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There is strong genetic association between type 1A diabetes (TID) and autoimmune thyroid disease (AITD). TID and AITD frequently occur together in the same individual, a condition classified as a variant of the autoimmune polyglandular syndrome type 3 (APS3). Because TID and AITD are individually strongly associated with different HLA class II sequences, we asked which HLA class II pocket sequence and structure confer joint susceptibility to both T1 D and AITD in the same individual (APS3v). We sequenced the HLA-DR gene in 105 APS3v patients and 153 controls, and identified a pocket amino acid signature, DR[beta]-Tyr-26, DR[beta]-Leu-67, DR[beta]-Lys-71, and DR[beta]-Arg-74, that was strongly associated with APS3v (P = 5.4 x [10.sup.-14], odds ratio = 8.38). Logistic regression analysis demonstrated that DR[beta]-Leu-67 (P = 9.4 x [10.sup.-13]) and DR[beta]-Arg-74 (P = 1.21 x [10.sup.-13]) gave strong independent effects on disease susceptibility. Structural modeling studies demonstrated that pocket 4 was critical for the development of T1 D+AITD; all disease-associated amino acids were linked to areas of the pocket that interact directly with the peptide and, therefore, influence peptide binding. The disease-susceptible HLA-DR pocket was more positively charged (Lys-71, Arg-74) compared with the protective pocket (Ala-71, Gin-74). We conclude that a specific pocket amino acid signature confers joint susceptibility to TID+AITD in the same individual by causing significant structural changes in the MHC II peptide binding pocket and influencing peptide binding and presentation. Moreover, Arg-74 is a major amino acid position for the development of several autoimmune diseases. These findings suggest that blocking the critical Arg-74 pocket might offer a method for treating certain autoimmune conditions. autoimmunity | gene | structure doi/ 10.1073/pnas.1009511107

A genome-wide association study of 2,120,505 SNPs in 2014 female twins from the TwinsUK study was performed to identify genetic loci associated with the metabolic phenotypes thyroid hormones which cause thyroid disorders, a common cause of ill health in the community. The study provide evidence for suggestive association of other SNPs with serum TSH, free T4, and free T3 concentrations and provide better insight into the genetic basis of pituitary-thyroid axis function and metabolic regulation.

A study was conducted to genotype 362, 129 SNPs in 4,300 Sardinians and identifies a strong association between alleles of rs4704397 and circulating thyroid-stimulating hormone (TSH) levels. Results revealed that PDE8B, by affecting cAMP concentrations in the thyroid, might alter thyroid-hormone levels in the serum and affect TSH release from the pituitary and thus might modulate thyroid physiology and the course of thyroid disease.

Byline: H. Monig (1), T. Arendt (1), M. Meyer (1), S. Kloehn (1), B. Bewig (1) Keywords: Key words Cytokines; Euthyroid sick syndrome; Non-thyroidal illness; Hypothalamo-pituitary-adrenal axis Abstract: Objective: To determine whether cytokine release or activation of the hypothalamo-pituitary-adrenal (HPA) axis is predominantly involved in the development of the euthyroid sick syndrome (ESS). Design: Prospective observational study. Setting: Intensive care unit at a tertiary care medical center in Germany. Patients: Nine patients with sepsis of different causes and eight patients with acute myocardial infarction. Interventions: None. Measurements and results: Immediately on admission and on day 7 the following parameters were determined: total thyroxine (T4), free thyroxine (FT4), total triiodothyronine (T3), thyrotropin (TSH), interleukin-1[beta] (IL-1[beta]), interleukin-2 (IL-2), soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), tumor necrosis factor [alpha] (TNF-[alpha]), serum cortisol and plasma adrenocorticotropin (ACTH). On admission, concentrations of all thyroid hormones and TSH were significantly lower in septic patients compared to non-septic patients, whereas all cytokines except IL-2 were significantly elevated in the sepsis group. By contrast, there was no difference in serum cortisol and plasma ACTH levels between the two groups. On day 7, T4 and T3 were still lower in the septic group, whereas IL-1[beta], sIL-2R and IL-6 were still elevated. Again, no differences were found with regard to cortisol and ACTH levels. Conclusions: Euthyroid sick syndrome occurs very early during the course of septic diseases. Significantly decreased levels of total T4, FT4, T3 and TSH in septic patients suggest central suppression of TSH as well as inhibition of thyroid hormone release in ESS. The HPA axis is activated in septic patients and in non-septic patients and does not contribute to the development of ESS. Author Affiliation: (1) Klinik fur Allgemeine Innere Medizin der Christian-Albrechts-Universitat zu Kiel, Schittenhelmstrasse 12, D-24105 Kiel, Germany e-mail: hmoenig@1med.uni-kiel.de Tel.: + 49-4 31-5 97 13 93 Fax: + 49-4 31-5 97 13 02, DE Article note: Received: 11 April 1999 Accepted: 19 October 1999

Generalized resistance to thyroid hormone (GRTH) is an inherited condition in which body tissues do not respond normally to high concentrations of thyroid hormone, causing delayed bone age and short stature, retardation, and learning disabilities. Increased awareness of this syndrome has resulted in a threefold increase in reported cases in the past few years. Diagnosis and treatment of GRTH at birth may help some patients to avoid the consequences associated with the syndrome. The case of an affected infant daughter of a mother who had GRTH suggests that early treatment may be beneficial, but only long-term follow-up will show whether it averted the mental and physical effects of GRTH. At this time, neonatal testing for a variety of treatable diseases, including hypothyroidism, is routine. The effects of GRTH are similar to those of untreated hypothyroidism, but no reliable test exists, and the condition can be confused with other defects, leading to inappropriate treatment. Cautious administration of graded doses of thyroid hormone after measurement of peripheral tissue responses will establish the presence of thyroid hormone resistance. Liothyronine worked faster than levothyroxine, and shortened the time to diagnose the condition and determine the dosage required for treatment. At this time, the criteria for treatment of GRTH have not been established, and in infants with high thyrotropin levels, hypothyroidism may be more harmful than treatment with thyroid hormone. Long-term observation of other family members with GRTH who do not receive treatment will help to resolve this question. If treatment proves effective in averting the effects of GRTH, a pilot study of systematic neonatal testing would help to establish its prevalence, and this would help determine the cost-effectiveness of routine neonatal screening for this condition. (Consumer Summary produced by Reliance Medical Information, Inc.)