12RB1), rs2045387 (IL12RB1), rs8118441 (CYP24A1), rs751089 (CYP24A1), rs6068816 (CYP24A1), rs4809958 (CYP24A1), rs2244719 (CYP24A1), rs2296241 (CYP24A1), rs17219266 (CYP24A1), rs6022999 (CYP24A1), rs17219315 (CYP24A1), rs11699278 (CYP24A1), rs2762942 (CYP24A1), rs2248137 (CYP24A1), rs2762943 (CYP24A1), rs2585427 (CYP24A1), rs2248359 (CYP24A1) and rs2426496 (CYP24A1).
Data handling and statistical analysis
Clinical data and genotypes were all transferred to a SQL 2000 database and checked for completeness, paternity, and Hardy-Weinberg equilibrium. Further analyses were performed using R 2.0 statistical software. Linkage disequilibrium was determined by Haploview  using the Gabriel method for block definition. TDT association for quantitative and qualitative traits was done with SIBPAIR  using the TDT option for qualitative and the Haseman-Elston regression for quantitative traits. Family-based haplotype association analysis was performed by FBAT  using a dominant model.
SNP information was obtained from dbSNP , Innate Immunity PGA  and UCSC genome browser . SNP selection was done with the help of Perlegen  and Hapmap  data. Sequence context annotation was done by SNPper , PUPA , TAMAL  and SNPPi ).
The total sample consisted of 947 individuals from 224 families where 872 serum measurements of 25-OH-D3, 876 1,25- OH2-D3 and 934 total IgE measurements could be performed. After exclusion of non-white families 903 individuals from 201 families remained under analysis with 812 assays of 25-OH-D3, 807 1,25- OH2-D3 and 903 total IgE.
Clinical characteristics of the included 210 families of the German Asthma Family
n/N or mean/s.d.
n/N or mean/s.d.
D.pter. (D1) > 0.5 kU/l
D.far. (D2) > 0.5 kU/l
grass(GX1) > 0.5 kU/l
birch (T3) > 0.5 kU/l
mean positive RASTs
mean RAST > 0.5 kU/l
The overall heritability index H2 for 25-OH-D3 was 80.3% while the H2 for 1,25-OH2-D3 was only 30.0% . There was neither an association of 25-OH-D3 and total IgE nor an association of 1,25-OH2-D3 and total IgE levels.
13 genes were selected for genotyping (IL10, GC, SPP, ADRB2, IL12B, RXRA, CYP2R1, VDR, CYP27B1, IL4R, CARD15, IL12RB1, CYP24A1) and could be successfully completed for 96 SNPs. 4 of these SNPs were not in Hardy-Weinberg equilibrium: rs221999 (GC, P = 0,0299), rs10500804 (CYP2R1, P = 0,0498), rs10766197 (CYP2R1, P = 0,0100) and rs2248359 (CYP24A1, P = 0,0299). SNP rs221999 was also not in Hardy-Weinberg equilibrium in controls. The population-based controls showed similar allele frequencies compared to the family samples except for SNPs rs4754, rs2288831 and rs3819545.
Transmission approach: TDT results of 30 from 96 tested SNPs in 210 families of the German Asthma Family Study. Shown are only SNPs with at least one TDT results of p < 0.05. The underlined 11 SNPs also appear in table 3.
Genomic position HG17
P log(25- OH-D3)
P log(1,25- OH2-D3)
Case-control approach: Multivariate regression results of 31 from 96 tested SNPs in 408 parents of the German Asthma Family Study adjusted for age, sex and month of examination. Shown are only SNPs with at least one p < 0.05 for heterocygotes and homocygote carriers of the minor allele. The underlined 11 SNPs also appear in table 2.
P log(25-OH- D3)
CYP24A1 haplotype transmission results in 213 families of the German Asthma Family Study. Haplotype was formed from all SNPs with p < 0.05 in the TDT (table 2).
We have shown that serum 25-OH-D3 (calcidiol) levels -although highly influenced by environmental sunlight exposure- is a heritable trait in asthma families. In contrast, a major genetic influence on 1,25-OH2-D3 (calcitriol) levels could not be found, a finding that requires replication in further family and population-based studies.
The reason for this discrepancy is not fully clear as the conversion of 25-OH-D3 to 1,25-OH2-D3 is closely regulated by a direct feedback loop. It is generally agreed, however, that 25-OH-D3 reflects best the current vitamin D status . Unfortunately standardized reference values for this age group are not available but values for 25-OH-D3 in children seem to be in the upper normal range . An explanation therefore could be that a delayed downstream metabolism is leading to an (unintended) afflux or -also possible- that an increased peripheral demand needs a larger reservoir.
The associated candidate genes are of particular interest. CYP24A1 is the major enzyme of the calcitriol degradation pathway that showed nearly 100-fold increase after vitamin D treatment of rats . Previous studies also suggest that CYP24A1 null mice cannot clear calcitriol efficiently  which would support the above mentioned afflux hypothesis. An alternative splicing variant in CYP24A1 has been described recently  leading to a truncated and catalytically dysfunctional protein while it is unclear if any of our tested SNPs will have functional relationship to this protein variant. Dark skinned Asian Indians seem to have increased 24-hydroxylase activity compared to white skinned Caucasians  whereas both skin colour and metabolic capacity seem to be adapted to less sun light exposure in Caucasians.
The evidence that the human CYP2R1 is a key vitamin D 25-hydoxylase is rather new  where the identity of the hepatic 25-hydroxylase has remained unclear for several decades. At least six CYPs can catalyze this step where the most viable candidates are CYP27A1 and CYP2R1  with the renal enzyme responsible for 1-α-hydroxylation being CYP27B1. A loss of function mutation in CYP2R1 has also been described  and deserves further testing.
Variants in CYP2R1, CYP27B1 and CYP24A1 or other genes in the metabolic pathway of vitamin D have not been tested so far with asthma or allergy but several of the VDR-controlled genes tested here already have been associated with asthma and allergy. These include IL12B [35–37], IL12RB [38, 39], IL10 , VDR [41, 42, 12], GC , ADRB2 , CARD15  and IL4R .
Of these, IL12B is a particular interesting cytokines. Macrophage engulfed microorganism are leading to IL12p70 production, a heterodimer of IL12p40 (IL12B) and IL12p35 (IL12A), which is a primary inducer of Th1 cell development and a critical factor in the development of allergy . Also IL10 seems to be important where production in circulating T cells from atopic asthmatics is maximally stimulated ; allergen specific IL10 producing T regulatory cells can inhibit allergen specific effector cells and represent an important line of defense in the allergic reaction . Functional variants in these genes leading to human disease are not known so far.
The many positive but weak associations represent a common dilemma in complex disease. In asthma more than 75 genes have now been claimed to be associated  but none of them has been shown to contribute to risk in all populations studied . Obviously there are only small genetic effects and a large heterogeneity; sometimes there is unidentified population stratification and there might be phenotyping and genotyping errors. Most likely, however, not the "center" SNPs have been choosen . The current pathway based approach seems to be an alternative in particular when an environmental trait can be included. It is likely that some of the genes identified here are acting in concert to determine the overall vitamin D sensitivity.
Besides increasing sample size and testing additional populations, further work may concentrate on monitoring vitamin D supplementation by immunological readouts and the identification of contributing functional genetic elements. The present rediscovery of a genetic vitamin D sensitivity  may be an important step in allergy induction and also surmount many other diseases including type 1 diabetes, osteoporosis, tuberculosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, and prostate cancer where adequate vitamin D support has been found to be beneficial.
single nucleotide polymorphism
- D3 :
cholecalciferol, vitamin D
- 25-OH-D3 :
- 1,25-OH2-D3 :
cytochrome P450, family 24, subfamily A, polypeptide 1
nuclear vitamin D receptor
interleukin 12 B (cytotoxic lymphocyte maturation factor 2, p40)
retinoid X receptor α
interleukin 4 receptor
ß2 adrenergic receptor
interleukin 12 receptor, ß1
group-specific component (vitamin D binding protein)
cytochrome P450, family 2, subfamily R, polypeptide 1
caspase recruitment domain family, member 15 (NOD2)
secreted phosphoprotein 1, osteopontin (OPN, ETA-1, BNSP,...)
cytochrome P450, family 27, subfamily B, polypeptide 1
We thank the participating families and clinical centers for their help: R. Nickel, K. Beyer, R. Kehrt, U.Wahn (Berlin), K. Richter, H. Janiki, R. Joerres, H. Magnussen (Grosshansdorf), I. M. Sandberg, L. Lindell, N.I.M. Kjellman (Linkoeping), C. Frye, G. Woehlke, I. Meyer, O. Manuwald (Erfurt), A. Demirsoy, M. Griese, D. Reinhardt (München), G. Oepen, A. Martin, A. von Berg, D. Berdel (Wesel), Y. Guesewell, M. Gappa, H. von der Hardt (Hannover), J. Tuecke, F. Riedel (Bochum), M. Boehle, G. Kusenbach [+], H. Jellouschek, M. Barker, G. Heimann (Aachen), S. van Koningsbruggen, E. Rietschel (Köln), P. Schoberth (Köln), G. Damm, R. Szczepanski, T. Lob-Corzilius (Osnabrück), L. Schmid, W. Dorsch (München), M. Skiba, C.Seidel, M. Silbermann (Berlin), A. Schuster (Düsseldorf), J. Seidenberg (Oldenburg), W. Leupold, J. Kelber (Dresden), W. Wahlen (Homburg), F. Friedrichs, K. Zima (Aachen), P. Wolff (Pfullendorf), D. Bulle (Ravensburg), W. Rebien, A.Keller (Hamburg) and M. Tiedgen (Hamburg). M. Hoeltzenbein organized the first part of the study, G. Schlenvoigt and L.Jaeger did the IgE determination and G. Fischer supervised data entry. T. Illig (former T.Immervoll), P. Lichtner and J. Heinrich supported the project during various stages; B. Wunderlich for excellent laboratory work during set up of the family study. We wish to thank also Amelie Elsaesser for programming the Jonkheere-Terpstra trend test and Michelle Emfinger for proof-reading of the manuscript.
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