Amit Allahabadia

Parameters for reliable results in genetic association studies in common disease

It is increasingly apparent that the identification of true genetic associations in common multifactorial disease will require studies comprising thousands rather than the hundreds of individuals employed to date. Using 2,873 families, we were unable to confirm a recently published association of the interleukin 12B gene in 422 type I diabetic families. These results emphasize the need for large datasets, small P values and independent replication if results are to be reliable.

Polymorphism of the CTLA-4 gene is associated with autoimmune hypothyroidism in the United Kingdom.

The cytotoxic T-lymphocyte-associated-4 (CTLA-4) molecule plays an important role in immune regulation by downregulating activation of T cells by antigen-presenting cells. Polymorphisms of the CTLA-4 gene have been shown to be associated with susceptibility to a number of autoimmune diseases. Some, but not all, studies suggest association between the CTLA-4 gene and autoimmune hypothyroidism. The aim of this study was to determine whether allelic association was present between the A-G single nucleotide polymorphism (SNP) at position 49 in exon 1 of the CTLA-4 gene and autoimmune hypothyroidism. The study was performed in 158 patients with autoimmune hypothyroidism and 384 control subjects. All subjects were white Caucasians from the United Kingdom. Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using the restriction enzyme Bbv1. There was a significant excess of the G allele in patients with autoimmune hypothyroidism compared with controls (43% vs. 32% respectively; chi2 = 10.7, p = 0.001; odds ratio 1.57). The GG and the AG genotypes were found to be more frequent in patients with autoimmune hypothyroidism than controls (17% vs. 8.8% and 50% vs. 46% respectively; chi2 = 11.7, p = 0.003). These results suggest that the CTLA-4 gene region on chromosome 2q33 is a susceptibility locus for autoimmune hypothyroidism in the United Kingdom.

The A-G polymorphism in exon 1 of the CTLA-4 gene is not associated with systemic lupus erythematosus.

OBJECTIVES Factors contributing to the development of systemic lupus erythematosus (SLE) remain largely unknown although are likely to include both environmental and genetic components. Studies on murine lupus have indicated a role for an antibody that blocks binding of cytotoxic T lymphocyte associated-4 (CTLA-4) to B7 on antigen presenting cells in the treatment of disease, suggesting that CTLA-4 may play an important part in the disease process. This study, therefore, investigated the frequency of a previously described A-G polymorphism in exon 1 of theCTLA-4 gene, the G allele of which has shown to be associated with both Graves’ disease and type I diabetes, to determine whether this polymorphism was playing a part in the development of SLE. METHODS One hundred and twenty six SLE patients and 363 control subjects were genotyped for the A-G polymorphism in exon 1 of theCTLA-4 gene. Target DNA was amplified using the polymerase chain reaction and the resulting product was digested using the BbvI restriction enzyme. RESULTS No differences in allele or genotype frequencies were observed between patients with SLE and control subjects. CONCLUSION These data suggest that the A-G polymorphism in exon 1 of theCTLA-4 gene does not play a part in the genetic susceptibility to the development of SLE.

Rituximab: a novel treatment for refractory Riedel’s thyroiditis

Summary This case report reviews the rare condition of Riedel’s thyroiditis via a patient case. The report highlights the difficulties that one may encounter when managing such a case in regards to patient symptoms, side effects of medications and the relapsing nature of the condition. The case report also highlights novel treatment in the treatment of Riedel’s thyroiditis, rituximab, how this works and the resolution of symptoms that we have achieved with our patient on this treatment. Learning points: Riedel’s thyroiditis is characterised by chronic inflammation, which causes dense fibrosis in the thyroid gland. Riedel’s thyroiditis can present with neck pain, dysphagia and dyspnoea with a firm, non-tender mass found on examination. Riedel’s thyroiditis is part of the IgG4-related systemic disorders. Rituximab is a monoclonal antibody that works against the protein CD20.

An unusual cause of breathlessness

A 68 year old woman was referred by her general practitioner with a history of exertional breathlessness over the past 10 years. Her symptoms had become more noticeable over the previous few months, especially when walking up inclines and climbing stairs. Echocardiography had shown good biventricular function and no evidence of valvular disease. Chest radiography was not performed at this time. She had been investigated for ischaemic heart disease in the past, and coronary angiography had excluded OK atherosclerotic disease. Basic spirometry was within normal limits and a flow-volume loop was not performed. Her medical history included hypertension, for which she was prescribed a calcium channel blocker. She had never smoked and drank alcohol very occasionally. On examination she appeared well and was not dyspnoeic at rest. Her blood pressure was slightly raised at 145/90 mm Hg and her pulse was 80 beats/min in sinus rhythm. Cardiovascular examination was normal and auscultation of her chest identified bilateral late inspiratory basal crepitations. Routine biochemical and haematological blood test results were normal. Thyroid stimulating hormone was slightly raised at 5.6 mIU/L (normal range 0.27-4.2) and free thyroxine 15.8 pmol/L (normal range 12.0-22.0; 1 pmol/L=0.08 ng/dL). She underwent chest radiography …