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Poult Sci 2008. 87:1112-1119. doi:10.3382/ps.2008-00006
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IMMUNOLOGY, HEALTH AND DISEASE

Association of a Marker in the Vitamin D Receptor Gene with Marek’s Disease Resistance in Poultry

D. Praslickova*, S. Sharif{dagger}, A. Sarson{dagger}, M. F. Abdul-Careem{dagger}, D. Zadworny*, A. Kulenkamp{ddagger}, G. Ansah{ddagger} and U. Kuhnlein*,1

* McGill University, Department of Animal Science, St. Anne de Bellevue, Quebec, Canada, H9X 1R9; {dagger} University of Guelph, Ontario Veterinary College, Department of Pathobiology, Guelph, Ontario, Canada, N1G 2W1; and {ddagger} Shaver Poultry Breeding Farms Ltd., Cambridge, Ontario, Canada, N1R 5V9

1 Corresponding author: urs.kuhnlein{at}mcgill.ca


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Vitamin D is an important immunomodulator that mediates its effect via a nuclear receptor. In this study, we analyzed 3 uncorrelated genetic markers (tag single nucleotide polymorphisms) in the vitamin D receptor gene for association with Marek’s disease (MD) resistance. The database consisted of 400 commercial White Leghorn chickens that had been vaccinated with herpes turkey virus and challenged by intraperitoneal injection of the virulent MD virus RB1B. Viral titers in feather tips were determined at weekly intervals for 8 wk, mortality was recorded, and necropsy analyses preformed on all chickens. The 3 genotypes defined by 1 of the markers were associated with significant differences in the viral load (integration of the viral titer over time; P = 3 x 10–4). The effect was additive, with the 2 homozygotes differing by a factor of 2. The ranking of the genotypes by viral load, frequency of MD lesions, mortality, and bursal atrophy were consistent. There was no effect on the tissue distribution of MD lesions. The degree of MD resistance in the 9 genotypes defined by the 3 tag single nucleotide polymorphisms was proportional to the frequency of major histocompatibility complex class II-positive peripheral blood leukocytes that had been previously measured in uninfected chickens in a different database.

Key Words: vitamin D receptor • tag single nucleotide polymorphism • Marek’s disease resistance • herpes virus • major histocompatibility complex class II expression


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Marek’s disease (MD) is a highly contagious disease in poultry caused by a virus of the herpes virus family. It induces lymphomas, neurological disorders. and immunosuppression requiring condemnation of infected flocks. The disease can be largely contained by vaccination, but more virulent viruses have evolved that lead to vaccine breaks, causing extensive economic losses. Much effort has therefore been directed toward identifying genetic variants in host genes that confer MD resistance with the aim of understanding the molecular mechanism of resistance and integrating selection for such markers in a breeding program. Such variants are generally identified by an association analysis of markers in genes that had been chosen on the basis of their chromosomal location (positional candidate genes) and on the basis of their biological properties (functional candidate genes). Alternatively, one may chose candidate genes based on studies in other organisms.

Vitamin D (VD) has received much attention as a modulator of immune-mediated diseases. Epidemiological studies in humans have linked VD deficiency with susceptibility to colorectal cancer (Lamprecht and Lipkin, 2003), autoimmune diseases such as insulin-dependent diabetes mellitus (Zella and DeLuca, 2003), multiple sclerosis (Ascherio and Munger, 2007), rheumatoid arthritis (Cantorna, 2000), and Crohn’s disease (Simmons et al., 2000). In addition, the VD status is thought to modulate the susceptibility to infectious diseases such as pulmonary tuberculosis (Selvaraj et al., 2004; Liu et al., 2006; Wilbur et al., 2007), influenza (Cannell et al., 2006), hepatitis caused by hepatitis B virus (Suneetha et al., 2006), and leprosy (Roy et al., 1999).

The association of the VD status with the incidence of autoimmune and infectious diseases in man prompted us to search for variants in genes of VD metabolism that affect the immune response and disease resistance in chickens. We previously identified noncorrelated single nucleotide polymorphisms (SNP; tag SNP) in 3 genes of the VD metabolism, the VD-binding protein, the VD receptor (VDR), and 1,25-hydroxyvitamin D3-24-hydroxylase (CYP24A1; Praslickova et al., 2006). The VD-binding protein is the main transporter of VD to target cells, VDR is the receptor that mediates the effect of VD on gene transcription, and CYP24A1 is a major regulatory enzyme that inactivates the active form of VD [1,25(OH)2D3] by hydroxylation at the 24 position (Omdahl et al., 2002; Dusso et al., 2005).

The tag SNP were identified in a noninbred strain of White Leghorns and were tested for association with the proportion of peripheral leukocytes classified on the basis of the cell surface markers CD3, CD4, CD8, major histocompatibility complex (MHC) class II, and lyb (a marker expressed on B-cells). The most significant association was found between a marker in the VDR gene and the proportion of MHC class II-positive cells. The MHC class II proteins display antigens on the cell surface of antigen-presenting cells, leading to the stimulation of effector cells of the adaptive immune system. Besides being mediators in the immune response, MHC class II proteins may also play a direct role in MD virus (MDV) replication, because they are upregulated in infected cells and their subunits physically interact with the viral proteins R-LORF10 and LORF4, respectively (Morgan et al., 2001; Niikura et al., 2004, 2007). These observations prompted us to analyze whether markers of the VDR gene are associated with MDV proliferation.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Strains of Chickens and Challenge Test

We used a database of 400 female commercial White Leghorn chickens from 2 different populations, S and U, which had been intraperitoneally injected with MDV. The first population (S) was generated by mating 2 lines of chickens that had been selected for markers in the growth hormone receptor gene, the growth hormone gene, and the chemokine CCL20 gene. Ten sires were mated to 10 females each. The second population (U) was a standard commercial cross of the nonselected parental strains used to generate population S. To produce this population, 12 pools of semen of 4 randomly chosen males were prepared and used to inseminate 17 females with each pool.

Two challenge tests were conducted in 2 hatches spaced 3 mo apart. For the population S, the same parents were used in both hatches. For the generation U, different pools of semen were used, but the inseminated females were the same. For the challenge, 100 female chickens of each strain were hatched, vaccinated with herpes turkey virus, banded, intermingled, and transported from the hatchery to the University of Guelph. They were housed intermingled and challenged at 5 d of age with 250 plaque-forming units of the MDV strain RB1B (passage 9) provided by K. A. Schat (Cornell University, Ithaca, NY; Schat et al., 1982).

DNA Extraction and Viral Titration

Feather samples were collected from the wings of the chickens on 7, 14, 21, 28, 35, 42, 49, and 56 d postinfection (dpi) and shipped from the University of Guelph to the McGill laboratory for analysis. Extraction of the DNA from feather tips was carried out using a protocol adapted from Kuhnlein et al. (2006). Feather tips were cut into small pieces with sterile scissors and placed into 1.5-mL tubes containing 400 µL of extraction buffer (2% 2-mercaptoethanol, 10 mM Tris-HCL at pH 8.0, 100 mM NaCl, 10 mM EDTA at pH 8.0, and 0.5% SDS). After an incubation period of 30 min, proteinase K was added to a final concentration of 200 µg/mL, and the incubation was continued at 50°C for 16 h. The DNA was extracted with phenol:chloroform:isoamyl alcohol (25:24:1), precipitated with an equal volume of ice-cold 100% ethanol and rinsed with 500 µL of 70% ethanol. The samples were air-dried and the DNA dissolved in 300 µL of deionized water. The DNA concentration was measured by spectrophotometry. The samples were diluted to 100 ng/µL, and 2 µL per each reaction was used in the competitive quantitative PCR. The competitive PCR to quantify viral DNA has been described (Kuhnlein et al., 2006).

Genetic Analysis of the VDR Gene

The VDR gene was analyzed in strain 7, a noninbred White Leghorn strain that had been generated by mating 4 North American commercial strains in 1955, and was propagated by pedigreed random mating without selection using 100 sires mated to 2 dams each (Gowe et al., 1993). Genetic variations were assessed by sequencing 2 segments of the gene in 20 offspring from different sire families (Figure 1Go). A total of 14 SNP were identified requiring at least 10 tag SNP to capture all 14 SNP at r2 > 0.8 (Carlson et al., 2004; Barrett et al., 2005). We restricted our analysis to the 3 tag SNP VDR S1P4, VDR S1P12, and VDR S2P2. The marker VDR S1P4 had previously been found to be associated with variations in the number of peripheral blood cells expressing the MHC class II antigen (Praslickova et al., 2006). The 3 markers also segregated in the commercial populations that were subjected to the challenge test. Genotyping was carried out at McGill University and Quebec Genome Innovation Center using fluorescence polarization detection of single base extension with an Analyst HT reader (Molecular Devices, Sunnyvale, CA) or by the GenomeLab SNP Stream Genotyping System (Beckman Coulter, Fullerton, CA), or both.


Figure 1
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  		Figure 1. Map of the vitamin D receptor (VDR) gene. The arrows (from left to right) indicate the position of the tags SNP VDR S1P4, VDR S1P12, and VSDR S2P2. The pair-wise correlation coefficients between the 3 markers in strain 7 (n = 187) were r2 < 0.297. The association with the viral load was significant for P4 in segment 1.

 
Statistical Analysis

For statistical evaluations and graphical illustrations, the programs NCSS 2004 (Hintze, 2004) and Haploview 4.0 (Barrett et al., 2005) were used. Associations between marker genotypes and viral load were analyzed by GLM after normalization of the data by log transformation. Survival and hazard rates were analyzed using the Kaplan-Meier procedure and Cox regression analysis.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Association of the VDR SNP with Viral Proliferation

The time course of viral proliferation in feather tips was bell-shaped with a peak at 21 dpi, coinciding with the onset of mortality. It was similar in shape for both populations in both hatches and for the genotypic groups defined by the 3 tag SNP but differed in the extent of viral proliferation (Figure 2Go).


Figure 2
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  		Figure 2. Time course of viral titers in feather tips for different vitamin D receptor S1P4 genotypes. The median viral titers (viral genome equivalent/cellular genome equivalent) from the population U in trial 2 are plotted for each week post-infection. The titers differed significantly at wk 3 postinfection (P = 0.024; Kruskal-Wallis 1-way analysis by rank). The profiles for the population U in trial 1 and the population S in both trials were similar, with the genotype AA being associated with lower titers than GG.

 
For statistical analysis, we integrated the viral titer by summing the weekly viral load before the onset of mortality (the viral load to 21 dpi) and to 35 dpi (viral load to 35 dpi). The latter measure only included the chickens that were still alive at 35 dpi. Significant single variable effects were observed for the VDR S1P4 genotype and the trial and significant interaction between the population and the trial (Table 1Go). In contrast, the interactions of the VDR genotypes with both trial and population were not significant, indicating that the effects of the VDR genotype were independent of the population and trial. The mean viral loads for the different VDR S1P4 genotypes are shown in Table 2Go. A comparison of the means indicated additivity for the VDR locus with the viral load differing between the homozygotes by a factor of 2.


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  		Table 1. General linear model analysis of the dependence of the integrated viral titers on trial, population, and VDR S1P4 genotype
 

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  		Table 2. Average values of Marek’s disease (MD)-associated parameters for different genotypes of the tag SNP S1P4
 
The 2 other tag SNP, VDR SP12 and VDR S2P2 (Figure 1Go), segregated for 2 and 3 genotypes, respectively. They were not significantly associated with the viral titers in feather tip extracts (data not shown).

Association with MD Lesions, Mortality, and Atrophy of the Bursa of Fabricius

Other indicators of MD are the presence of MD lesions, the cumulative mortality, and the atrophy of the bursa. These parameters were not significantly dependent on the VDR S1P4 genotype (Table 2Go). However, the ranking of these parameters by the 3 genotypes was concordant with the ranking of the viral titers. The magnitude of the means again indicated an additive effect of the VDR polymorphism.

The frequency of chickens with lesions categorized by tissue is shown in Figure 3Go. For each tissue, the frequency of chickens that had lesions was lowest for the genotype AA, followed by genotype AG and GG. Hence, the ranking of the genotypic classes on the bases of the presence of 1 or more lesions was concordant. The ranking of the tissues by the genotypic classes was also concordant, indicating that the tissue distribution of lesions was not significantly influenced by the VDR receptor genotype.


Figure 3
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  		Figure 3. Tissue distribution of Marek’s disease lesions for different vitamin D receptor S1P4 genotypes. The bars indicate the frequency of chickens that had proliferative lesions in the tissues indicated. The ranking of the tissues by the genotypes was concordant (Kendall coefficient of concordance W = 1, P = 3 x 10–5). Similarly, the ranking of the 3 genotypes by the tissues was significant (W = 1, P = 0.006).

 
An analysis of the time course of mortality suggests that the VDR S1P4 genotype may affect the time dependency of the rate of mortality (Figure 4Go). In genotype AA chickens, the mortality rate peaked at 28 dpi. This peak VDR alone accounted for 5.6% of the total sum of squares was shifted by 1 wk in genotype GG chickens. The mortality rate curve in genotype AG chickens was between the curves for the 2 homozygotes.


Figure 4
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  		Figure 4. Survival (left panel) and hazard rate (right panel) for different vitamin D receptor S1P4 genotypes. The genotypes AA and GG were associated with the lowest and highest viral loads at 21 days postinfection, respectively.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we screened a population of 400 White Leghorn chickens for the association of MD resistance with 3 polymorphisms in the VDR gene. One of the markers, VDR S1P4, that had previously been found to be associated with the frequency of MHC class II-expressing peripheral leukocytes (Praslickova et al., 2006), had a significant association with the MD resistance. The effect of this marker was additive, similar to its effect on MHC class II expression that had been measured in a different strain of White Leghorn chickens.

Marek’s disease resistance was assessed using 4 different indicators, viral titers in feather pulp, survival to 56 dpi, the frequency of MD lesions, and the weight of the bursa. A significant association of the marker VDR S1P4 with MD resistance was only observed for the viral titer in feather tips. However, the other indicators of MD behaved concordantly as expected from the relationship of mortality, frequency of lesions, and viral titer in feather tips.

The ranking of the number of lesions on the basis of the 3 genotypes was the same in each of 8 types of tissues and was concordant with the effect of the VDR S1P4 genotype on the viral titer (AA < AG < GG). Similarly, the ranking of the tissues by lesion frequency was the same for each of the 3 genotypes. It indicates that there were no tissue-specific effects of the VDR genotype on the susceptibility of tissues to virally induced proliferative lesions.

The VDR may affect the level of cell transformation and of viral proliferation independently. In humans, mutations in the VDR gene leading to hereditary VD-resistant rickets have been shown to be associated with hair loss (alopecia; Malloy et al., 1999). Similarly, VDR-null mice display alopecia, presumably due to a defect in keratinocyte stem cell function that is essential for hair follicle homeostasis leading to the absence of the initiation of new hair growth cycles (Cianferotti et al., 2007; Demay et al., 2007). Viral proliferation of MDV in the epithelial cells of feather tips may be dependant on a normal progression of cell differentiation in feather follicles. In particular, the decline of viral proliferation that we observed 21 dpi may not reflect the course of the disease but may be related to the age-dependent development of feather follicles.

Vitamin D has also antiproliferative actions (Bouillon et al. 2006). The VDR-null mice are more prone to develop tumors when exposed to oncogenes or carcinogens, and epidemiological studies indicate that there is an inverse relationship between ultraviolet B exposure and the incidence of colorectal, breast, and prostate cancer. Hence, VDR may affect tumor formation and survival independently of its effect on viral proliferation.

Alternatively to independent actions on several steps in the progression of MD, VD via its receptor may exert its effect on MD by modulating the immune system (Griffin et al., 2003). In general, it exerts an inhibitory effect by attenuating the differentiation and proliferation of cells of the immune system. Specifically, it reduces the surface expression of MHC class II and other co-stimulatory ligands on dendritic cells and induces a shift from a T helper (Th)1 response to a Th2 response (Overbergh et al., 2000; Chen et al., 2007). The association of autoimmune diseases with VD deficiency is thought to be due to a relatively high Th1 response that leads to the activation of cytotoxic T lymphocytes and subsequent tissue damage. However, an inhibitory effect of 1,25(OH)2D on the B-cell maturation, proliferation, and IgE production has also been reported (Chen et al., 2007). An example of the effect of VD on the innate immune system is the upregulation of the VDR and VD-1 hydroxylase in response to activation of Toll-like receptors, leading to the induction of the antimicrobial peptide cathelicidin (Liu et al., 2006). This mechanism has been proposed to be a major reason for the association of VD and Mycobacterium tuberculosis susceptibility.

Marek’s disease resistance is affected by the innate immune system as well as the acquired immune response. As expected from the early cytolytic mode of MD replication, natural killer cells and cytotoxic T cells are of special importance (Davison and Kaiser, 2004). A general attenuation of the response of the immune system or a shift to a Th1 response by VD, or both, would therefore be expected to increase the susceptibility to MD.

Most herpes viruses downregulate MHC class II as part of their strategy to escape immune surveillance. The most important pathways are the inhibition of the induction of MHC class II gene expression and the MHC class II antigen presentation (Hegde et al., 2003). Surprisingly, MDV does not subscribe to this strategy. To the contrary, the surface expression of MHC class II antigens in MDV-infected cells is upregulated, apparently by an intracellular pathway unrelated to a paracrine action of interferon-{gamma} (Gimeno et al., 2001; Niikura et al., 2007). Whether the overexpression of MHC class II leads to an increased presentation of antigens to CD4+ cells remains to be determined. In particular, the physical interaction of MHC class II protein subunits with 2 viral proteins may indicate a role of MHC class II in the viral assembly that is unrelated to antigen presentation (Niikura et al., 2004).

The relationship between proportion of MHC class II-positive peripheral blood leukocytes and parameters of MD resistance is shown in Figure 5Go. In light of the upregulation of MHC class II expression in MD-infected cells, it may seem paradoxical that the most resistant genotype was the genotype that had been found to be associated with the highest proportion of MHC class II-expressing leukocytes. However, it remains to be seen whether upregulation of MHC class II in MD-infected cells is indeed conducive to the progression of the disease. Further, the relationship between disease resistance and MHC class II-positive peripheral leukocytes is based on leukocytes that constitutively express MHC class II. Whether the VDR polymorphism that is associated with constitutive expression of MHC class II also has an effect on the induction of MHC class II genes by viral infection remains to be determined. Further, it has to be considered that our challenge test was conducted in chickens vaccinated with herpes turkey virus, an attenuated virus of the Mardi virus family. The association of the VDR polymorphism with susceptibility to MD may therefore reflect an association with the response to vaccination (Ivanov et al., 2006).


Figure 5
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  		Figure 5. Means of the mortality, viral load to 21 dpi, and frequency of lesions/chicken plotted against the mean proportions of major histocompatibility complex (MHC) class II-positive peripheral leukocytes in strain 7. The data points are the means for the 8 genotypes defined by the 3 markers in the vitamin D receptor (VDR) gene. The left ordinate indicates the mortality in percentages and the viral load in virus/cell equivalents, and the right ordinate indicates the frequency of lesions/chicken. The arrows indicate the 3 genotypes defined by VDR S1P4. The R2 values are the square of Pearson correlation coefficients. They were significant at P < 0.006.

 
Despite the fact that the messenger RNA encoding the VDR was first cloned in chickens, there has been no attempt to correlate SNP with production traits (McDonnell et al., 1987). The only exception was the usage of a VDR SNP to follow the segregation of VDR genes in a layer-broiler cross. It was found that the VDR region segregated for a quantitative trait locus that affected the humerus bone density at 35 wk of age (Bennett et al., 2006). More data are available from human studies, in which a series of restriction fragment length polymorphism markers were found to be associated with many hereditary disorders such as susceptibility to hepatitis B virus and tuberculosis (Olesen et al. 2007; Wilbur et al., 2007), inflammatory bowel disease (Rodriguez-Bores et al., 2007), hereditary VD-resistant rickets (Malloy et al., 1999), and modulation of the immune system (van Etten et al., 2007).

Efforts are now underway to characterize the haplotype patterns associated with MD resistance. Similar to humans, our analysis indicates that the chicken VDR gene has a high density of SNP that form numerous haplotypes (Nejentsev et al., 2004). A total of 14 SNP were identified, requiring 10 tag SNP to distinguish the groups of markers with an r2 > 0.8 (Carlson et al., 2004). Because only 7% of the gene was sequenced, the number of SNP required to tag the entire gene may be much higher. High resolution linkage disequilibrium and tag SNP analysis are now in progress to better define the patterns of VDR polymorphisms that are associated with MD resistance.


   ACKNOWLEDGMENTS
 
The Shaver Poultry Breeding Farms Ltd., the Natural Sciences and Engineering Research Council of Canada (Ottawa, Ontario, Canada), and the Poultry Industry Council of Canada (Guelph, Ontario, Canada) are gratefully acknowledged.

Received for publication January 4, 2008. Accepted for publication February 25, 2008.


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 DISCUSSION
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