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Human Molecular Genetics Advance Access originally published online on December 1, 2005
Human Molecular Genetics 2006 15(1):155-161; doi:10.1093/hmg/ddi436
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© The Author 2005. Published by Oxford University Press. All rights reserved.
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Association of the truncating splice site mutation in BTNL2 with multiple sclerosis is secondary to HLA-DRB1*15

James A. Traherne1,{dagger}, Lisa F. Barcellos2,3,4,{dagger}, Stephen J. Sawcer5, Alastair Compston5, Patricia P. Ramsay2, Stephen L. Hauser3, Jorge R. Oksenberg3 and John Trowsdale1,*

1Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 2XY, UK, 2Division of Epidemiology, School of Public Health, University of California, Berkeley, CA 94720-7360, USA, 3Department of Neurology and Human Genetics Program, School of Medicine, University of California, San Francisco, CA 94143-0435, USA, 4Division of Research, Kaiser Permanente, Oakland, CA 94612, USA and 5Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK

* To whom correspondence should be addressed. Tel: +44 1223763220; Fax: +44 1223762640; Email: jt233{at}cam.ac.uk

Received October 21, 2005; Accepted November 23, 2005


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
The major histocompatibility complex human leukocyte antigen (HLA)-DRB1*15 (DR2) haplotype is strongly associated with risk of multiple sclerosis (MS). The primary susceptibility has been localized to only ~200 kb encompassing the HLA-DR and -DQ loci. Further dissection of disease association with this region is demanding because of the high levels of linkage disequilibrium (LD). Recently, evidence was obtained for the involvement of a gene, potentially encoding an immune co-receptor, in another DR2-associated inflammatory condition, sarcoidosis. The implicated gene, BTNL2, is adjacent to DR and is in strong LD with HLA-DRB1. This fact, combined with a sequence relationship between BTNL2 and myelin oligodendrocyte glycoprotein, an autoantigen associated with MS, makes the gene an attractive candidate. To determine whether BTNL2 contributes to MS, we genotyped 1136 well-characterized MS families from the UK and the USA, as well as an African-American case–control data set, making this among the largest genetic studies in MS. Family-based and case–control association studies were performed for the BTNL2 and HLA-DRB1 loci. In all family data sets, the protein-truncating allele of BTNL2, implicated in sarcoidosis, was significantly over-transmitted to cases (combined data sets: global P=2.4x10–11). Given that the protein-truncating allele of BTNL2 virtually always occurred with DRB1*15, an effect could only be tested in DRB1*15-negative individuals or pedigrees. However, despite adequate power to detect an independent association, no difference in transmission of BTNL2 alleles or genotypes was observed in DRB1*15-negative individuals with MS. Conditional logistic regression modeling also strongly supported the conclusion that BTNL2 does not confer additional disease risk. The association of BTNL2 with MS observed in the African-American data set was also secondary to the primary DRB1*15 association.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Multiple sclerosis (MS) is a severe autoimmune disorder of the central nervous system (CNS) characterized by chronic inflammation, myelin loss, gliosis, varying degrees of axonal pathology and progressive neurological dysfunction (1Go). A large body of research supports a multifactorial etiology for MS, with an underlying complex genetic component likely acting in concert with undefined environmental factors. Family-based and case–control studies in MS have convincingly and consistently shown association between the human leukocyte antigen (HLA)-DR2 (DRB1*1501–DQB1*0602) haplotype and disease susceptibility (2Go–6Go). Because of the extensive linkage disequilibrium (LD) within the major histocompatibility complex (MHC) (7Go), however, it is still unclear, whether the HLA genes directly determine the susceptibility or whether associations may be due to other genes within this region.

We have previously described a polymorphic locus, BTNL2 (BTL-II), with homology to the butyrophilin gene family and myelin oligodendrocyte glycoprotein (MOG) (8Go). MOG is a component of the myelin sheath and is an autoantigen associated with MS. BTNL2 is situated ~170 kb from HLA-DRB1 on the MHC haplotype reference sequence (NCBI35) at the border between the MHC class II and class III regions (Fig. 1). Between these two loci, different HLA haplotypes have large insertions or deletions of genomic sequence resulting in different arrangements of DRB genes. Consequently, the physical distance between BTNL2 and DRB1 can vary substantially (>20 kb) between different MHC haplotypes (9Go). BTNL2 is a member of the immunoglobulin superfamily. On the basis of the amino acid homology to B7 (CD80 and CD86) proteins (10Go,11Go), a role as a costimulatory receptor involved in modulation of T-cell responses has been proposed. BTNL2 expression has been observed in various tissues including the CNS (cerebellum) (12Go). Expression of BTNL2 can be induced by TNF{alpha} and IL1-ß in the myelomonocytic cell line THP-1, and by Mycobacterium tuberculosis and lipopolysaccharide in monocyte-derived macrophages, consistent with a potential immunological role (12Go). Recently, a single nucleotide polymorphism within BTNL2, rs2076530, has been implicated as a risk factor for sarcoidosis (12Go,13Go), a polygenic and multisystematic immune disorder characterized by non-caseating granuloma and an exaggerated cellular immune response resulting from amplified inflammatory activity of macrophages and CD4 helper T-cells (14Go).



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  		Figure 1. Genomic organization of 180 kb of the MHC region of human chromosome 6, at 6p21.31, showing the relative location of BTNL2 and HLA-DRB1. HLA haplotypes have different arrangements of genes at the HLA-DRB variable region such that the physical distance between BTNL2 and HLA-DRB1 can vary depending on HLA haplotype. The illustrated sequence represents the MHC haplotype reference sequence (NCBI35; http://vega.sanger.ac.uk) which possesses the HLA-DRB1*15 (DR2) allele. Exons are shown as filled boxes and open boxes indicate 5'- and 3'-untranslated regions. Pseudogenes are shown in gray.

 
Rs2076530 is located within a donor splice site and the G to A nucleotide transition results in the recruitment of an alternative splice site located four base pairs upstream of the affected donor site (Fig. 2A) (12Go). The exclusion of the four base pairs from the spliced mRNA transcript derived from the A allele produces a frameshift and a premature stop codon in the following downstream exon (Fig. 2C). In the corresponding protein product, the C-terminal residues in the untruncated protein are replaced by five different amino acids. The resulting protein lacks the IgC domain and the transmembrane helix, thus disrupting the membrane localization of the protein. It has been hypothesized that the truncating polymorphism results in impairment of a potential T-cell downregulatory function of BTNL2, possibly by mis-localization from the membrane, leading to dysregulated T-helper cell activation in autoimmune scenarios (12Go). Given the close proximity of BTNL2 to HLA-DRB1, the sequence relationship between BTNL2 and MOG and the increasingly recognized importance of costimulation and its dysfunction in many autoimmune disorders, we have directly assessed rs2076530 involvement in susceptibility to MS.



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  		Figure 2. BTNL2 exon arrangement and alternative transcripts resulting from rs2076530. (A) Allele-specific splicing at SNP rs2076530 in exon 5 of BTNL2. The A and G alleles are shown in bold. Arrows indicate the exon–intron boundaries in the presence of each allele. The four base pairs excluded from the spliced mRNA transcript derived from the A allele are underlined. (B) BTNL2 exon arrangement. IgV and IgC, exon-encoded immunoglobulin-like variable and constant domain, respectively; TM, transmembrane domain. (C) Allele-specific BTNL2 mRNA transcripts. Coding sequence is shaded. Recruitment of an alternative splice site in transcripts derived from BTNL2-1 (A) results in a frameshift and a premature stop after five codons.

 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Strong associations overall with HLA-DRB1 were observed in the MS data sets (all families, P=1.8x10–45; UK families only, P=8.9x10–26; US families only, P=1.2x10–16; AA cases and controls, P=4.0x10–4), specifically with DRB1*15 (P=2.2x10–44, 3.5x10–28, 7.2x10–18 and 0.0005, respectively, data not shown) and have been previously reported (2Go,15Go,16Go). For family-based analyses of the US and UK families, DRB1*15 refers exclusively to the DRB1*1501 allele, whereas in the African-American data set, the DRB1*15 designation includes both DRB1*1501 and DRB1*1503 alleles. DRB1*1503 is the most common DRB1*15 allele in this particular population, and both alleles are significantly associated with MS (16Go). There was no evidence for over-transmission of other DRB1 alleles.

We performed an extensive evaluation of the BTNL2 rs2076530 (G->A) polymorphism and its relationship to both MS and DRB1*15, using large family-based and case–control comparisons. Results from pedigree disequilibrium test (PDT) analyses for the US and UK MS families are shown in Table 1. Strong evidence of transmission distortion for BTNL2 was observed in analyses of the combined data set, both UK and US data sets considered individually and independent trio families analyzed separately from other family members (Table 1). In all data sets, the protein-truncating allele, BTNL2-1 (A), was significantly over-transmitted to cases. However, strong LD, overall, is present between the BTNL2 and DRB1 loci (D'=0.76 and D'=0.81, P<0.0001, observed in a random group of 1012 unrelated pedigree founders and 800 unrelated MS cases analyzed separately, respectively). Almost all DRB1*15 haplotypes included a BTNL2-1 (A) allele with very few carrying a BTNL2-2 (G) allele (Table 2; haplotypes frequencies estimated in 1012 unrelated founders). Only 1.2% of DRB1*15 haplotypes (n=6 in founders) carried the BTNL2-2 (G) allele, whereas 98.8% carried the BTNL2-1 (A) allele. Consequently, a direct comparison of DRB1*15 risk on BTNL2-1 (A) and BTNL2-2 (G) haplotypes could not be made. Both BTNL2 alleles were present on other common DRB1 haplotypes (Table 2); however, strong associations were also observed between the BTNL2-1 (A) allele and both DRB1*03 and DRB1*11 haplotypes, whereas the BTNL2-2 (G) allele was much more common on DRB1*04 haplotypes (91.3% of observed haplotypes).


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  		Table 1. PDT results for analysis of BTNL2 rs2076530 (G->A) SNP in MS families
 

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  		Table 2. Frequency of BTNL2 rs2076530 (G->A) SNP on common DRB1 haploytpesa
 
Given that analysis could not be performed for heterogeneity on DRB1*15 haplotypes, to determine whether the observed BTNL2 association was independent of DRB1*15, MS families in which DRB1*15 was not present in either affected individuals or pedigree founders were analyzed as a separate group. No difference in transmission of either BTNL2 allele or genotypes (AA, AG or GG) was observed in this subgroup of DRB1*15-negative families (P=0.43 and 0.40, respectively) (Table 1). Examination of DRB1–BTNL2 haplotypes in the MS families also revealed no differences in BTNL2 allele frequencies on DRB1*15-negative haplotypes (Table 3). Transmitted and non-transmitted BTNL2 allele distributions were virtually identical [P=0.92, odds ratio (OR)=1.0, 95% CI=0.8–1.2]. Similarly, a strong association with BTNL2 and MS observed in the African-American data set (P=0.0027, OR=1.4, 95% CI=1.1–1.8) was also secondary to the primary DRB1*15 association (Table 3). In addition to DRB1*15, an association with HLA-DRB1*03 has been reported in African-Americans with MS (16Go). Accordingly, we also removed DRB1*03–BTNL2-1 haplotypes from the analyses described in Table 3. The results were very similar (data not shown).


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  		Table 3. BTNL2 SNP rs2076530 (G->A) allele frequencies on MS case (transmitted) and control (non-transmitted) chromosomes
 
Conditional logistic regression modeling was also used to evaluate whether any additional effect of the BTNL2 polymorphism on disease risk in the MS family data set was present after accounting for DRB1*15 carrier status. All family members were categorized according to the DRB1*15 and BTNL2-1 (A) status (grouped as positive/negative for each). Results are shown in Table 4. As expected, a significant effect on disease risk was observed for DRB1*15 (OR=3.1, 95% CI=2.5–3.8, P<0.0001); however, carriage of BTNL2-1 (A) did not confer additional risk after adjustment for the DRB1*15 effect (OR=1.0, 95% CI=0.8–1.3, P=0.89).


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  		Table 4. Conditional logistic regression analyses of DRB1 and BTNL2 rs2076530 (G->A) SNP in MS familiesa
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIALS AND METHODS
 REFERENCES
 
Overall, we observed no evidence of an independent genetic association between the known functional BTNL2 polymorphism rs2076530 (G->A) and the MS susceptibility in both Caucasian and African-American data sets. Strong LD was observed between DRB1*15 and BTNL2, particularly for DRB1*15 and BTNL2-1 (A), and therefore, only a small fraction (~1.0%) of DRB1*15 haplotypes carried BTNL2-2 (G). This prevented a direct comparison of DRB1*15 risk on BTNL2-1 (A) and -2 (G) haplotypes. However, in the absence of DRB1*15, our data sets were adequately powered to detect an independent association with BTNL2. We calculated power for PDT analyses in the MS families (n=300) who did not carry a DRB1*15 allele under a multiplicative model (17Go), assuming a BTNL2-1 (A) frequency of 60% and a type 1 error rate of 5%. On the basis of these assumptions, we have >80% power to detect a modest genotype relative risk of 1.4 for disease susceptibility in the MS family data set. In addition, our haplotype-based analysis in MS families, as expected, had 80% power to identify even a very modest relative risk (as low as 1.2–1.3, assuming {alpha}=0.05) for BTNL2-1 (A), independent of HLA-DRB1*15. Results from conditional logistic regression modeling of MS family data also strongly support a primary role for DRB1*15 rather than for BTNL2-1 (A).

Our findings have significant implications because the BTNL2 gene encodes a co-receptor in the immune system that may be important in autoimmunity. Valentonyte et al. (12Go) have recently reported an association between this particular BTNL2 variant and sarcoidosis and have argued that the effect is independent of HLA-DRB1 associations. In this study, cases with sarcoidosis and controls were grouped by the presence or absence of HLA-DRB1 risk alleles to compare BTNL2 genotype distributions. However, the arbitrary categorization strategy for ‘risk’ and ‘non-risk’ HLA-DRB1 alleles (ORs >1.3 and <1.3, respectively) utilized by Valentonyte et al. makes it difficult to fully interpret results obtained from analyses of ‘non-risk’ (DRB1) BTNL2 genotypes and haplotypes. Given the strong association observed in our data set between DRB1*03 and BTNL2-1 (A) (98.5% of *03 haplotypes have the A allele) (Table 2), it is also surprising that DRB1*03 is not among the ‘risk’ HLA-DRB1 alleles in sarcoidosis, if BTNL2-1 (A) is truly a disease allele. A full determination of whether BTNL2 effects are independent from HLA-DRB1 in sarcoidosis will require careful inspection of individual DRB1–BTNL2 haplotypes, and the inclusion of additional BTNL2 variants (13Go) in a much larger data set. Indeed, it is important to note that the complex biological mechanisms underlying susceptibility to MS and sarcoidosis are likely to have distinct features, and although the presence of common genes for autoimmunity has been postulated (18Go) and confirmed (19Go–25Go), these findings have not extended to all autoimmune diseases (26Go–28Go).

There is still a question of the functional status of the BTNL2 gene in humans. Rodents appear to have one or more functional btnl2 loci and a reduced complement of related btn2/3 genes (8Go,29Go). The human genome, in contrast, contains five expressed BTN2/3 loci, some of which are functional, in the extended MHC class I region (11Go). This contrasts with the DRA-proximal BTNL2 locus, which seems to have an aberrant exon arrangement (8Go). The structure of the BTNL2 locus is similar to that described for the human B7-H3 gene in terms of the arrangement of structural domain-encoding exons (30Go). B7-H3 is among the most recently discovered additions to the B7 superfamily of costimulatory molecules and comprises two consecutively arranged pairs of IgV–IgC domains (31Go). The BTNL2 transcripts isolated to date exclude one exon (predicted to encode a complete IgC domain), despite having an intact open-reading frame and splice junctions (Fig. 2B), resulting in an IgV–IgV–IgC configuration for the extracellular portion of the protein product. Structural and functional analysis of B7 family genes will develop our understanding of the regulation of the adaptive immune system, although it remains to be determined whether BTNL2 is involved in immunological costimulation.

A defined functional role for DRB1*15 in susceptibility to MS is consistent with a pathogenesis model that involves a T-cell-mediated autoimmune response to self-antigen, specifically myelin basic protein (MBP) (32Go–35Go). Immunologic studies and current understandings of the molecular structure of DRB1*15 alleles propose that DRB1*15 alleles bind the autoantigen peptide and present it to DRB1*1501-restricted MBP-specific T-cells (36Go).

The DRB1*15 (DR2)-bearing haplotype has been associated with predisposition and protection to a number of common autoimmune conditions (2Go,37Go,38Go). Miretti et al. (7Go) have proposed that the DRB1*15 haplotype has been involved in recent positive selection resulting in an unusually extended haplotype that reaches into the extended MHC region. DRB1*15 itself is a strong candidate for the selected variant and generally remains the major determinant of DR2-associated disease (39Go). However, the possibility remains that other functional variation on this haplotype may be the true or additional causal determinants. The strong LD between BTNL2 and HLA-DR/DQ requires that BTNL2 be considered relevant to any immune-related disease associated with HLA-DR/DQ. Only when a comprehensive knowledge of variation within this gene-dense and highly polymorphic region is attained will the precise mapping of the disease genes be possible. Undertakings are currently in progress to accomplish this (9Go). Detailed association analysis of each allele in a large sample of subjects will subsequently be required to distinguish candidates for the causal variant from other polymorphism associated with the variant through LD. Accurate clinical diagnosis will remain crucially important, especially where disease heterogeneity is known to exist (40Go). The analysis of different ethnically defined cohorts with different haplotypic diversity will provide additional power to dissect gene effects by association (16Go). The study design presented here thus serves as a model system for the resolution of class II alleles from other linked polymorphisms in the MHC in studies of complex, multigenic MHC-associated diseases.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
REFERENCES
 
To determine whether the rs2076530 marker in BTNL2 plays a role in susceptibility to MS, we genotyped two large, well-characterized family-based data sets including 1136 families in total: 482 trio families (an affected individual and both parents) from the UK, together with 469 nuclear families comprised of trios and discordant sib pair families and 185 multicase families all from the USA. All individuals and their known ancestors were non-Hispanic whites of European descent. Diagnostic criteria, ascertainment protocols and clinical and demographic characteristics are summarized elsewhere (2Go,6Go,41Go). A third African-American data set was ascertained using similar clinical criteria and consisted of 470 cases and 284 controls (primarily patient spouses) (16Go). The increased haplotypic diversity and distinct patterns of LD in populations of African origin are valuable in differentiating specific gene effects, particularly within the HLA region (42Go). Appropriate institutional review boards approved all studies, and informed consent was obtained from all participants. Genotyping for BTNL2 rs2076530 (G->A) was performed using a TaqMan (Applied Biosystems, Foster City, CA, USA) probe-based assay. This assay was validated using samples of known genotype. HLA-DRB1 genotypes were determined as previously described (2Go,15Go,16Go). All family genotypes were examined for Mendelian inconsistencies using PEDCHECK (43Go) and any discrepancies addressed. To extract as much transmission information as possible, we performed initial family-based association analyses using the PDT v. 5.1 (44Go–46Go). The PDT is a powerful analytical method that uses genetic data from related nuclear families and discordant sibships within extended pedigrees. In order to evaluate BTNL2–DRB1 haplotypes in the family data set, the TDTPHASE program in the UNPHASED software package was used (47Go). The TDTPHASE program is based on likelihood ratio tests in a log-linear model (48Go) and was used to calculate transmissions of BTNL2–DRB1 haplotypes in the MS families. This analysis applies unconditional logistic regression on the full likelihood of parents and offspring, which treats all transmitted haplotypes as cases and all non-transmitted haplotypes as controls as previously described (the so-called HHRR) (49Go). Here, transmissions of both homo- and heterozygote parents are used in the analysis. The expectation–maximization (EM) algorithm was used to obtain maximum-likelihood estimates of transmitted and non-transmitted parental haplotype frequencies in order to include families where phase was unknown. Analyses were also restricted to phase known families. In this case, the conditional logistic regression model is used, corresponding to the probability of the offspring, conditional upon the parents as previously described (50Go). Haplotype frequencies for BTNL2 and DRB1 were estimated in African-American cases and controls, and exact tests for pairwise LD between BTNL2 and DRB1 loci in unrelated MS family founders and African-American controls were conducted using the PYPOP software package, which also applies the EM algorithm (51Go). P-values, ORs and confidence intervals for chi-square or Fisher's exact test of allele case–control comparisons were derived using SAS (v. 9.0; SAS Institute, Cary, NC, USA). Conditional logistic regression modeling of BTNL2 and DRB1 genotypes in MS families was also performed using PROC TPHREG as implemented in SAS (v. 9.0; SAS Institute).


   ACKNOWLEDGEMENTS
 
We are grateful to the patients with MS and their families for participating in this study. We thank Gary Artim and Stacy Caillier for technical support. We thank David Rhodes for helpful suggestions and critical reading of this manuscript. This work was funded by the MRC and the Wellcome Trust. Genotyping of the US data sets was funded by grants of the National Institutes of Health (NS 46297), National Multiple Sclerosis Society (RG2901). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.

Conflict of Interest statement. None declared.


   FOOTNOTES
 
{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors. Back


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 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
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