help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-2183
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow All Versions of this Article:
92/3/1106    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
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 Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Owen, C. J.
Right arrow Articles by Merriman, T. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Owen, C. J.
Right arrow Articles by Merriman, T. R.
Related Collections
Right arrow Thyroid
Right arrow Autoimmunity
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 3 1106-1111
Copyright © 2007 by The Endocrine Society

Analysis of the Fc Receptor-Like-3 (FCRL3) Locus in Caucasians with Autoimmune Disorders Suggests a Complex Pattern of Disease Association

Catherine J. Owen, Hannah Kelly, James A. Eden, Marilyn E. Merriman, Simon H. S. Pearce and Tony R. Merriman

Institute of Human Genetics and School of Clinical Medical Sciences (C.J.O., J.A.E., S.H.S.P.), University of Newcastle upon Tyne, Newcastle upon Tyne NE1 3BZ, United Kingdom; and Department of Biochemistry (H.K., M.E.M., T.R.M.), University of Otago, Dunedin 9001, New Zealand

Address all correspondence and requests for reprints to: Dr. C. J. Owen, Institute of Human Genetics, University of Newcastle, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK. E-mail: c.j.owen{at}ncl.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: A four-marker haplotype in the 5' region of the Fc receptor-like 3 gene (markers FCRL3_3 to FCRL3_6) has been identified recently as contributing to rheumatoid arthritis (RA) susceptibility in the Japanese population. The promoter FCRL3_3*C allele also showed significant association with autoimmune thyroid disease and systemic lupus erythematosus. These findings raise the possibility that this locus may influence autoimmune disease susceptibility across many populations.

Patients and Design: We analyzed the same four 5' FCRL3 single nucleotide polymorphism markers, together with three additional exonic single nucleotide polymorphisms in the FCRL3 gene, in cohorts of white Caucasians with Graves’ disease (n = 625), type 1 diabetes (n = 279), autoimmune Addison’s disease (AAD; n = 200), and RA (n = 769). Healthy controls from the United Kingdom (n = 490) and New Zealand (n = 593) were used.

Results: Six of the seven FCRL3 markers showed association with AAD (P = 0.005–0.0001), with maximum evidence at the FCRL3_3*T allele [P[corrected] = 0.0008; odds ratio (OR), 1.61; 5–95% confidence intervals (CIs), 1.26–2.05]. The most common seven-marker FCRL3 haplotype (TGGGAAA) was also found to be significantly associated with AAD (P[corrected] = 1.1 x 10–4; OR, 1.71; 5–95% CIs, 1.33–2.18). There was nominal evidence for allelic association at the marker FCRL3_8 in Graves’ disease (OR, 1.50; 5–95% CIs, 1.06–2.13) and at FCRL3_9 with RA (OR, 1.25; 5–95% CIs, 1.01–1.54).

Conclusions: The FCRL3 haplotype that is associated with AAD in Caucasians appears to be protective for autoimmune diseases in the Japanese population, demonstrating that this haplotype is unlikely to contain a single primary etiological allele for autoimmunity. Our observations suggest that the susceptibility to autoimmunity at the FCRL3 locus is more complex than initially thought and may extend either side of the currently associated region to include the adjacent FCRL2 gene.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
AUTOIMMUNE ENDOCRINOPATHIES, together with immune-mediated rheumatological disorders, contribute the major burden of disease caused by autoimmunity in the population, with around 5% of women in developed societies being affected by such conditions. All the common autoimmune conditions have a complex genetic basis, with autoimmune endocrinopathies and rheumatoid arthritis (RA) commonly occurring in the same individual and clustering within families (1). Graves’ disease (GD), RA, and type 1 diabetes (T1D) are frequent disorders (prevalence, 0.4–1%), and each has a {lambda}s (ratio of risk to sibling vs. unrelated background population) of between 7 and 15, suggesting a significant genetic component to susceptibility. In contrast, autoimmune Addison’s disease (AAD) is a much rarer condition, with a prevalence of about one per 10,000 people in the United Kingdom (UK) (2) but a risk to first degree relatives of about 2%, suggesting a more marked genetic influence on disease susceptibility. Whole-genome linkage studies have shown clustering of susceptibility loci for many of these different disorders, and several loci consistently appear to contribute to multiple forms of autoimmunity across diverse populations. Examples of such loci include the major histocompatibility complex (MHC) (3, 4), the cytotoxic T lymphocyte antigen-4 gene (CTLA4) (5, 6, 7, 8, 9, 10), and the protein tyrosine phosphatase nonreceptor type 22 gene (PTPN22) (11, 12, 13). A second class of autoimmunity susceptibility locus is represented by the disease-specific loci, such as the insulin gene (INS, IDDM2) (14) or the TSH receptor (15, 16), whose contribution is unique to the relevant target tissue or specific antigen of the autoimmune response. A final class of loci is those loci where replicable disease associations are found in some populations studied but for which there appears to be little or no contribution to disease in well-powered studies of other populations. For example, the PADI4 gene is associated with RA in the Japanese population (17, 18, 19) but with a weak effect, only demonstrable by metaanalysis, in European populations (20, 21, 22). Thus, it remains imperative to study putative autoimmune disease susceptibility alleles in different autoimmune conditions and also in several populations of varied ethnic background. The latter approach, sometimes termed transracial mapping, can give important clues to the identity of etiologically important alleles (23).

One recently identified novel susceptibility gene in RA is the Fc receptor-like 3 gene (FCRL3) (24), located at 1q21, a region implicated in susceptibility to several autoimmune diseases in whole-genome linkage studies (25, 26, 27). Kochi et al. (24) identified a four-single nucleotide polymorphism (SNP) haplotype (FCRL3_3-6) as being associated with RA in two separate cohorts of Japanese patients. The greatest association with RA [P = 8.5 x 10–7; odds ratio (OR), 2.15] was found in individuals who were homozygote carriers of a particular promoter allele, FCRL3_3*C, at position –169 relative to the FCRL3 transcription start site. This allele (FCRL3_3*C) was also found to be associated in Japanese cohorts with autoimmune thyroid disease (P = 1.7 x 10–5; OR, 1.74) and systemic lupus erythematosus (P = 0.0017; OR, 1.49). This same allele was also found to produce higher promoter activity in a reporter gene assay and to be more avidly bound by NF{kappa}B in gel-shift studies, suggesting a direct functional role (24). FCRL3 is an orphan cell surface receptor with homology to the Fc immunoreceptors and is expressed predominantly in B lymphocytes in lymph node germinal centers. In this study, we have analyzed the same four-marker FCRL3 SNP haplotype and three additional exonic SNP markers in four cohorts of white Caucasians with autoimmune disorders including GD, AAD, RA, and T1D.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The GD (n = 625) and AAD (n = 105) probands were recruited through endocrine and combined physician-ophthalmologist thyroid-associated ophthalmopathy clinics at the Newcastle upon Tyne Hospitals Trust and surrounding district hospitals. A further cohort of 95 AAD probands was recruited via the UK Addison’s disease self-help group. The diagnostic criteria of these cohorts have been published previously (28, 29). Of the GD probands 78% were female, 38% had significant thyroid-associated ophthalmopathy (NOSPECS class 3 or worse), and 55% were smokers. The UK GD subjects all had parents born in the northeast of the UK. Isolated AAD accounted for 36% of the AAD cohort, the other 64% had at least one other associated autoimmune disease (hypothyroidism, 77; GD, 24; primary gonadal failure, 23; T1D, 12; pernicious anemia, 13; vitiligo, six; celiac disease, six; RA, four; alopecia, three; hemolytic anemia, two; and autoimmune hepatitis, one). The AAD cohort included 151 females (75.5%) and 49 males (24.5%). The mean age of onset was 40 yr old. Four of the 200 AAD probands also had an affected first degree relative with AAD (two siblings, two offspring). None of the AAD subjects had autoimmune hypoparathyroidism or candidiasis (subjects with type 1 polyendocrinopathy were excluded from the cohort) (28). UK controls (n = 490; 66.3% females, 33.7% males) also recruited from the local population had no clinical features or family history of autoimmune disease. The RA (n = 769) cases were recruited from rheumatology clinics throughout New Zealand (NZ), and details of their clinical characterization and of the NZ control cohort (n = 563) have been published previously (13). The T1D cohort comprised 279 subjects with hyperglycemia and ketosis who were commenced on insulin therapy at diagnosis, recruited from endocrinology clinics throughout NZ. They had an average age of onset of 12.5 yr.

SNP genotyping

The SNPs within the four-marker haplotype described by Kochi et al. (24) were genotyped either by PCR and restriction enzyme digest (restriction fragment length polymorphism) (UK cohort SNPs FCRL3_3, 3_4; NZ cohort FCRL3_3-6) or primer extension-matrix-assisted laser desorption/ionization time of flight assay (Sequenom, Inc., San Diego, CA) (UK cohort SNPs FCRL3_5, 3_6). Furthermore, we examined three additional exonic FCRL3 SNPs, two of which are nonsynonymous coding SNPs (cSNPs). The additional markers were located as follows: rs7522061, exon 3 cSNP (D28N); rs2282284 (FCRL3_8), exon 14 cSNP (N721S); and rs2282283 (FCRL3_9), 3' untranslated region (Fig. 1Go) and were genotyped by PCR/restriction fragment length polymorphism (UK cohort SNP D28N; NZ cohort D28N, FCRL3_8 and 3_9) or primer extension-matrix-assisted laser desorption/ionization time of flight assay (UK cohort SNPs FCRL3_8, 3_9). Details of the assay oligonucleotide sequences and conditions are available from the authors (published as supplemental Table 1 on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org).


Figure 1
View larger version (22K):
[in this window]
[in a new window]

  		FIG. 1. LD r2 measures for FCRL3 in the UK control population. In the schematic diagram of the FCRL3 gene, exons are depicted by black boxes and noncoding regions as white boxes. The position of the seven SNPs (FCRL3_3, -4, -5, -6, N28D, -8, -9) spanning 22.435 kb of the FCRL3 gene region are shown.

 
Statistical analysis

The case-control association studies were analyzed using {chi}2 tests on two x two and two x three contingency tables for allele and genotype frequencies, respectively. Haplotype frequencies were estimated, and linkage disequilibrium (LD) (r2) measures were calculated using the SHEsis package (30). ORs and confidence intervals (CIs) were calculated using Woolf’s method. No significant deviation from Hardy Weinberg equilibrium was observed for any of the SNPs in this study (all P > 0.05). The overall genotype call rate was 98.2% (range, 91.6–100%), and the accuracy was more than 99% according to duplicate genotyping of 7–10% of samples. We estimate that our studies of GD and RA had more than 80% power to detect an effect ({alpha} = 0.001) of the same magnitude (allelic OR of 1.4) as that found in the Japanese GD cohorts (24), using our control allele frequencies and a binomial model. The powers of our studies of AAD and T1D were more than 80% and more than 90%, respectively, assuming an allelic OR of 1.4 ({alpha} = 0.05). P values were Bonferroni corrected for multiple tests assuming that the seven SNP markers carried information for four independent linkage groups and that each of the four disease states was independent.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
We found significant LD between markers at the 5' end of FCRL3 but lesser association between the other 3' alleles, with pair-wise r2 values based on the UK control population as follows: FCRL3_3 – [0.412] – FCRL3_4 – [0.410] – FCRL3_5 – [0.987] – FCRL3_6 – [0.915] – N28D – [0.088] – FCRL3_8 – [0.024] – FCRL3_9 (Fig. 1Go). The corresponding figures for the NZ control population are: FCRL3_3 – [0.396] – FCRL3_4 – [0.420] –FCRL3_5 – [0.834] – FCRL3_6 – [0.749] – N28D – [0.068] – FCRL3_8 – [0.011] – FCRL3_9. In contrast to the finding of strong association with disease of the FCRL3_3–6 SNPs in Japanese RA and GD subjects, we could find no evidence to support disease association with alleles at any of these markers in UK whites with GD or in NZ whites with RA or T1D (Table 1Go). Markers in the 3' end of the gene showed nominal evidence for association at FCRL3_8 in GD [A allele, OR, 1.50; 5–95% CIs, 1.06–2.13] and at FCRL3_9 in RA (C allele, OR, 1.25; 5–95%; CIs, 1.01–1.54); however, these findings were not robust to correction for multiple statistical testing (Table 1Go).


View this table:
[in this window]
[in a new window]

  		TABLE 1. Genotype and allele data for each of the seven FCRL3 SNPs in each population studied, together with case control analysis of the alleles and genotypes in each disease group in comparison with the relevant controls

 
In contrast, there was substantial allelic association at six of the seven FCRL3 markers studied in the cohort of UK subjects with AAD, with maximum evidence at FCRL3_3. The T allele of this marker (FCRL3_3*T) was present in 254 of 400 (63.5%) AAD chromosomes compared with 467 of 898 (52.0%) control chromosomes (P[corrected] = 0.0008; OR, 1.61; 5–95% CIs, 1.26–2.05) (Table 1Go). The most common seven marker haplotype containing the FCRL3_3*T allele (TGGGAAA) was also significantly associated with AAD (P = 1.8 x 10–5, P[corrected] = 1.1 x 10–4; OR, 1.71; 5–95% CIs, 1.33–2.18), with a P value of 0.001 using a global test of the six common haplotypes found in the AAD patients (Table 2Go). There were no significant haplotype associations with disease in the GD, RA, or T1D cohorts (Table 2Go). There was no significant heterogeneity in the allelic associations in the various cohorts when divided by diagnostic subgroups (supplemental Table 2).


View this table:
[in this window]
[in a new window]

  		TABLE 2. Haplotype structures and frequencies of FCRL3 in the different populations with a frequency of more than 1%

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The association of multiple autoimmune disorders in the Japanese population with alleles of FCRL3 by Kochi et al. (24) suggested that this locus may affect susceptibility to different autoimmune diseases across many populations in a similar way to the action of alleles at CTLA4 (5, 6, 7, 8, 9, 10). The association of the FCRL3_3*C allele with susceptibility to autoimmune conditions found in this initial study has been replicated recently in a further cohort of Japanese subjects with RA (n = 752) (31). Furthermore, a study of a white UK population showed a weak effect in GD, with FCRL3 markers having nominal association (FCRL3_3*C, P = 0.024, OR, 1.17) (32). However, similar investigation of several additional large cohorts of Caucasian subjects with T1D and RA have failed to replicate the FCRL3_3 association (33, 34, 35, 36). In contrast to these studies, our investigation found that the FCRL3_3*C allele was associated with protection from AAD, an observation that largely refutes the hypothesis that this allele is the disease-causing polymorphism for autoimmunity at this locus, at least not in Caucasians. In addition, our extended genotyping points to the exon 3 cSNP (D28N) as also being tightly associated with FCRL3_3 (r2 > 0.9; Fig. 1Go), and this marker certainly warrants examination in Japanese and other autoimmune disease cohorts. Although our analyses of RA and GD were well-powered to detect an effect of similar magnitude to that found in the Japanese cohorts, only marginal evidence for association was found in these conditions, this being found at the 3' FCRL3 SNPs (designated FCRL3_9 and FCRL3_8, respectively), which are not in the haplotype block containing the promoter and exon 3 markers (Fig. 1Go).

The contradiction of the apparent protection conferred in the Addison’s disease cohort by the Japanese autoimmune susceptibility haplotype could be explained in three ways. Firstly, the association reported here in the AAD cohort could be a chance finding. It is important that other AAD cohorts are genotyped for the FCRL3 variants analyzed here. However, genotype data at other loci do not support population stratification or mismatching between the AAD cohort and UK controls as an explanation for this result (37, 38) (supplemental Table 3). Secondly, the disparate FCRL3 genetic association could reflect genuine differences in FCRL3-mediated autoimmune disease etiology between the Japanese and Caucasian populations. In addition, it is possible that different immunopathological mechanisms underlie the disease process in AAD compared with RA, GD, and the other more common autoimmune diseases. With this regard, the lower promoter activity of the FCRL3_3*T allele that would be predicted based on the existing functional analysis at this locus (24) could have a distinct pathogenic role in AAD but still be protective for other forms of autoimmunity. Lastly, the susceptibility allele at FCRL3 may lie elsewhere within the block of LD that contains the 5' region of the FCRL3 gene or within the adjacent FCRL2 transcript (Fig. 1Go). The 5' region of FCRL3 is in a LD block that extends across an intragenic region to the 3' end of the FCRL2 gene, including several coding FCRL2 exons. In addition, the 3' region of FCRL3 (centromeric to exon 5 and encoding the critical cytoplasmic tail of the receptor) is sparsely covered by existing markers and appears to contain a substantial interval with weak or no LD between markers (39). Furthermore, there may be additional subtle differences in LD structure between Japanese and Caucasians at this locus that will not be evident until a denser marker map is genotyped. Evidence for association of FCRL3 promoter alleles with autoimmune disease is currently consistent in Japanese populations but equivocal or absent in most Caucasian populations (32, 33, 34, 35, 36). To further clarify a possible role for this locus in autoimmunity in Caucasians, our findings suggest that more detailed genetic analysis of an extended haplotype block containing both FCRL3 and FCRL2 is warranted.


   Acknowledgments
 
We thank the New Zealand Rheumatology Research Network for patient recruitment and patients and controls for making the gift of blood samples, including those at the Addison’s disease self-help group (UK). We thank Prof. Heather Cordell and Dr. Richard Quinton for helpful comments on the manuscript and Dr. Cushla McKinney for help with the data analysis.


   Footnotes
 
This work was supported by the Wellcome Trust (United Kingdom) and by the Health Research Council (New Zealand). C.J.O. was supported by a Medical Research Council (UK) Training Fellowship.

The authors have nothing to disclose.

First Published Online January 2, 2007

Abbreviations: AAD, Autoimmune Addison’s disease; CI, confidence interval; cSNP, coding SNP; GD, Graves’ disease; LD, linkage disequilibrium; NZ, New Zealand; OR, odds ratio; RA, rheumatoid arthritis; SNP, single nucleotide polymorphism; T1D, type 1 diabetes.

Received October 6, 2006.

Accepted December 21, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Walker D, Griffiths M, Griffiths I 1986 Occurrence of autoimmune diseases and autoantibodies in multicase rheumatoid arthritis families. Ann Rheum Dis 45:323–326[Abstract/Free Full Text]
  2. Kong MF, Jeffcoate W 1994 Eighty-six cases of Addison’s disease. Clin Endocrinol (Oxf) 43:130–131
  3. Pociot F, Karlsen AE 2002 Combined genome and proteome approach to identify new susceptibility genes. Am J Med Genet 115:55–60[CrossRef][Medline]
  4. Tait KF, Gough SC 2003 The genetics of autoimmune endocrine disease. Clin Endocrinol (Oxf) 59:1–11[CrossRef][Medline]
  5. Yanagawa T, Hidaka Y, Guimaraes V, Soliman M, DeGroot LJ 1995 CTLA-4 gene polymorphism associated with Graves’ disease in a Caucasian population. J Clin Endocrinol Metab 80:41–45[Abstract]
  6. Marron MP, Raffel LJ, Garchon HJ, Jacob CO, Serrano-Rios M, Martinez Larrad MT, Teng WP, Park Y, Zhang ZX, Goldstein DR, Tao YW, Beaurain G, Bach JF, Huang HS, Luo DF, Zeidler A, Rotter JI, Yang MC, Modilevsky T, Maclaren NK, She JX 1997 Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. Hum Mol Genet 6:1275–1282[Abstract/Free Full Text]
  7. Yangawa T, Taniyama M, Enomoto S, Gomi K, Maruyama H, Ban Y, Saruta T 1997 CTLA4 gene polymorphism confers susceptibility to Graves’ disease in Japanese. Thyroid 7:843–846[Medline]
  8. Seidl C, Donner H, Fischer B, Usadel KH, Seifried E, Kaltwasser JP, Badenhoop K 1998 CTLA4 codon 17 dimorphism in patients with rheumatoid arthritis. Tissue Antigens 51:62–66[Medline]
  9. Vaidya B, Imrie H, Perros P, Young ET, Kelly WF, Carr D, Large DM, Toft AD, McCarthy MI, Kendall-Taylor P, Pearce SH 1999 The cytotoxic T lymphocyte antigen-4 is a major Graves’ disease locus. Hum Mol Genet 8:1195–1199[Abstract/Free Full Text]
  10. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RC, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, Metzker ML, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Tuomilehto-Wolf E, Tuomilehto J, Bingley P, Gillespie KM, Undlien DE, Ronningen KS, Guja C, Ionescu-Tirgoviste C, Savage DA, Maxwell AP, Carson DJ, Patterson CC, Franklyn JA, Clayton DG, Peterson LB, Wicker LS, Todd JA, Gough SC 2003 Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511[CrossRef][Medline]
  11. Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T 2004 A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 36:337–338[CrossRef][Medline]
  12. Velaga MR, Wilson V, Jennings CE, Owen CJ, Herington S, Donaldson PT, Ball SG, James RA, Quinton R, Perros P, Pearce SH 2004 The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J Clin Endocrinol Metab 89:5862–5865[Abstract/Free Full Text]
  13. Simkins HM, Merriman ME, Highton J, Chapman PT, O’Donnell JL, Jones PB, Gow PJ, McLean L, Pokorny V, Harrison AA, Merriman TR 2005 Association of the PTPN22 locus with rheumatoid arthritis in a New Zealand Caucasian cohort. Arthritis Rheum 52:2222–2225[CrossRef][Medline]
  14. Bennett ST, Wilson AJ, Cucca F, Nerup J, Pociot F, McKinney PA, Barnett AH, Bain SC, Todd JA 1996 IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus. J Autoimmun 9:415–421[CrossRef][Medline]
  15. Dechairo B, Zabaneh D, Collins J, Brand O, Dawson GJ, Green AP, Mackay I, Franklyn JA, Connell JM, Wass JA, Wiersinga WM, Hegedus L, Brix T, Robinson BG, Hunt PJ, Weetman AP, Carey AH, Gough SC 2005 Association of the TSHR gene with Graves’ disease: the first disease specific locus. Eur J Hum Genet 13:1223–1230[CrossRef][Medline]
  16. Hiratani H, Bowden DW, Ikegami S, Shirasawa S, Shimizu A, Iwatani Y, Akamizu T 2005 Multiple SNPs in intron 7 of thyrotropin receptor are associated with Graves’ disease. J Clin Endocrinol Metab 90:2898–2903[Abstract/Free Full Text]
  17. Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, Ohtsuki M, Furukawa H, Yoshino S, Yukioka M, Tohma S, Matsubara T, Wakitani S, Teshima R, Nishioka Y, Sekine A, Iida A, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K 2003 Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34:395–402[CrossRef][Medline]
  18. Ikari K, Kuwahara M, Nakamura T, Momohara S, Hara M, Yamanaka H, Tomatsu T, Kamatani N 2005 Association between PADI4 and rheumatoid arthritis: a replication study. Arthritis Rheum 52:3054–3057[CrossRef][Medline]
  19. Tamiya G, Shinya M, Imanishi T, Ikuta T, Makino S, Okamoto K, Furugaki K, Matsumoto T, Mano S, Ando S, Nozaki Y, Yukawa W, Nakashige R, Yamaguchi D, Ishibashi H, Yonekura M, Nakami Y, Takayama S, Endo T, Saruwatari T, Yagura M, Yoshikawa Y, Fujimoto K, Oka A, Chiku S, Linsen SE, Giphart MJ, Kulski JK, Fukazawa T, Hashimoto H, Kimura M, Hoshina Y, Suzuki Y, Hotta T, Mochida J, Minezaki T, Komai K, Shiozawa S, Taniguchi A, Yamanaka H, Kamatani N, Gojobori T, Bahram S, Inoko H 2005 Whole genome association study of rheumatoid arthritis using 27 039 microsatellites. Hum Mol Genet 14:2305–2321[Abstract/Free Full Text]
  20. Barton A, Bowes J, Eyre S, Spreckley K, Hinks A, John S, Worthington J 2004 A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis Rheum 50:1117–1121[CrossRef][Medline]
  21. Caponi L, Petit-Teixeira E, Sebbag M, Bongiorni F, Moscato S, Pratesi F, Pierlot C, Osorio J, Chapuy-Regaud S, Guerrin M, Cornelis F, Serre G, Migliorini P; ECRAF 2005 A family based study shows no association between rheumatoid arthritis and the PADI4 gene in a white French population. Ann Rheum Dis 64:587–593[Abstract/Free Full Text]
  22. Iwamoto T, Ikari K, Nakamura T, Kuwahara M, Toyama Y, Tomatsu T, Momohara S, Kamatani N 2006 Association between PADI4 and rheumatoid arthritis: a meta-analysis. Rheumatology (Oxford) 45:804–807
  23. Todd JA, Mijovic C, Fletcher J, Jenkins D, Bradwell AR, Barnett AH 1989 Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping. Nature 338:587–589[CrossRef][Medline]
  24. Kochi Y, Yamada R, Suzuki A, Harley JB, Shirasawa S, Sawada T, Bae SC, Tokuhiro S, Chang X, Sekine A, Takahashi A, Tsunoda T, Ohnishi Y, Kaufman KM, Kang CP, Kang C, Otsubo S, Yumura W, Mimori A, Koike T, Nakamura Y, Sasazuki T, Yamamoto K 2005 A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet 37:478–485[CrossRef][Medline]
  25. Capon F, Semprini S, Chimenti S, Fabrizi G, Zambruno G, Murgia S, Carcassi C, Fazio M, Mingarelli R, Dallapiccola B, Novelli G 2001 Fine mapping of the PSORS4 psoriasis susceptibility region on chromosome 1q21. J Invest Dermatol 116:728–730[CrossRef][Medline]
  26. Dai KZ, Harbo HF, Celius EG, Oturai A, Sorensen PS, Ryder LP, Datta P, Svejgaard A, Hillert J, Fredrikson S, Sandberg-Wollheim M, Laaksonen M, Myhr KM, Nyland H, Vartdal F, Spurkland A 2001 The T cell regulator gene SH2D2A contributes to the genetic susceptibility of multiple sclerosis. Genes Immun 2:263–268[CrossRef][Medline]
  27. Kyogoku C, Dijstelbloem HM, Tsuchiya N, Hatta Y, Kato H, Yamaguchi A, Fukazawa T, Jansen MD, Hashimoto H, van de Winkel JG, Kallenberg CG, Tokunaga K 2002 Fc{gamma} receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility. Arthritis Rheum 46:1242–1254[CrossRef][Medline]
  28. Vaidya B, Imrie H, Geatch DR, Perros P, Ball SG, Baylis PH, Carr D, Hurel SJ, James RA, Kelly WF, Kemp EH, Young ET, Weetman AP, Kendall-Taylor P, Pearce SH 2000 Association analysis of the cytotoxic T lymphocyte antigen-4 (CTLA-4) and autoimmune regulator-1 (AIRE-1) genes in sporadic autoimmune Addison’s disease. J Clin Endocrinol Metab 85:688–691[Abstract/Free Full Text]
  29. Houston FA, Wilson V, Jennings CE, Owen CJ, Donaldson P, Perros P, Pearce SH 2004 Role of the CD40 locus in Graves’ disease. Thyroid 14:506–509[CrossRef][Medline]
  30. Shi YY, He L 2005 SHEsis, a powerful software platform for analysis of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 15:97–98[CrossRef][Medline]
  31. Ikari K, Momohara S, Nakamura T, Hara M, Yamanaka H, Tomatsu T, Kamatani N 2006 Supportive evidence for a genetic association of the FCRL3 promoter polymorphism with rheumatoid arthritis 10. Ann Rheum Dis 65:671–673[Abstract/Free Full Text]
  32. Simmonds MJ, Heward JM, Carr-Smith J, Foxall H, Franklyn JA, Gough SCL 2006 Contribution of single nucleotide polymorphisms within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves’ disease. J Clin Endocrinol Metab 91:1056–1061[Abstract/Free Full Text]
  33. Hu X, Chang M, Saiki RK, Cargill MA, Begovich AB, Ardlie KG, Criswell LA, Seldin MF, Amos CI, Gregersen PK, Kastner DL, Remmers EF 2006 The functional -169T->C single-nucleotide polymorphism in FCRL3 is not associated with rheumatoid arthritis in white North Americans. Arthritis Rheum 54:1022–1025[CrossRef][Medline]
  34. Smyth DJ, Howson JM, Payne F, Maier LM, Bailey R, Holland K, Lowe CE, Cooper JD, Hulme JS, Vella A, Dahlman I, Lam AC, Nutland S, Walker NM, Twells RC, Todd JA 2006 Analysis of polymorphisms in 16 genes in type 1 diabetes that have been associated with other immune-mediated diseases. BMC Med Genet 7:20–31[CrossRef][Medline]
  35. Turunen JA, Wessman M, Kilpikari R, Parkkonen M, Forsblom C, Groop PH; FinnDiane Study Group 2006 The functional variant –169C/T in the FCRL3 gene does not increase susceptibility to type 1 diabetes. Diabet Med 23:925–927[CrossRef][Medline]
  36. Eyre S, Bowes J, Potter C, Worthington J, Barton A 2006 Association of the FCRL3 gene with rheumatoid arthritis: a further example of population specificity? Arthritis Res Ther 8:R117
  37. Jennings CE, Owen CJ, Wilson V, Pearce SH 2005 No association of the codon 55 methionine to valine polymorphism in the SUMO4 gene with Graves’ disease. Clin Endocrinol (Oxf) 62:362–365[CrossRef][Medline]
  38. Owen CJ, Eden JA, Jennings CE, Wilson V, Cheetham TD, Pearce SH 2006 2006 Genetic association studies of the FOXP3 gene in Graves’ disease and autoimmune Addison’s disease in a UK population. J Mol Endocrinol 37:97–104[Abstract/Free Full Text]
  39. Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, Donnelly P; International HapMap Consortium 2005 A haplotype map of the human genome. Nature 437:1299–1320[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Ann Rheum DisHome page
M C Eike, G B N Nordang, T H Karlsen, K M Boberg, M H Vatn on behalf of the IBSEN study group, K Dahl-Jorgensen, K S Ronningen, G Joner, B Flato, A Bergquist, et al.
The FCRL3 -169T>C polymorphism is associated with rheumatoid arthritis and shows suggestive evidence of involvement with juvenile idiopathic arthritis in a Scandinavian panel of autoimmune diseases
Ann Rheum Dis, September 1, 2008; 67(9): 1287 - 1291.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. Sutherland, J. Davies, C. J. Owen, S. Vaikkakara, C. Walker, T. D. Cheetham, R. A. James, P. Perros, P. T. Donaldson, H. J. Cordell, et al.
Genomic Polymorphism at the Interferon-Induced Helicase (IFIH1) Locus Contributes to Graves' Disease Susceptibility
J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3338 - 3341.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow All Versions of this Article:
92/3/1106    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
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 Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Owen, C. J.
Right arrow Articles by Merriman, T. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Owen, C. J.
Right arrow Articles by Merriman, T. R.
Related Collections
Right arrow Thyroid
Right arrow Autoimmunity

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals