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Influences of Age, Gender, Smoking, and Family History on Autoimmune Thyroid Disease Phenotype

Division of Medical Sciences (N.M., J.D.C.-S., K.B., S.C.G., J.A.F.), The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Northern General Hospital (A.A.), Sheffield S5 7AU, United Kingdom; Royal Bournemouth Hospital (M.A.), Bournemouth BH7 7DW, United Kingdom; University of Cambridge (V.K.C.), Addenbrookes Hospital, Cambridge CB2 2QQ, United Kingdom; Centre for Endocrine and Diabetes Sciences (J.H.L.), Cardiff University, Cardiff CF10 3US, United Kingdom; Institute of Human Genetics (S.H.S.P.), School of Clinical Medical Sciences, Newcastle University, Newcastle NE1 3BZ, United Kingdom; and Royal Devon and Exeter Hospital (B.V.), Exeter EX2 5DW, United Kingdom

Address all correspondence and requests for reprints to: Professor J. A. Franklyn, Institute of Biomedical Research, The Medical School, University of Birmingham, Edgbaston, Second Floor, Birmingham B15 2TT, United Kingdom. E-mail: j.a.franklyn{at}bham.ac.uk.

Context: Both genetic and environmental factors contribute to susceptibility to Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), as well as disease manifestations.

Objective: The objective of the study was to define how endogenous/environmental factors contribute to variation in phenotype.

Design/Setting: This was a multicenter cohort study.

Patients/Outcome Measures: We prospectively collected clinical/biochemical data as part of the protocol for a United Kingdom DNA collection for GD and HT. We investigated, in 2805 Caucasian subjects, whether age at diagnosis, gender, family history (FH), smoking history, and presence of goiter influenced disease manifestations.

Results: For 2405 subjects with GD, the presence of goiter was independently associated with disease severity (serum free T₄ at diagnosis) (P < 0.001). Free T₄ (P < 0.05) and current smoking (P < 0.001) were both independent predictors of the presence of ophthalmopathy. Approximately half of those with GD (47.4% of females, 40.0% of males) and HT (n = 400) (56.4% of females, 51.7% of males) reported a FH of thyroid dysfunction. In GD, a FH of hyperthyroidism in any relative was more frequent than hypothyroidism (30.1 vs. 24.4% in affected females, P < 0.001). In HT, a FH of hypothyroidism was more common than hyperthyroidism (42.1 vs. 22.8% in affected females, P < 0.001). For GD (P < 0.001) and HT (P < 0.05), a FH was more common in maternal than paternal relatives. The reporting of a parent with thyroid dysfunction (hyper or hypo) was associated with lower median age at diagnosis of both GD (mother with hyperthyroidism, P < 0.001) and HT (father with hypothyroidism, P < 0.05). In GD and HT, there was an inverse relationship between the number of relatives with thyroid dysfunction and age at diagnosis (P < 0.01).

Conclusions: Marked associations among age at diagnosis, disease severity, goiter, ophthalmopathy, smoking, and FH provide evidence for interactions between genetic and environmental/endogenous factors; understanding these may allow preventive measures or better tailoring of therapies.

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