Paul R. Newby

Analysis of HLA class II genes in Hashimoto's thyroiditis reveals differences compared to Graves’ disease

Graves’ disease (GD) and Hashimotos thyroiditis (HT) represent the commonest forms of autoimmune thyroid disease (AITD) each presenting with distinct clinical features. Progress has been made in determining association of HLA class II DRB1, DQB1 and DQA1 loci with GD demonstrating a predisposing effect for DR3 (DRB1*03-DQB1*02-DQA1*05) and a protective effect for DR7 (DRB1*07-DQB1*02-DQA1*02). Small data sets have hindered progress in determining HLA class II associations with HT. The aim of this study was to investigate DRB1-DQB1-DQA1 in the largest UK Caucasian HT case control cohort to date comprising 640 HT patients and 621 controls. A strong association between HT and DR4 (DRB1*04-DQB1*03-DQA1*03) was detected (P=6.79 × 10−7, OR=1.98 (95% CI=1.51–2.59)); however, only borderline association of DR3 was found (P=0.050). Protective effects were also detected for DR13 (DRB1*13-DQB1*06-DQA1*01) (P=0.001, OR=0.61 (95% CI=0.45–0.83)) and DR7 (P=0.013, OR=0.70 (95% CI=0.53–0.93)). Analysis of our unique cohort of subjects with well characterized AITD has demonstrated clear differences in association within the HLA class II region between HT and GD. Although HT and GD share a number of common genetic markers this study supports the suggestion that differences in HLA class II genotype may, in part, contribute to the different immunopathological processes and clinical presentation of these related diseases.

The TNFalpha gene relates to clinical phenotype in alpha-1-antitrypsin deficiency.

BackgroundGenetic variation may underlie phenotypic variation in chronic obstructive pulmonary disease (COPD) in subjects with and without alpha 1 antitrypsin deficiency (AATD). Genotype specific sub-phenotypes are likely and may underlie the poor replication of previous genetic studies. This study investigated subjects with AATD to determine the relationship between specific phenotypes and TNFα polymorphisms.Methods424 unrelated subjects of the PiZZ genotype were assessed for history of chronic bronchitis, impairment of lung function and radiological presence of emphysema and bronchiectasis. A subset of subjects with 3 years consecutive lung function data was assessed for decline of lung function. Four single nucleotide polymorphisms (SNPs) tagging TNFα were genotyped using TaqMan® genotyping technologies and compared between subjects affected by each phenotype and those unaffected. Plasma TNFα levels were measured in all PiZZ subjects.ResultsAll SNPs were in Hardy-Weinberg equilibrium. A significant difference in rs361525 genotype (p = 0.01) and allele (p = 0.01) frequency was seen between subjects with and without chronic bronchitis, independent of the presence of other phenotypes. TNFα plasma level showed no phenotypic or genotypic associations.ConclusionVariation in TNFα is associated with chronic bronchitis in AATD.

Tag SNP screening of the PDCD1 gene for association with Graves' disease.

Objective  The Programmed Cell Death 1 gene (PDCD1) on chromosome 2q37.3 encodes PD‐1 which is involved in providing a negative signal to activated T cells. Large case‐control studies have shown association of PDCD1 with several autoimmune diseases although, to date, no such studies have been performed for Graves’ disease (GD). The objective of our study was to investigate eight tag SNPs representing the majority of common variation in PDCD1 within a well‐characterized large UK Caucasian GD dataset.

Phenotypic differences in alpha 1 antitrypsin-deficient sibling pairs may relate to genetic variation.

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 FEV1 < 80% predicted. Index siblings had lower FEV1 and FEV1/FVC ratio, a higher incidence of emphysema (all P ≤ 0.001) and lower gas transfer (P = 0.02). There was no correlation of FEV1 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 FEV1 (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.

Association of Fc receptor-like 5 (FCRL5) with Graves' disease is secondary to the effect of FCRL3.

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.

Association of FcGRIIa with Graves’ disease: a potential role for dysregulated autoantibody clearance in disease onset/progression

Objective  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.

CTLA4 polymorphisms and COPD.

To the Editors: We read with interest the article by Zhu et al. 1 describing the association of two single nucleotide polymorphisms (SNPs; rs231775 and rs3087243) within the CTLA4 gene and chronic bronchitis. Both of these polymorphisms may be risk factors for autoimmunity 2, and are often referred to as A49G and CT60, respectively. As alluded to briefly by the authors in their discussion, there has been recent interest in a possible role for autoimmunity in chronic obstructive pulmonary disease (COPD), hence shared genetic susceptibility with other autoimmune diseases would support this hypothesis. Although the authors report their association in two independent cohorts, general acceptance of the importance of this locus would require further validation in other COPD populations. We would …

Use of Tag single nucleotide polymorphisms (SNPs) to screen PTPN21: no association with Graves' disease

Objective  The protein‐tyrosine‐phosphate nonreceptor 22 gene (PTPN22) has recently been identified as a susceptibility locus for a number of autoimmune diseases including Graves’ disease (GD). PTPN21 is another member of the PTPN family and its gene PTPN21 maps to the first reported region of genetic linkage to GD, GD−1, on chromosome 14q31. The aim of this study was to determine whether PTPN21 is acting as a GD susceptibility locus in UK Caucasian subjects.