-
[show abstract]
[hide abstract]
ABSTRACT: The Fc receptor-like 3 (FCRL3) molecule, involved in controlling B-cell signalling, may contribute to the autoimmune disease process. Recently, a genome-wide screen detected association of neighbouring gene FCRL5 with Graves' disease (GD). To determine whether FCRL5 represents a further independent B-cell signalling GD susceptibility loci, we screened 12 tag SNPs, capturing all known common variation within FCRL5, in 5192 UK Caucasian GD index cases and controls.
A case-control association study investigating twelve tag SNPs within FCRL5 which captured the majority of known common variation within this gene region.
A data set comprising 2504 UK Caucasian patients with GD and 2688 geographically matched controls taken from the 1958 British Birth cohort.
We used the chi-squared test and haplotype analysis to investigate the association between the tag SNPs and GD before performing logistic regression analysis to determine whether association at FCRL5 was independent of the known FCRL3 association.
Three of the FCRL5 tag SNPs, rs6667109, rs3811035 and rs6692977 showed association with GD (P = 0·015-0·001, OR = 1·15-1·16). Logistic regression performed on all FCRL5 and, previously screened, FCRL3 tag SNPs revealed that association with FCRL5 was secondary to linkage disequilibrium with the FCRL3, rs11264798 and rs10489678 SNPs.
FCRL5 does not appear to be exerting an independent effect on the development of GD in the UK. Fine mapping of the entire FCRL region is required to determine the exact location of the aetiological variant/s present.
Clinical Endocrinology 11/2010; 73(5):654-60. · 3.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Objective The Fc receptor-like 3 (FCRL3) molecule, involved in controlling B-cell signalling, may contribute to the autoimmune disease process. Recently, a genome-wide screen detected association of neighbouring gene FCRL5 with Graves’ disease (GD). To determine whether FCRL5 represents a further independent B-cell signalling GD susceptibility loci, we screened 12 tag SNPs, capturing all known common variation within FCRL5, in 5192 UK Caucasian GD index cases and controls.Design A case–control association study investigating twelve tag SNPs within FCRL5 which captured the majority of known common variation within this gene region.Patients A data set comprising 2504 UK Caucasian patients with GD and 2688 geographically matched controls taken from the 1958 British Birth cohort.Measurements We used the chi-squared test and haplotype analysis to investigate the association between the tag SNPs and GD before performing logistic regression analysis to determine whether association at FCRL5 was independent of the known FCRL3 association.Results Three of the FCRL5 tag SNPs, rs6667109, rs3811035 and rs6692977 showed association with GD (P = 0·015–0·001, OR = 1·15–1·16). Logistic regression performed on all FCRL5 and, previously screened, FCRL3 tag SNPs revealed that association with FCRL5 was secondary to linkage disequilibrium with the FCRL3, rs11264798 and rs10489678 SNPs.Conclusions FCRL5 does not appear to be exerting an independent effect on the development of GD in the UK. Fine mapping of the entire FCRL region is required to determine the exact location of the aetiological variant/s present.
Clinical Endocrinology 10/2010; 73(5):654 - 660. · 3.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A recent association scan using a genome-wide set of nonsynonymous coding single-nucleotide polymorphisms (nsSNPs) conducted in four diseases including Graves' disease (GD), identified nine novel possible regions of association with GD. We used a case-control approach in an attempt to replicate association of these nine regions in an independent collection of 1578 British GD patients and 1946 matched Caucasian controls. Although none of these loci showed evidence of association with GD in the independent data set, when combined with the original Wellcome Trust Case-Control Consortium study group, minor differences in allele frequencies (P>or=10(-3)) remained in the combined collection of 5924 subjects for four of the nsSNPs, present within HDLBP, TEKT1, JSRP1 and UTX. An additional 29 Tag SNPs were screened within these four gene regions to determine if further associations could be detected. Similarly, minor differences only (P=0.042-0.002) were detected in two HDLBP and two TEKT1 Tag SNPs in the combined UK GD collection. In conclusion, it is unlikely that the SNPs selected in this replication study have a significant effect on the risk of GD in the United Kingdom. Our study confirms the need for large data sets and stringent analysis criteria when searching for susceptibility loci in common diseases.
European journal of human genetics: EJHG 05/2010; 18(9):1021-6. · 3.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Previous genome-wide microsatellite screening in Graves' disease (GD) has suggested several regions of linkage to disease. Although replication has been inconsistent, some regions such as chromosome 5q31-33 have been associated with several Oriental GD patient cohorts. Recently, two studies have reported association of single-nucleotide polymorphism (SNP) rs31480 in interleukin 3 (IL-3) and the rs1368408 and SNP75 (-623 approximately -622 AG/-T) SNPs in secretoglobulin family 3a member 2 (SCGB3A2) with GD and suggested that this may account for linkage to the 5q31-33 region in Oriental GD datasets. We sought to confirm this association in a large Caucasian U.K. GD cohort.
The rs31480 SNP was shown to tag all known common variations in IL-3 and the rs1368408 SNP was shown to tag all common variations in SCGB3A2. The SCGB3A2 SNP75 was found to be rare in the U.K. Caucasian population and, therefore, was not screened. We genotyped rs31480 and rs1368408 and performed a case-control association study in 2504 GD cases and 2688 controls from the U.K.
Association between the SCGB3A2 rs1368408 SNP and GD was detected (p = 0.007, odds ratio = 1.18, 95% confidence intervals = 1.05-1.33). No association between the IL-3 rs31804 SNP and U.K. Caucasian GD patients was observed.
These data suggest that chromosome 5q31-q33 contains a susceptibility locus for Caucasian GD patients as well as Oriental GD patients. Although association was detected between SCGB3A2 and U.K. Caucasian GD subjects, the size of effect was smaller than that seen in the Oriental population (odds ratio = 1.28-1.73). Fine mapping within this region will be required to determine the exact location of the etiological variants present within this region for both Caucasian and Oriental GD patients.
Thyroid: official journal of the American Thyroid Association 03/2010; 20(4):413-7. · 2.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Although autoantibody production is a key feature of autoimmunity, it is not known whether variation in autoantibody production and clearance pathways is involved in disease susceptibility. The Fc Gamma Receptor IIa (FcGRIIa) molecule is involved in the clearance of autoantibodies and a functional single nucleotide polymorphism (SNP), rs1801274, which has been shown to alter autoantibody clearance, has been associated with a number of autoimmune diseases (AIDs) including systemic lupus erythematosus and type 1 diabetes. This study aimed to determine whether FcGRIIa is associated with Graves' disease (GD) in the UK Caucasian population by Tag SNP screening common polymorphisms within the FcGRIIa region.
A case control association study investigating nine Tag SNPs within FcGRIIa, which captured the majority of known common variation within this gene region.
A dataset comprising 2504 UK Caucasian GD patients and 2784 geographically matched controls taken from the 1958 British Birth cohort.
We used the chi(2)-test to investigate association between the Tag SNPs and GD.
Association between the rs1801274 (P = 0.003, OR = 1.12 [95% CI = 1.03-1.22] and rs6427598 (P = 0.012, OR = 0.90 [95% CI = 0.83-0.98]) SNPs and GD was observed. No other SNPs showed association with GD. No associations were seen between any of the SNPs investigated and specific GD clinical phenotypes.
This study suggests that variation in FcGRIIa predisposes to GD and further supports the role of FcGRIIa as a susceptibility locus for AIDs in general.
Clinical Endocrinology 02/2010; 73(1):119-25. · 3.17 Impact Factor
-
Kristien Boelaert, Paul R Newby,
Matthew J Simmonds,
Roger L Holder,
Jacqueline D Carr-Smith,
Joanne M Heward,
Nilusha Manji,
Amit Allahabadia,
Mary Armitage,
Krishna V Chatterjee,
John H Lazarus,
Simon H Pearce,
Bijay Vaidya,
Stephen C Gough,
Jayne A Franklyn
[show abstract]
[hide abstract]
ABSTRACT: Common autoimmune disorders tend to coexist in the same subjects and to cluster in families.
We performed a cross-sectional multicenter study of 3286 Caucasian subjects (2791 with Graves' disease; 495 with Hashimoto's thyroiditis) attending UK hospital thyroid clinics to quantify the prevalence of coexisting autoimmune disorders. All subjects completed a structured questionnaire seeking a personal and parental history of common autoimmune disorders, as well as a history of hyperthyroidism or hypothyroidism among parents.
The frequency of another autoimmune disorder was 9.67% in Graves' disease and 14.3% in Hashimoto's thyroiditis index cases (P=.005). Rheumatoid arthritis was the most common coexisting autoimmune disorder (found in 3.15% of Graves' disease and 4.24% of Hashimoto's thyroiditis cases). Relative risks of almost all other autoimmune diseases in Graves' disease or Hashimoto's thyroiditis were significantly increased (>10 for pernicious anemia, systemic lupus erythematosus, Addison's disease, celiac disease, and vitiligo). There was relative "clustering" of Graves' disease in the index case with parental hyperthyroidism and of Hashimoto's thyroiditis in the index case with parental hypothyroidism. Relative risks for most other coexisting autoimmune disorders were markedly increased among parents of index cases.
This is one of the largest studies to date to quantify the risk of diagnosis of coexisting autoimmune diseases in more than 3000 index cases with well-characterized Graves' disease or Hashimoto's thyroiditis. These risks highlight the importance of screening for other autoimmune diagnoses if subjects with autoimmune thyroid disease present with new or nonspecific symptoms.
The American journal of medicine 02/2010; 123(2):183.e1-9. · 4.47 Impact Factor
-
Oliver J Brand,
Jeffrey C Barrett,
Matthew J Simmonds, Paul R Newby,
Christopher J McCabe,
Christopher K. Bruce,
Boris Kysela,
Jackie D Carr-Smith,
Thomas Brix,
Penny J Hunt,
Wilmar M Wiersinga,
Laszlo Hegedüs,
John Connell,
John A H Wass,
Jayne A Franklyn,
Anthony P Weetman,
Joanne M Heward,
Stephen C L Gough
[show abstract]
[hide abstract]
ABSTRACT: Graves’ disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclusive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800 kb region of the TSHR to refine association in a cohort of 768 GD subjects and 768 matched controls. In total, 28 SNPs revealed association with GD ( P < 0.05), with strongest SNP associations at rs179247 ( χ 2 = 32.45, P = 8.90 × 10−8, OR = 1.53, 95% CI = 1.32–1.78) and rs12101255 ( χ 2 = 30.91, P = 1.95 × 10−7, OR = 1.55, 95% CI = 1.33–1.81), both located in intron 1 of the TSHR . Association of the most associated SNP, rs179247, was replicated in 303 GD families ( P = 7.8 × 10−4). In addition, we provide preliminary evidence that the disease-associated genotypes of rs179247 (AA) and rs12101255 (TT) show reduced mRNA expression ratios of flTSHR relative to two alternate TSHR mRNA splice variants.
Human Molecular Genetics 02/2009; · 7.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Alpha-1-antitrypsin deficiency is associated with variable development of airflow obstruction and emphysema. Index patients have greater airflow obstruction than subjects detected by screening, but it is unclear if this reflects smoking differences and/or ascertainment bias, or is due to additional genetic factors. In this study 72 sibling pairs with alpha-1-antitrypsin deficiency were compared using lung function measurements and HRCT chest. Tag single nucleotide polymorphisms to cover all common variation in four genes involved in relevant inflammatory pathways (Tumour necrosis factor alpha, Transforming growth Factor beta, Surfactant protein B and Vitamin D binding protein) were genotyped using TaqMan technology and compared between pairs for their frequency and relationship to lung function. 63.5% of non-index siblings had airflow obstruction and 59.5% an FEV(1) < 80% predicted. Index siblings had lower FEV(1) and FEV(1)/FVC ratio, a higher incidence of emphysema (all P <or= 0.001) and lower gas transfer (P = 0.02). There was no correlation of FEV(1) between siblings but KCO was significantly correlated (r = 0.42, P = 0.002). Quantitative analyses against lung function showed that a polymorphism in Surfactant protein B was associated with FEV(1) (P = 0.002). This result was replicated in a non-sibling group (P = 0.01). Our results show that clinical differences in families with alpha-1-antitrypsin deficiency are not solely explained by smoking or ascertainment bias and may be due to variation within genes involved in inflammatory pathways.
COPD Journal of Chronic Obstructive Pulmonary Disease 12/2008; 5(6):353-9. · 1.79 Impact Factor
-
Paul R Burton,
David G Clayton,
Lon R Cardon,
Nick Craddock,
Panos Deloukas,
Audrey Duncanson,
Dominic P Kwiatkowski,
Mark I McCarthy,
Willem H Ouwehand,
Nilesh J Samani, [......],
Anne-Marie Sims,
Alison Dowling,
Jacqueline Taylor,
Tracy Doan,
John C Davis,
Laurie Savage,
Michael M Ward,
Thomas L Learch,
Michael H Weisman,
Mathew Brown
[show abstract]
[hide abstract]
ABSTRACT: We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.
Nature Genetics 12/2007; 39(11):1329-37. · 35.53 Impact Factor
-
Melanie Newport,
Giorgio Sirugo,
Emily Lyons,
Fredrik Vannberg,
Adrian V. S. Hill,
Linda A. Bradbury,
Claire Farrar,
Jennifer J. Pointon,
Paul Wordsworth,
Matthew A. Brown, [......],
Sarah L. Mitchell, Paul R. Newby,
Oliver J. Brand,
Jackie Carr-Smith,
Simon H. S. Pearce,
R. McGinnis,
A. Keniry,
P. Deloukas,
John D. Reveille,
others
[show abstract]
[hide abstract]
ABSTRACT: We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis ( AS), autoimmune thyroid disease (AITD), multiple sclerosis ( MS) and breast cancer ( BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major `seronegative' diseases.
Nature Genetics. 01/2007; 39(11):1329-1337.
