0021-972X/01/$03.00/0 The Journal of Clinical Endocrinology & Metabolism Copyright © 2001 by The Endocrine Society
Vol. 86, No. 2 Printed in U.S.A.
Evidence for a Graves’ Disease Susceptibility Locus at Chromosome Xp11 in a United Kingdom Population* HELEN IMRIE, BIJAYESWAR VAIDYA, PETROS PERROS, WILLIAM F. KELLY, ANTHONY D. TOFT, ERIC T. YOUNG, PAT KENDALL-TAYLOR, AND SIMON H. S. PEARCE Endocrine Group, Department of Medicine, University of Newcastle upon Tyne (H.I., B.V., P.K.-T., S.H.S.P.), Newcastle upon Tyne, United Kingdom NE2 4HH; Department of Medicine, Freeman Hospital (P.P.), Newcastle upon Tyne, United Kingdom NE7 7DN; Diabetes Care Center, Middlesbrough General Hospital (W.F.K.), Middlesbrough, United Kingdom TS5 5AZ; Endocrine Unit, Royal Infirmary of Edinburgh (A.D.T.), Edinburgh, United Kingdom EH3 9YW; and Department of Medicine, Wansbeck General Hospital (E.T.Y.), Ashington, Northumbria, United Kingdom NE63 9JJ ABSTRACT Graves’ disease (GD), which has a strong female preponderance (female/male ratio, ⬎5:1), is inherited as a complex genetic trait. Loci for GD have started to be defined using genome-wide approaches for genetic linkage. To date, 3 loci have been confirmed in at least 2 cohorts of GD patients, the strongest effect being at the cytotoxic T lymphocyte antigen-4 (CTLA-4) locus on chromosome 2q33 in our population. Two other loci for GD have recently been proposed, but not confirmed, on chromosomes Xq21 (GD3) and 14q31 (GD1). We studied a cohort of 75 sibling pairs with GD from the United Kingdom for linkage to 12 markers over a 83-cM region of the X chromosome and
for 8 markers over a 36-cM region of 14q31-q33. A peak multipoint nonparametric linkage score of 2.21 (P ⫽ 0.014) was found at marker DXS8083 on Xp11, which increased to a nonparametric linkage score of 3.18 (P ⫽ 0.001) in data that had been conditioned for allele sharing at the CTLA-4 locus under an epistatic model. There was no evidence to support linkage of GD to Xq21.33-q22 (GD3) or at the 14q31-q33 (GD1) region in our population. A locus with a moderate contribution to GD susceptibility (s ⫽ 1.4) is likely to exist in the Xp11 region, but we are unable to confirm that the GD1 or the GD3 regions contain major susceptibility loci in our United Kingdom GD population. (J Clin Endocrinol Metab 86: 626 – 630, 2001)
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RAVES’ DISEASE (GD), which is characterized by hyperthyroidism due to TSH receptor (TSHR)-stimulating autoantibodies, is inherited as a complex trait. Loci that confer susceptibility to GD are starting to be identified using the recent advances in complex genetic linkage methodologies, such as affected sibling pair studies and nonparametric linkage analysis. Historically, linkage studies of GD have not provided consistent evidence to favor linkage, for instance, at the major histocompatibility complex (MHC) locus where differences in study design, such as a small numbers of kindreds studied, different phenotype selection, and different linkage methodologies have led to conflicting linkage results (1– 4). Using larger collections of kindreds and more rigorous linkage methodologies, evidence for linkage of GD to several loci, including the MHC (6p21), CTLA-4 (2q23), and GD2 (20q13), have now been provided by studies of kindreds from two or more different populations (5–9). Three other loci, on chromosomes 14q31, Xq21, and 18q21, have also been implicated in GD susceptibility, but these studies only examined a single population and await confirmation (10 –12). In common with many other autoimmune disorders, there is a marked gender bias to the prevalence of GD, with a female to male ratio of at least 5:1 (13). Although there are
many possible explanations for this distribution of GD subjects, one simple hypothesis is that the dosage of an X chromosome-linked allele may be important in GD pathogenesis. Recently, Barbesino et al. demonstrated a putative GD locus at Xq21 (designated GD3), suggesting that an X-linked susceptibility allele may indeed have a role in GD (11). Linkage of type 1 diabetes (IDDM) to the short arm of the X chromosome (Xp13-p11) in MHC-conditioned data has also been reported, but the linked region is at least 50 cM from the putative GD3 locus (14). Chromosome Xp11 has also been linked to other autoimmune disorders, including rheumatoid arthritis and multiple sclerosis (15–17), suggesting that this colocalization of autoimmune loci may be a result of a common susceptibility polymorphism(s). As the TSH receptor (TSHR), which is located on 14q31, is the major autoantigen in GD, studies have been performed to look for antigenic polymorphisms within the large extracellular domain of the receptor. One such polymorphism, encoding a proline to threonine change at codon 52, was found to be associated with GD in a U.S. population (18). However, subsequent investigation has failed to confirm this result (19, 20). Recently, Tomer et al. reported linkage of GD to a nearby marker, D14S81, on chromosome 14q31 (designated the GD1 locus) using 19 families with autoimmune thyroid disease (AITD) containing 14 GD patients (10). This study has subsequently been enlarged to include 53 AITD families, containing 60 GD patients from the U.S., Italian, Israeli, and United Kingdom (UK) populations (21). Our aim in the current study was to examine in detail whether an
Received May 16, 2000. Revision received September 1, 2000. Accepted October 31, 2000. Address all correspondence and requests for reprints to: Dr. Simon Pearce, Department of Medicine, 4th Floor, Leech Building, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom NE2 4HH. E-mail:
[email protected]. * This work was supported by the Wellcome Trust.
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X CHROMOSOME AND GRAVES’ DISEASE
X-linked locus could be responsible for the female preponderance of GD cases and to confirm the preliminary evidence for linkage of GD to the Xq21 (GD3) and 14q31 (GD1) regions. Experimental Subjects Sixty-eight families with 2 or more siblings affected by GD [including 154 individuals with GD, 18 with autoimmune hypothyroidism (AH), and 71 unaffected subjects] were recruited from the north of England and the Lothian region of Scotland. GD was confirmed by the finding of biochemical hyperthyroidism, with evidence of 1 of the following: 1) significant thyroid-associated orbitopathy (American Thyroid Association class 3 or worse) (22), 2) diffuse increase in thyroid uptake on radionuclide scan, and 3) positive serum TSH binding inhibitory Ig antibodies. Blood samples were obtained from all siblings and from the parents of each sibship wherever possible. The cohort of families comprised 58 full siblings both with GD, 5 GD sibling trios, 1 GD quartet, 4 half-siblings with GD, and 8 mixed GD/AH full siblings. Additional second degree relatives had GD, AH, or were unaffected. There were 128 female and 26 male GD patients, with a mean age of onset of 36 yr (range, 9 – 67). All members of these sibships were Caucasian, and more than 95% of grandparents were of mainland UK or Irish origin. DNA from 100 normal control subjects without evidence or family history of autoimmune disease were also obtained from the local population. All studies were carried out with the approval of the regional and district ethics committees.
Materials and Methods Microsatellite genotyping Twelve markers spanning an 83-cM region of chromosome X encompassing Xp11 and Xq21.33-q22 were genotyped using fluorescently labeled PCR and were resolved on a semiautomated 373 sequencer (PE Applied Biosystems, Foster City, CA). The primers were taken from the Genethon genetic linkage map (http://www.genethon.fr/genethon_ en.html) with marker order of: ptel-DXS1052–13 cM-DXS1214 –10 cM-DXS1068 – 8 cM-DXS993–5 cM-DXS8035– 6 cM-DXS8083–2 cMDXS1055–10 cM-DXS8023– 8 cM-DXS8107–14 cM-DXS990 – 4 cMDXS8020 –3 cM-DXS8112-qtel. Similarly, for 14q31-q33 seven microsatellite markers were genotyped with a marker order of: cen-D14S74 –10 cM-D14S68(IDDM11)-13 cMD14S81(GD1)-5 cM-D14S1054(MNG1)-2 cM-D14S51–2 cM-D14S65– 4 cM-D14S267-qtel. The TSHR region lies 5 cM telomeric of D14S74. Alleles were scored using Genotyper 2.0 software (PE Applied Biosystems).
PCR genotyping of the TSHR polymorphism Detection of the Pro52Thr (CCC3 ACC) polymorphism in exon 1 of the TSHR gene was performed by PCR using an oligonucleotide primer that produces a Tth111I restriction site in the presence of A253, but not in C253 (23). Overnight digestion of the 227-bp fragment with Tth111I (New England Biolabs, Beverly, MA) yielded two fragments of 201 and 16 bp only in the presence of the A253 variant. Products were resolved on ethidium-stained 2% agarose gels. The Tth111I digestion assay for the P52T polymorphism was validated by direct DNA sequencing in six subjects, as previously described.
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their allele sharing at these markers using the modified GENEHUNTER Plus version 2.0, as previously described (25, 26). Briefly, to assess epistasis, the weighting file (0 or 1) was constructed by assigning families weight 0 if the NPL score was 0 or negative at the modifying locus, and weight 1 if their NPL score was positive. To test for heterogeneity, the weighting (1 or 0) was made by assigning families weight 1 if their NPL was zero or negative at the modifying locus and weight 0 if their NPL score was positive (26).
Results X chromosome
Linkage analysis. An 83-cM region of the X chromosome encompassing IDDMX on Xp11 and GD3 on Xq22 was analyzed for linkage to 83 AITD sibling pairs (Table 1) with 12 polymorphic markers. Two-point analysis showed a peak NPL score of 2.05 at DXS1055 on the proximal short arm, which is at least 35 cM away from DXS8020 (GD3; Table 2). Multipoint analysis showed a peak NPL of 2.21 (P ⫽ 0.014) at the marker DXS8083, close to DXS1055, using GD as the affected phenotype (Fig. 1). Scoring subjects with AITD as affected decreased the probability of linkage with a peak NPL score of 1.74 (P ⫽ 0.042) at DXS8083. The proportion of the 75 GD affected sibling pairs sharing zero alleles (z0) was 0.36 at DXS8083, suggesting that the locus-specific s for this region is 1.4. The peak multipoint NPL score in the 42 families with only affected females (affected sisters) was 1.73, which was similar to that found in the 26 families with an affected male-female sibling pair (NPL, 1.49). Conditioning for allele sharing at CTLA-4, MHC, and IDDM6. Families were weighted, in a binary fashion, according to the NPL scores at CTLA-4 (2q33, marker D2S117), at MHC (6p21, marker TNF␣), and at IDDM6 (18q21, marker D18S487), and nonparametric linkage analysis was carried out. Weighting GD families according to the NPL score at CTLA-4 (D2S117) showed evidence for an epistatic interaction between the chromosome Xp11 locus and CTLA-4, with a peak NPL score of 3.18 (P ⫽ 0.001) for the CTLA-4 weighted data vs. 2.21 (P ⫽ 0.014) before weighting (Fig. 1 and Table 3). However, weighting for CTLA-4 under a heterogeneity model showed a peak NPL score of 0.26 (P ⫽ 0.401). Weighting the GD families for MHC (TNF␣) showed some evidence to favor epistasis (peak NPL, 2.60; P ⫽ 0.005), but not heterogeneity (peak NPL, 0.71; P ⫽ 0.243) between the Xp11 and MHC loci, compared with the unweighted NPL score of 2.21. There was no effect of weighting for IDDM6 (D18S487) under an epistatic or heterogeneity model (peak NPL, 1.54 and 1.69, respectively) compared with the unweighted NPL score of 2.21 (Table 3).
Linkage analysis Two-point and multipoint nonparametric linkage (NPL) scores and marker information content were calculated using the score all function of the X-GENEHUNTER Plus and GENEHUNTER Plus packages (24, 25). The population allele frequencies for each marker were derived from local Caucasian controls. The case-control study of the P52T polymorphism was analyzed by Fisher’s exact test.
Conditioning data for CTLA-4, MHC and IDDM6 Possible interactions between the MHC (TNF␣), CTLA-4 (D2S117), and IDDM6 (D18S487) loci and the multipoint linkage data from the 12 X chromosome markers were analyzed by weighting families based on
TABLE 1. Phenotypes of affected sib-pairs with autoimmune thyroid disease
Full sib-pairs Half sib-pairs Total
Graves’ disease only (GD-GD)
Mixed Graves’ disease and autoimmune hypothyroid (GD-AH)a
All autoimmune thyroid disease
71 4 75
8 0 8
79 4 83
a Families were selected on the basis of two affected GD siblings. GD-AH sib-pairs make up additional members of the same families.
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TABLE 2. Two-point nonparametric analysis of the chromosome Xp22-q22 region in Graves’ disease and autoimmune thyroid disease Marker
Map position (cM)
DXS1052 DXS1214 DXS1068 DXS993 DXS8035 DXS8083 DXS1055 DXS8023 DXS8107 DXS990 DXS8020 DXS8112
0 13.1 23.5 31.3 36.2 42.0 43.8 52.9 61.5 75.0 79.7 82.7
Graves’ disease
Autoimmune thyroid disease
NPL score
P value
NPL score
P value
⫺0.281 0.910 1.037 1.036 1.420 1.058 2.046 1.116 ⫺0.973 ⫺0.285 ⫺0.854 ⫺1.120
0.609 0.182 0.150 0.151 0.079 0.146 0.021 0.133 0.834 0.610 0.803 0.869
⫺0.301 1.007 1.359 0.617 0.957 0.962 1.930 1.125 ⫺1.111 0.013 ⫺0.657 ⫺0.790
0.616 0.158 0.088 0.268 0.170 0.168 0.028 0.131 0.866 0.492 0.743 0.784
Information content
0.605 0.608 0.530 0.669 0.725 0.618 0.516 0.465 0.653 0.525 0.729 0.543
TABLE 3. Effect of weighting on peak multipoint NPL of GD families at Xp11 Weighted for
Unweighted CTLA-4 epistasis (2q33) CTLA-4 heterogeneity (2q33) HLA epistasis (6p21) HLA heterogeneity (6p21) IDDM6 epistasis (18q21) IDDM6 heterogeneity (18q21)
Peak NPL
P value
No. of families
2.21 3.18 0.26 2.60 0.71 1.54 1.69
0.014 0.001 0.401 0.005 0.243 0.059 0.047
68 34 34 29 39 34 34
either GD or AITD to the 14q31–33 markers (Table 4). Multipoint analysis showed a peak NPL score of 0.36 (P ⫽ 0.36, NS) at the marker D14S81, using AITD as the affected phenotype (Fig. 2). Scoring only subjects with GD as affected lessened the probability of linkage with a peak NPL score of 0.29 (P ⫽ 0.39, NS) at D14S81 (Fig. 2). Association analysis at the TSH receptor P52T polymorphism. A case-control study of the P52T polymorphism was carried out in 105 unrelated GD probands and 100 unaffected controls. There was no evidence to suggest allelic association of this polymorphism with GD with the Thr carrying allele present in 4 of 210 GD alleles (1.9%) compared with 10 of 200 control alleles (5%; P ⫽ 0.072, by Fisher’s exact test). FIG. 1. Nonparametric linkage analysis of chromosome Xp13-q22 in Graves’ disease and autoimmune thyroid disease. A, Information content (percentage) over the 12-marker map, spanning 83 cM. B, The multipoint NPL score obtained by scoring all affected subjects with the X-GENEHUNTER Plus package is shown, against the marker map on the x-axis. The NPL score designating only subjects with GD as affected is shown by the solid line; the NPL score designating all subjects with AITD as affected is shown by the dashed line, and the NPL score of GD affected subjects when weighted (0 or 1) for allele sharing at the CTLA-4 (D2S117) marker under an epistatic model is shown by the interrupted dash line. The peak unweighted NPL of 2.21 (P ⫽ 0.014) occurs at the marker DXS8083. The peak CTLA-4weighted NPL of 3.18 (P ⫽ 0.001) occurs 2 cM away at the marker DXS1055.
Chromosome 14
Linkage analysis. We examined the cohort of 83 affected AITD sibling pairs for linkage to 8 polymorphic markers over a 36-cM region of chromosome 14q31–33, which encompassed the TSHR and D14S81 (GD1) regions. Two-point nonparametric analysis showed no evidence to support linkage of
Discussion
Over the last 5 yr, there have been significant advances in knowledge about the genetic basis of autoimmune disorders, including Graves’ disease, rheumatoid arthritis, and systemic lupus erythematosus, which are all characterized by a preponderance of females. Both the candidate gene approach and genome-wide scanning in multiplex GD families have identified several chromosomal regions of linkage, including 6p21 (MHC) (5, 6), 2q33 (CTLA-4) (5, 6), and 20q13 (GD2) (8, 9), which have been confirmed in at least two separate populations. These results show that GD, like the majority of autoimmune diseases, is inherited as a complex multigenic trait. Furthermore, as has previously been demonstrated by genome-wide linkage scans in different populations with IDDM, multiple sclerosis, and rheumatoid arthritis, some of these susceptibility loci for GD are more important in some populations studied than in others. For instance, the CTLA-4 and MHC loci were linked with GD in families from the UK (5, 6), but the linkage of GD to these loci was not detected in
X CHROMOSOME AND GRAVES’ DISEASE
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TABLE 4. Two-point nonparametric analysis of the chromosome 14q31-33 region in Graves’ disease and autoimmune thyroid disease Marker
Map position (cM)
D14S74 TSHR D14S68 D14S81 D14S1054 D14S51 D14S65 D14S267
0 5.3 9.5 23.2 28.5 30.5 32.5 36.7
Graves’ disease
Autoimmune thyroid disease
NPL score
P value
NPL score
P value
0.125 0.339 ⫺1.812 0.314 0.457 ⫺0.635 ⫺0.333 ⫺1.683
0.449 0.366 0.965 0.376 0.323 0.736 0.629 0.954
0.334 0.347 ⫺1.435 0.481 0.404 ⫺0.871 0.001 ⫺1.437
0.368 0.363 0.925 0.314 0.342 0.807 0.498 0.925
Information content
0.561 0.056 0.614 0.552 0.537 0.598 0.570 0.721
putative IDDM locus IDDMX (14). Further evidence for a GD locus at this location (NPL, 3.18) was found in the subset of 34 families who shared alleles at the CTLA-4 locus, which strengthens the likelihood of linkage to this region and suggests a possible epistatic interaction between these loci. Further studies are needed to confirm these findings, but as this region of Xp contains putative IDDM, rheumatoid arthritis, and multiple sclerosis loci, a susceptibility polymorphism(s) common to several autoimmune disorders could underlie these comparable findings. The hypothesis that the dosage of an allele at this locus on Xp11 may account for the excess prevalence of GD in women is not supported by our data, as peak multipoint NPLs of female-female and female-male affected sibling pairs are similar at 1.73 and 1.49, respectively. In addition, as linkage of GD to CTLA-4 is strongest in families with affected males (5), and most evidence of linkage to Xp11 was found in families sharing CTLA-4 alleles, it is unlikely that this finding explains the preponderance of GD in females. Larger numbers of affected GD males will need to be studied to elucidate the basis for the relative protection of men against GD and other autoimmune disorders. FIG. 2. Nonparametric linkage analysis of chromosome 14q31–33 in GD and autoimmune thyroid disease. A, Information content (percentage) over the eight-marker map, spanning 36 cM. B, The NPL score obtained by scoring all affected subjects with the GENEHUNTER Plus package is shown against the marker map on the x-axis. The NPL score designating only subjects with GD as affected is shown by the solid line, and the NPL score designating all subjects with AITD as affected is shown by the dashed line. The peak NPL of 0.36 (P ⫽ 0.36) occurs at the marker D14S81. Please note the change in the y-axis scale between this panel and that of B in Fig. 1.
initial studies from the U.S. (10, 11). Thus, failure to replicate a linkage result in a complex autoimmune disease may be due to genuine genetic heterogeneity between populations, differences in family structure or phenotype, or a false positive linkage result (9). We investigated two putative loci for GD that had been postulated on the basis of parametric linkage analyses in a mixed European/American white population (10, 11). In our comparatively homogeneous UK population there is little evidence to support a locus for Graves’ disease susceptibility on either Xq21 (GD3) or 14q31 (GD1). Furthermore, in common with two other studies of the TSHR P52T polymorphism (19, 20), we are unable to confirm association of the Tcarrying allele with GD, although a role for TSHR gene polymorphisms cannot be excluded by this limited analysis. However, some evidence supportive of linkage to GD was found at Xp11 (NPL 2.21), an area that is within 10 cM of the
Acknowledgments We are grateful to Kim Johnson, Kath Brown, and Jean Gerrard for collecting patient samples; to Drs. D. Carr and D. M. Large for recruiting families; and to Dr. M. I. McCarthy for statistical advice.
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American Physiological Society Conference Topic: ”Genome & Hormones: An Integrative Approach to Gender Differences in Physiology” Date: October 18 –20, 2001 Location: Pittsburgh, Pennsylvania Abstracts Deadline: June 1, 2001 Advance Registration Deadline: August 3, 2001 For more information, or to receive a Call for Papers, contact the APS Membership Department, 9650 Rockville Pike, Bethesda, Maryland 20814-3991. Call 301-530-7171; Fax: 301-571-8313; E-mail:
[email protected]; Web: www.the-aps.org.
