help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on July 28, 2004, doi:10.1164/rccm.200403-412OC
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200403-412OCv1
170/9/967    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Poon, A. H.
Right arrow Articles by Hudson, T. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Poon, A. H.
Right arrow Articles by Hudson, T. J.
American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 967-973, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200403-412OC

Original Article

Association of Vitamin D Receptor Genetic Variants with Susceptibility to Asthma and Atopy

Audrey H. Poon, Catherine Laprise, Mathieu Lemire, Alexandre Montpetit, Donna Sinnett, Erwin Schurr and Thomas J. Hudson

McGill Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montreal; Université du Québec à Chicoutimi; Community Genomic Medicine Centre, University of Montreal, Chicoutimi Hospital, Chicoutimi; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada

Correspondence and requests for reprints should be addressed to Thomas J. Hudson, M.D., McGill University and Genome Quebec Innovation Centre, 740 Penfield Avenue, Room 7105, Montreal, PQ, H3A 1A4 Canada. E-mail: tom.hudson{at}mcgill.ca


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Genome scans for asthma have identified suggestive or significant linkages on 17 different chromosomes, including chromosome 12, region q13–23, housing the vitamin D receptor (VDR) gene. Through interaction with VDR, 1,25-dihydroxyvitamin D3 mediates numerous biological activities, such as regulation of helper T-cell development and subsequent cytokine secretion profiles. Variants of the VDR have been found to be associated with immune-mediated diseases that are characterized by an imbalance in helper T-cell development, such as Crohn's disease and tuberculosis. The VDR, hence, is a good candidate to be investigated for association with asthma, which is characterized by enhanced helper T-cell type 2 activity. Here, we examined VDR genetic variants in an asthma family-based cohort from Quebec. We report six variants to be strongly associated with asthma and four with atopy (0.0005 <= p <= 0.05). Analysis of the linkage disequilibrium pattern and haplotypes also revealed significant association with both phenotypes (0.0004 <= p <= 0.01). The findings have been replicated by another research team in a second but not in a third cohort. These results identify VDR variants as genetic risk factors for asthma/atopy and implicate a non-human leukocyte antigen immunoregulatory molecule in the pathogenesis of asthma and atopy.

Key Words: genetic predisposition • polymorphism • vitamin D receptor

The interaction of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) with the vitamin D receptor (VDR) modulates many biological activities of the neural, immune, and endocrine systems, including calcium and phosphorous homeostasis, apoptosis, and cell differentiation (reviewed in 1, 2). Once bound to 1,25(OH)2D3, VDR binds to specific DNA sequence elements in vitamin D-responsive genes, termed VDR response elements, to influence the rate of RNA polymerase II–mediated transcription (3–5). Vitamin D–dependent rickets and osteomalacia are classic manifestations of vitamin D deficiency (OMIM 601769).

Abnormalities related to the pleiotropic functions of VDR underlie the pathogenesis of several diseases. Table E1 in the online supplement summarizes results of association studies of four VDR variants (FokI, BsmI, ApaI, and TaqI) with serum osteocalcin levels, bone mineral density, prostate cancer, hyperparathyroidism, insulin-dependent diabetes mellitus, Crohn's disease, leprosy, tuberculosis, and acquired immunodeficiency syndrome (6–13). Among the biological effects of ligand-bound VDR, its influence on Th cell development (14) is of particular interest for diseases involving the immune system. In the mouse, 1,25(OH)2D3 has been shown to inhibit Th1 development and interferon-{gamma} production and to stimulate Th2 cell development and the production of interleukin-4 and interleukin-10 (15–17). In humans, although vitamin D has been shown to inhibit Th1 responses, Th2 enhancement has not been demonstrated (18). However, several of the associated phenotypes in Table E1 are characterized by an imbalance in Th1/Th2 cell activity, for example, acquired immunodeficiency syndrome progression (19, 20), tuberculoid leprosy (12), lepromatous leprosy (12), Crohn's disease (11), and tuberculosis (13, 21–23). Because of the well-known immunoregulatory role of VDR and its known association with several immune-mediated diseases, VDR presents itself to be a candidate gene for asthma susceptibility. Because asthma is characterized by a shift of Th cell responses toward type 2, we hypothesized that VDR may function as a regulator of asthma and atopy susceptibility. We investigated this hypothesis through the characterization of genetic variants of VDR in an asthma family-based cohort from northeastern Quebec. Some of the results of this study have been previously reported in the form of an abstract (24).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Cohort Description
Families are from the Saguenay-Lac-St-Jean region of northeastern Quebec, Canada. Probands were recruited if they fulfilled at least two of the following three criteria: (1) a minimum of three clinic visits for acute asthma within 1 year, (2) two or more asthma-related hospital admissions within 1 year, or (3) steroid dependency, as defined by either 6 months of oral or 1 year of inhaled corticosteroid use. Families were included for study if at least one parent was available for phenotypic assessment, at least one parent was unaffected, and all four grandparents were of French Canadian origin. When possible, grandparents and other relatives were also recruited to the study.

After recruitment of probands and their family members, the affection status of all study participants was determined by clinical evaluation and the completion of a standard respiratory questionnaire that was modified to include questions about asthma and atopy severity, family history of asthma and/or atopy, age of onset, and the presence of other respiratory failure diagnoses (25). In 41 cases, the age of onset described by parents was below 2 years; because of the uncertainty of this information, we used a default class of 2 years. We defined participants as having asthma if (1) a reported history of asthma (questionnaire based) and a history of physician-diagnosed asthma (past/current) were available or (2) confirmation by a positive methacholine provocation test was done only on subjects older than 12 years of age (see online supplement methods section for a description of the clinical tests performed). Subjects were deemed atopic if they had at least one positive response (wheal diameter >= 3 mm at 10 minutes) to skin-prick tests. The family participation rate was approximately 60%, and all subjects gave informed consent. A total of 223 independent families (1,139 individuals) with family size ranging from 3 to 17 and the number of affected family members (including probands) ranging from 1 to 10 were analyzed.

Single Nucleotide Polymorphism Selection and Genotyping
We investigated 93 kb of genomic DNA harboring VDR, spanning from chromosome 12 position 46586093 to 46492363 on build 34 hg16 genome assembly released by the National Center for Biotechnology Information. An initial panel of 20 single nucleotide polymorphisms (SNPs) was selected from public databases (National Center for Biotechnology Information and the SNP Consortium) based on (1) the location in the gene, (2) relative distances to each other, (3) compatibility with the genotyping methods employed, which is dependent on types of base change and flanking sequences, and (4) the known associations with diseases. A final collection of 12 SNPs was tested for associations. The remaining eight SNPs were discarded because of low information content or unreliable genotyping data. SNPs described in this report are cited using their reference SNP identifier from the National Center for Biotechnology Information database, except for VDR SNPs having commonly used aliases (ApaI, BsmI, FokI, and TaqI).

SNP genotyping was performed using SNPstream UltraHigh Throughput Genotyping System (Orchid Biosciences, Princeton, NJ) (26). All protocols and reaction conditions are available in this journal's online supplement (see Table E3 in the online data supplement for oligonucleotides used in genotyping and Table E4 for those used in sequencing).

Statistical Analysis
Hardy-Weinberg equilibrium was tested in a subset of DNA samples using MERLIN (27). These samples correspond to parents of probands whose DNA are available. These samples are independent so that unbiased estimates of Hardy-Weinberg equilibrium for the variants can be obtained.

Allele distribution patterns were assessed by the family-based association test (FBAT, version 1.4) (28, 29). This software uses an empirical variance–covariance estimator to account for the possibility of nonindependent allelic transmission to affected sibs (30). Asthma and atopy phenotypes were tested separately under an additive genetic model.

Associations between VDR variants were assessed. Strength of linkage disequilibrium (LD) between pairs of SNPs was measured as D' (31), using Haploview (http://www.broad.mit.edu/personal/jcbarret/haplo/documentation.php). Regions of strongly associated markers (LD blocks) were inferred and modified from the definition proposed by Gabriel and colleagues (32) as implemented in Haploview. Specifically, the parameter confidence interval minima for strong LD was relaxed from the definition of Gabriel and colleagues, and the upper confidence level was set from 0.98 to 0.90.

Haplotype-specific associations were investigated using the "hbat" command implemented in FBAT (version 1.4) (28, 29). An empirical variance estimator was used (30). Asthma and atopy phenotypes were tested separately under an additive genetic model.

VDR Resequencing
The promoter region and all exons were sequenced to detect novel coding SNPs using ABI PRISM BigDye Terminator (version 2) kit on an ABI 3,700 DNA sequencer (Applied BiosSystems, Foster City, CA) as described elsewhere (33). The protocols, reaction conditions, and primers used are described in this article's online data supplement and at http://www.genomequebec.mcgill.ca/VDR.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Clinical characteristics were obtained for 1,139 individuals (Table 1). At the time of recruitment, study participants were aged 3 to 88 years. There were 570 subjects with asthma, of which 223 are probands. The median age of onset for cases and their affected siblings is 5 years (2–46 years). We note that 419 of the 570 subjects (74%) with asthma and 218 of the 569 subjects (38%) without asthma were atopic. The sex ratio (male:female) for probands is 1:1.2, for affected family members is 1:1.4, and for unaffected family members is 1:1.2. Compared with their affected family members, the probands with asthma had higher immunoglobulin E levels and coexistence of atopy.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Clinical characteristics of subjects

 
Genetic Analysis of the VDR Locus
A final panel of 12 SNPs was used from an initial collection of 20 obtained from public databases for VDR characterization and association testing (see Table E2 in the online supplement for SNPs characteristics). Of the eight discarded SNPs, seven are uninformative, with minor allele frequencies of less than 0.025, and one SNP failed the genotyping assay. Among the 12-SNP panel are four widely studied variants: FokI C>T (rs2228570) (13, 22, 34), ApaI A>C (rs7975232) (35, 36), BsmI G>A (rs1544410) (7, 37–40), and TaqI C>T (rs731236) (13, 21, 23). Of the 12 SNPs, FokI and TaqI reside in the coding region, whereas the remaining 10 SNPs are located in noncoding regions, between 4.8 kb upstream of the translation start site and 32 kb downstream of exon 9 (Figure 1A).



View larger version (16K):
[in this window]
[in a new window]
  		Figure 1. (A) Genomic organization of VDR and (B) association plot between VDR variants and the two phenotypes: asthma and atopy. Exons are represented by black boxes connected by a straight line representing introns and 3' and 5' noncoding regions. Locations of exons 1a–1f are described elsewhere (54). Positions and names of the 12 single nucleotide polymorphisms (SNPs) analyzed are represented by arrows below the gene structure. (B) Significance of association given as –log10 (p value) is plotted against relative SNP position given in kilobases. Three levels of significance (p = 0.05, p = 0.005, and p = 0.0005) are indicated by straight lines drawn across the plot. Association with asthma is depicted by blue diamonds and atopy by pink squares. Chromosome positions are based on the July 2003 freeze of the University of California Santa Cruz genome browser (http://genome.ucsc.edu/).

 
Of the 12 SNPs, only rs2239182 gave a significant deviation from Hardy-Weinberg equilibrium (p = 0.039); given the number of SNPs tested, this deviation can be expected to occur by chance alone.

Family-based Association Analysis of VDR with Asthma and Atopy
The 12 SNPs were tested individually for association with asthma and atopy (Figure 1B). In the absence of a priori evidence for transmission models at this locus, we tested allelic associations under an additive genetic model. Six alleles (rs3782905C, rs1540339A, rs2239185C, rs2239185G, BsmIG, and TaqIT) and four alleles (rs2239185C, BsmIG, ApaIC, and TaqIT) were significantly overtransmitted to offspring with asthma and offspring that were atopic (p < 0.05), respectively.

IgE data were collected and analyzed both as quantitative and dichotomous traits, independent of atopy status. In a dichotomous trait model, subjects can be classified as either high or low responders according to their IgE levels. In this cohort, log (IgE) values were normally distributed, and a cut-off point of 100 mg/L divided the subjects into low (two-thirds of participants) and high (one-third) responders. Under an additive model, three alleles (rs2239185C, ApaIC, and TaqIT) are associated with being a high responder at 0.006 less than p less than 0.02. The alleles associated with high IgE are the ones also seen associated with asthma and atopy. As a quantitative trait, the phenotype investigated is high IgE responder. When regressed on age and sex, two alleles (rs2239185C and TaqIT) are associated at p of less than 0.005.

Intragenic LD Structure of VDR
Associations among the 12 SNPs were assessed by measuring pairwise LD using D' (Figure 2A). The two flanking upstream SNPs (rs2238136, FokI) and the most downstream SNP (rs757344) are not in significant LD (D' <= 0.30) with any other marker tested. Thus, the LD of the two central VDR blocks is unlikely to have extended to these SNPs, and they are likely to be outside the core VDR blocks. The remaining nine SNPs are distributed within a 28-kb region, between intron 2 and exon 9 of VDR, and are in strong LD (D' >= 0.8) with at least one additional SNP (80% of the pairwise LDs are D' >= 0.80). Of the 36 pairwise LDs calculated between these nine SNPs, eight D's are low (0.09 <= D' <= 0.73), and they further separate the region into two blocks of tightly associated SNPs. We relaxed Gabriel's criteria for haplotype block definition: the outermost marker pair was required to be in LD with an upper confidence limit that exceeds 0.90 and a lower confidence limit that exceeds 0.7. Block 1 locates toward the 3' end of VDR and consists of SNPs TaqI, ApaI, BsmI, and rs2239185, whereas block 2 locates toward the 5' end of VDR and comprises SNPs rs2239182, rs2107301, rs1540339, rs2239179, and rs3782905. Block 1 spans approximately 5.8 kb, and block 2 spans roughly 8.4 kb. The two blocks, which are separated by 10.8 kb, show moderate LD between blocks (D' = 0.77, data not shown). Three common haplotypes (frequency > 0.1) are observed within block 1: haplotypes TCGC (frequency = 0.45), CAAT (0.39), and TAGT (0.15); within block 2, four common haplotypes are observed: haplotypes GCGGG (0.29), ATAAC (0.27), ACGAC (0.16), and ACAAC (0.11). Three common haplotypes of the nine SNPs that extended across the two blocks were observed: (3' to 5' SNPs) CAATGCGGG, TCGCATAAC, and TCGCACGAC (Figure 2B).



View larger version (99K):
[in this window]
[in a new window]
  		Figure 2. (A) Pairwise linkage disequilibrium (LD) pattern of VDR measured by D' and (B) the common haplotypes of the 28-kb LD region. The location of each tested SNP along the chromosome is indicated on top. The number in each diamond indicates the magnitude of LD (D' x 10–2) between respective pairs of SNPs. For example, the pairwise D' for SNPs rs1540339 and rs2107301 is 0.96. Squares without D' written on them represent perfect LD (D' = 1.0). The strength of LD is depicted by progression of color, for all D' with LOD of more than two, the color moves from red to light blue as D' runs from 1 to 0; for D' with LOD of less than two, it is represented by white. (B) Common haplotypes of the two blocks are listed with their frequencies within parentheses. Thick lines joining haplotypes from each block represent combined haplotypes with a frequency of more than 0.1 and thin lines for a frequency of less than 0.01.

 
Haplotype-specific Association Analysis
FBAT results and LD patterns indicate that associations between VDR variants and asthma/atopy occur across the two blocks within a 28-kb region. To characterize haplotype transmission in this region, 10 common haplotypes previously inferred using Haploview were assessed for nonrandom transmissions using FBAT, version 1.4 (28, 29) (Figure 3). For asthma, 5 of the 10 common haplotypes show nonrandom distribution of haplotypes. In block 1, the nonrandomly transmitted haplotypes were TCGC (overtransmitted, p = 0.007) and CAAT (p = 0.02, undertransmitted). In block 2, haplotype ATAAC was overtransmitted (p = 0.004). In the combined block, haplotype TCGCATAAC was overtransmitted (p = 0.005), and haplotype CAATGCGGG was undertransmitted (p = 0.008).



View larger version (32K):
[in this window]
[in a new window]
  		Figure 3. Haplotype transmission patterns for (A) asthma and (B) atopy. E(S) = expected FBAT statistic; S = FBAT statistic; Z = Z score.

 
For atopy, 3 of the 10 common haplotypes show nonrandom distribution of haplotypes. In block 1, haplotype TCGC was overtransmitted (p = 0.0004). In the combined block, haplotype TCGCATAAC was overtransmitted (p = 0.01), and haplotype CAATGCGGG was undertransmitted (p = 0.03).

VDR Resequencing
To exclude the presence of a coding VDR polymorphism that was not seen in previous analyses of VDR, we sequenced the proximal promoter region housing the six alternatively spliced exons 1 (1a–1f), exons 2–9 and intron/exon boundaries of VDR locus from genomic DNA obtained from 24 cases; the selection was based on their haplotype diversity. A total of 15 SNPs were identified, including FokI, ApaI, and TaqI. The remaining 12 SNPs were only seen in noncoding regions; these SNPs are listed in Table E5 in the online supplement.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Using a family-based cohort, we observed association between common allelic variants of VDR and phenotypes of asthma and atopy in a French-Canadian founder population. Six SNPs, in introns 2, 3, 6, and 8 and exon 9 of VDR spanning approximately 28 kb of genomic sequence, were associated with asthma. These markers fall into two haplotype blocks, with very substantial LD among markers of both blocks. With our present LD pattern obtained from 12 SNPs, the precise boundaries of the two blocks are unknown, and additional SNPs might be needed to represent better the LD pattern at this locus. Nevertheless, significant nonrandom segregation of marker haplotypes spanning this 28-kb region of VDR further confirmed association of this region with asthma and atopy.

Interestingly, the same 28-kb haplotypes spanning both core VDR LD blocks are associated with asthma and atopy. If considering the blocks individually, the same haplotypes show the same direction of over or undertransmission, but some of these haplotypes do not reach statistical significance for association with one of the phenotypes. At this point, the current level of information is not sufficient for us to assign a greater likelihood of association for any of the two haplotype blocks to either of the phenotypes. Given the high clinical correlation between both phenotypes and the similarity of their haplotype associations, we believe it likely that there is one or more functional variants at the 3' end of the VDR locus responsible for susceptibility to both asthma and atopy.

In a separate association study of VDR variants described in a companion article (Raby and colleagues) (41), association with asthma was evaluated in two study populations: a family-based cohort and a case control cohort. The family cohort is part of the Childhood Asthma Management Program (CAMP) study (42, 43), with families being recruited from eight centers across North America (www.jhucct.com/camp/open/sites.htm). The case control cohort is part of the Nurses' Health Study (44) and included only women.

In the Nurses' Health Study cohort, four of the five SNPs tested are associated with asthma (Table 2). Of these four SNPs, three are with the same alleles found to be associated in the Quebec cohort. For the remaining associated SNP ApaI, the C allele was overtransmitted in both the Quebec and the Nurses' Health Study cohorts but only reaches the 95% significance level in the Nurses' Health Study cohort. In the Quebec cohort, SNP ApaI showed significant association with the atopy phenotype. SNP ApaI is the only tested SNP being associated with asthma in the CAMP cohort, but the distribution pattern of its alleles was different from both the Quebec and the Nurses' Health Study cohorts: allele A was overtransmitted in the CAMP cohort and was undertransmitted in the other two cohorts. Hence, the same VDR alleles were observed to be associated with asthma in two of three study populations.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Comparison of associations observed in the quebec, childhood asthma management program, and nurses' health study cohorts

 
We note that the CAMP study recruited patients with median age of onset of three (boys) and four (girls) (ranging from 2 to 6 years), comparable to that of the Quebec probands (5 years, with a wide range of 2 to 46 years). However, the median age of recruitment of the Quebec probands was older (16 years), which correlates with a longer duration of disease and/or recurrence in adulthood. The Nurses' Health Study cohort includes female nurses with asthma present in adulthood (44). The lack of VDR associations in the CAMP study may be explained by differences in phenotypes related to age or duration of disease and/or sample size issues (45, 46).

By sequencing the promoter, exons, and their surrounding regions, we excluded novel missense polymorphisms that could have been responsible for the observed associations. Of the SNPs associated with asthma/atopy, only TaqI resides in the coding region (exon 9), and the polymorphism does not result in an amino acid change. TaqI has been shown to be associated with many metabolic and immune-mediated diseases. The T allele, which is associated with asthma and atopy in our cohort, is also associated with tuberculosis (13, 21–23), chronic hepatitis B infection (23), lepromatous leprosy (12) and type 1 diabetes in Eastern Europeans (47) and South Indians (39). The C allele, on the other hand, is associated with Crohn's disease (11), tuberculoid leprosy (12), and type 1 diabetes in Germans (48). The functional consequence of this polymorphism is not fully understood. In lymphocytes, the TaqIC allele is 30% less abundant (49), whereas in pituitary adenomas and transfected green monkey kidney (COS-7) cells, the same allele is associated with higher mRNA levels (7, 37).

Similar to variant TaqI, SNPs ApaI and BsmI have been widely studied and have been shown to be associated with many diseases. Alleles BsmIG and ApaIC are associated with asthma/atopy in this cohort; the same alleles are also associated with high bone mass density (7) and sporadic hyperparathyroidism in females (37), whereas allele BsmIA is associated with fast acquired immunodeficiency syndrome progression (6) and type 1 diabetes risk per se and acute-onset type 1 diabetes (40).

Given that association of asthma with VDR involves variants from intron 2 to exon 9, spanning approximately 28 kb and that no SNPs giving rise to an amino aid change were found, it is possible that the functional variant that confers susceptibility to asthma is a regulatory SNP (50), located in a VDR intron. Because VDR is a known immunoregulatory switch molecule and many of the associated phenotypes have the characteristics of Th1/Th2 imbalance, the mechanism of VDR in immune-mediated diseases may involve varying levels of VDR in immune cells on stimuli.

In summary, we identified a strong association between genetic variants at the VDR locus and asthma/atopy in a Quebec cohort. Along with other known asthma risk genes identified such as ADAM33 (51), TNFA (52), RANTES (53), and GPRA (54), the addition of VDR involvement in the understanding of asthma/atopy pathogenesis will shed light for better control and treatment.


   Acknowledgments
 
The authors thank all families for their enthusiastic participation in this study. They also thank D. Gagné and P. Bégin for their invaluable participation in the ascertainment of the subjects and Y. Renaud and C. Darmond-Zwaig for technical assistance.


   FOOTNOTES
 
Supported by Fonds pour la recherche en santé du Québec (C.L.), a Clinician-scientist Award in Translational Research from the Burroughs Wellcome Fund (T.J.H.), the Canadian Institutes of Health Research (T.J.H.), and the Canadian Genetic Diseases Network.

A.H.P. and C.L. contributed equally to this work.

This article is a companion article to Raby BA, Lazarus R, Silverman EK, Lake S, Lange C, Wjst M, Weiss ST. Association of Vitamin D Receptor Gene Polymorphisms with Childhood and Adult Asthma. The article will appear in the November 15, 2004 issue of the Journal. The published-ahead-of-print version of the article may be accessed now at http://dx.doi.org/10.1164/rccm.200404-447OC

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Conflict of Interest Statement: A.H.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; E.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.J.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A report of invention is being reviewed by McGill University Office of Technology Transfer.

Received in original form March 25, 2004; accepted in final form July 27, 2004


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Holick MF. Vitamin D: A millennium perspective. J Cell Biochem 2003;88:296–307.[CrossRef][Medline]
  2. Lemire JM. Immunomodulatory actions of 1,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol 1995;53:599–602.[CrossRef][Medline]
  3. Haussler MR, Whitfield GK, Haussler CA, Hsieh JC, Thompson PD, Selznick SH, Dominguez CE, Jurutka PW. The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res 1998;13:325–349.[CrossRef][Medline]
  4. Haussler MR, Haussler CA, Jurutka PW, Thompson PD, Hsieh JC, Remus LS, Selznick SH, Whitfield GK. The vitamin D hormone and its nuclear receptor: molecular actions and disease states. J Endocrinol 1997;154:S57–S73.[Abstract]
  5. Kraichely DM, MacDonald PN. Transcriptional activation through the vitamin D receptor in osteoblasts. Front Biosci 1998;3:D821–D833.
  6. Barber Y, Rubio C, Fernandez E, Rubio M, Fibla J. Host genetic background at CCR5 chemokine receptor and vitamin D receptor loci and human immunodeficiency virus (HIV) type 1 disease progression among HIV-seropositive injection drug users. J Infect Dis 2001;184:1279–1288.[CrossRef][Medline]
  7. Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA. Prediction of bone density from vitamin D receptor alleles. Nature 1994;367:284–287.[CrossRef][Medline]
  8. Sainz J, Van Tornout JM, Loro ML, Sayre J, Roe TF, Gilsanz V. Vitamin D-receptor gene polymorphisms and bone density in prepubertal American girls of Mexican descent. N Engl J Med 1997;337:77–82.[Abstract/Free Full Text]
  9. Morrison NA, Yeoman R, Kelly PJ, Eisman JA. Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphism and circulating osteocalcin. Proc Natl Acad Sci USA 1992;89:6665–6669.[Abstract/Free Full Text]
  10. Taylor JA, Hirvonen A, Watson M, Pittman G, Mohler JL, Bell DA. Association of prostate cancer with vitamin D receptor gene polymorphism. Cancer Res 1996;56:4108–4110.[Abstract/Free Full Text]
  11. Simmons JD, Mullighan C, Welsh KI, Jewell DP. Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility. Gut 2000;47:211–214.[Abstract/Free Full Text]
  12. Roy S, Frodsham A, Saha B, Hazra SK, Mascie-Taylor CG, Hill AV. Association of vitamin D receptor genotype with leprosy type. J Infect Dis 1999;179:187–191.[CrossRef][Medline]
  13. Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, Wright D, Latif M, Davidson RN. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 2000;355:618–621.[CrossRef][Medline]
  14. Lemire JM, Archer DC, Beck L, Spiegelberg HL. Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr 1995;125:1704S–1708S.
  15. Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O'Garra A. 1Alpha,25-dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol 2001;167:4974–4980.[Abstract/Free Full Text]
  16. Cantorna MT, Woodward WD, Hayes CE, DeLuca HF. 1,25-Dihydroxy-vitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4. J Immunol 1998;160:5314–5319.[Abstract/Free Full Text]
  17. Cantorna MT, Humpal-Winter J, DeLuca HF. In vivo upregulation of interleukin-4 is one mechanism underlying the immunoregulatory effects of 1,25-dihydroxyvitamin D(3). Arch Biochem Biophys 2000;377:135–138.[CrossRef][Medline]
  18. Alroy I, Towers TL, Freedman LP. Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. Mol Cell Biol 1995;15:5789–5799.[Abstract]
  19. Becker Y. The changes in the T helper 1 (Th1) and T helper 2 (Th2) cytokine balance during HIV-1 infection are indicative of an allergic response to viral proteins that may be reversed by Th2 cytokine inhibitors and immune response modifiers–a review and hypothesis. Virus Genes 2004;28:5–18.[CrossRef][Medline]
  20. Ofori H, Jagodzinski PP. Increased in vitro replication of CC chemokine receptor 5-restricted human immunodeficiency virus type 1 primary isolates in Th2 lymphocytes may correlate with AIDS progression. Scand J Infect Dis 2004;36:46–51.[CrossRef][Medline]
  21. Selvaraj P, Narayanan PR, Reetha AM. Association of vitamin D receptor genotypes with the susceptibility to pulmonary tuberculosis in female patients & resistance in female contacts. Indian J Med Res 2000;111:172–179.[Medline]
  22. Liu W, Zhang CY, Wu XM, Tian L, Li CZ, Zhao QM, Zhang PH, Yang SM, Yang H, Zhang XT, et al. A case-control study on the vitamin D receptor gene polymorphisms and susceptibility to pulmonary tuberculosis. Zhonghua Liu Xing Bing Xue Za Zhi 2003;24:389–392.[Medline]
  23. Bellamy R, Ruwende C, Corrah T, McAdam KP, Thursz M, Whittle HC, Hill AV. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis 1999;179:721–724.[CrossRef][Medline]
  24. Poon A, Laprise C, Jimnez-Corona A, Palacios-Martinez M, Sifuentes-Osornio J, Ponce-de-Len A, Bodailla M, Kato M, Lemire M, Montpetit A, et al. Comparative genetic study of tuberculosis and asthma susceptibilities [abstract]. Am J Hum Genet 2003;73:S385.[CrossRef]
  25. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma: this official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986. Am Rev Respir Dis 1987;136:225–244.[Medline]
  26. Bell PA, Chaturvedi S, Gelfand CA, Huang CY, Kochersperger M, Kopla R, Modica F, Pohl M, Varde S, Zhao R, et al. SNPstream UHT: ultra-high throughput SNP genotyping for pharmacogenomics and drug discovery. Biotechniques 2002;Suppl:70–72, 74, 76, 77.
  27. Abecasis GR, Cherny SS, Cookson WO, Cardon LR. Merlin: rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002;30:97–101.[CrossRef][Medline]
  28. Laird NM, Horvath S, Xu X. Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000;19:S36–S42.
  29. Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST, Laird NM. Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol 2004;26:61–69.[CrossRef][Medline]
  30. Lake SL, Blacker D, Laird NM. Family-based tests of association in the presence of linkage. Am J Hum Genet 2000;67:1515–1525.[CrossRef][Medline]
  31. Lewontin RC. On measures of gametic disequilibrium. Genetics 1988;120:849–852.[Abstract/Free Full Text]
  32. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, et al. The structure of haplotype blocks in the human genome. Science 2002;296:2225–2229.[Abstract/Free Full Text]
  33. Engert JC, Vohl MC, Williams SM, Lepage P, Loredo-Osti JC, Faith J, Dore C, Renaud Y, Burtt NP, Villeneuve A, et al. 5' flanking variants of resistin are associated with obesity. Diabetes 2002;51:1629–1634.[Abstract/Free Full Text]
  34. Wong HL, Seow A, Arakawa K, Lee HP, Yu MC, Ingles SA. Vitamin D receptor start codon polymorphism and colorectal cancer risk: effect modification by dietary calcium and fat in Singapore Chinese. Carcinogenesis 2003;24:1091–1095.[Abstract/Free Full Text]
  35. Chang TJ, Lei HH, Yeh JI, Chiu KC, Lee KC, Chen MC, Tai TY, Chuang LM. Vitamin D receptor gene polymorphisms influence susceptibility to type 1 diabetes mellitus in the Taiwanese population. Clin Endocrinol 2000;52:575–580.[CrossRef][Medline]
  36. Simmons JD, Mullighan C, Welsh KI, Jewell DP. Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility. Gut 2000;47:211–214.
  37. Carling T, Rastad J, Akerstrom G, Westin G. Vitamin D receptor (VDR) and parathyroid hormone messenger ribonucleic acid levels correspond to polymorphic VDR alleles in human parathyroid tumors. J Clin Endocrinol Metab 1998;83:2255–2259.[Abstract/Free Full Text]
  38. Lorentzon M, Lorentzon R, Nordstrom P. Vitamin D receptor gene polymorphism is associated with birth height, growth to adolescence, and adult stature in healthy Caucasian men: a cross-sectional and longitudinal study. J Clin Endocrinol Metab 2000;85:1666–1670.[Abstract/Free Full Text]
  39. McDermott MF, Ramachandran A, Ogunkolade BW, Aganna E, Curtis D, Boucher BJ, Snehalatha C, Hitman GA. Allelic variation in the vitamin D receptor influences susceptibility to IDDM in Indian Asians. Diabetologia 1997;40:971–975.[CrossRef][Medline]
  40. Motohashi Y, Yamada S, Yanagawa T, Maruyama T, Suzuki R, Niino M, Fukazawa T, Kasuga A, Hirose H, Matsubara K, et al. Vitamin D receptor gene polymorphism affects onset pattern of type 1 diabetes. J Clin Endocrinol Metab 2003;88:3137–3140.[Abstract/Free Full Text]
  41. Raby BA, Lazarus R, Silverman EK, Lake S, Lange C, Wjst M, Weiss S. Association of vitamin D receptor gene polymorphisms with childhood and adult asthma. Am J Respir Crit Care Med (In press)
  42. Long-term effects of budesonide or nedocromil in children with asthma: the Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054–1063.[Abstract/Free Full Text]
  43. The Childhood Asthma Management Program (CAMP): design, rationale, and methods: Childhood Asthma Management Program Research Group. Control Clin Trials 1999;20:91–120.[CrossRef][Medline]
  44. Camargo CA Jr, Weiss ST, Zhang S, Willett WC, Speizer FE. Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med 1999;159:2582–2588.[Abstract/Free Full Text]
  45. Ioannidis JP. Genetic associations: false or true? Trends Mol Med 2003;9:135–138.[CrossRef][Medline]
  46. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003;33:177–182.[CrossRef][Medline]
  47. Fassbender WJ, Goertz B, Weismuller K, Steinhauer B, Stracke H, Auch D, Linn T, Bretzel RG. VDR gene polymorphisms are overrepresented in german patients with type 1 diabetes compared to healthy controls without effect on biochemical parameters of bone metabolism. Horm Metab Res 2002;34:330–337.[CrossRef][Medline]
  48. Pani MA, Knapp M, Donner H, Braun J, Baur MP, Usadel KH, Badenhoop K. Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans. Diabetes 2000;49:504–507.[Abstract]
  49. Verbeek W, Gombart AF, Shiohara M, Campbell M, Koeffler HP. Vitamin D receptor: no evidence for allele-specific mRNA stability in cells which are heterozygous for the Taq I restriction enzyme polymorphism. Biochem Biophys Res Commun 1997;238:77–80.[CrossRef][Medline]
  50. Hudson TJ. Wanted: regulatory SNPs. Nat Genet 2003;33:439–440.[CrossRef][Medline]
  51. Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, Torrey D, Pandit S, McKenny J, Braunschweiger K, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002;418:426–430.[CrossRef][Medline]
  52. Noguchi E, Yokouchi Y, Shibasaki M, Inudou M, Nakahara S, Nogami T, Kamioka M, Yamakawa-Kobayashi K, Ichikawa K, Matsui A, et al. Association between TNFA polymorphism and the development of asthma in the Japanese population. Am J Respir Crit Care Med 2002;166:43–46.[Abstract/Free Full Text]
  53. Hizawa N, Yamaguchi E, Konno S, Tanino Y, Jinushi E, Nishimura M. A functional polymorphism in the RANTES gene promoter is associated with the development of late-onset asthma. Am J Respir Crit Care Med 2002;166:686–690.[Abstract/Free Full Text]
  54. Laitinen T, Polvi A, Rydman P, Vendelin J, Pulkkinen V, Salmikangas P, Makela S, Rehn M, Pirskanen A, Rautanen A, et al. Characterization of a common susceptibility locus for asthma-related traits. Science 2004;304:300–304.[Abstract/Free Full Text]
  55. Crofts LA, Hancock MS, Morrison NA, Eisman JA. Multiple promoters direct the tissue-specific expression of novel N-terminal variant human vitamin D receptor gene transcripts. Proc Natl Acad Sci USA 1998;95:10529–10534.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200403-412OCv1
170/9/967    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Poon, A. H.
Right arrow Articles by Hudson, T. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Poon, A. H.
Right arrow Articles by Hudson, T. J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2004 American Thoracic Society