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

Manji, Nilusha; Carr‐Smith, Jackie; Boelaert, Kristien; Allahabadia, Amit; Armitage, Mary; Chatterjee, Krishna; Lazarus, John H.; Pearce, Simon H. S.; Vaidya, Bijay; Gough, Stephen; Franklyn, Jayne A.

doi:10.1210/jc.2006-1402

Cited by 217 publications

(192 citation statements)

References 33 publications

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“…In addition, we confirmed the strong association of cigarette smoking and older age of onset of GD with ophthalmopathy in Polish-Caucasian patients. 29 Apart from NFKB1 genotypes, no other variables had a significant effect on the development of ophthalmopathy in Japanese GD patients, confirming our previous results. 30 Thus, the predisposing factors to ophthalmopathy in Japanese population remain to be established.…”

Section: Nfkb1 Promoter Polymorphism In Graves' Disease a Kurylowicz supporting

confidence: 88%

Association of NFKB1 −94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves' disease

et al. 2007

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Recently, a functional polymorphism in the NFKB1 gene promoter (À94ins/del ATTG) has been identified and associated with chronic inflammatory diseases. The aim of this study was to analyze the association of NFKB1 polymorphism with susceptibility to and phenotype of Graves' disease (GD). The initial case-control association study, performed in a Polish-Warsaw cohort (388 GD patients and 688 controls), was followed by the two replication studies performed in Polish-Gliwice and JapaneseKurume cohorts (198 GD patients and 194 controls, and 424 GD patients and 222 controls, respectively). The frequency of the À94del ATTG (D) allele was increased in GD compared to controls in Warsaw cohort. This finding was replicated in Gliwice cohort. Combining both Polish-Caucasian cohorts showed that the NFKB1 polymorphism was significantly associated with susceptibility to GD with a codominant mode of inheritance (P ¼ 0.00005; OR ¼ 1.37 (1.18-1.60)). No association with GD was found in Japanese cohort. However, subgroup analysis in Japanese GD patients revealed a correlation between the NFKB1genotype and the development of ophthalmopathy (P ¼ 0.009; OR ¼ 1.49 (1.10-2.01)), and the age of disease onset (P ¼ 0.009; OR ¼ 1.45 (1.09-1.91)). Our results suggest that NFKB1 À94ins/del ATTG polymorphism may be associated with susceptibility to and/or phenotype of GD.

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Section: Nfkb1 Promoter Polymorphism In Graves' Disease a Kurylowicz supporting

confidence: 88%

Association of NFKB1 −94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves' disease

et al. 2007

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“…The one-way ANOVA and Kruskal-Wallis tests were used for comparison between means and medians of different subgroups respectively. Regression analyses were performed between the five subgroups and serum fT 3 -index, fT 4 -index, and HSSscore. Trend analyses between the five subgroups for duration of symptoms and age, serum TSH, serum TBII, serum TPO-Ab, smoking pack years, and stress scores were performed using the Jonckheere-Terpstra test.…”

Section: Discussionmentioning

confidence: 99%

“…Serum T 3 and T 4 were measured with in-house RIA (11). T 3 -uptake was determined by a no-extraction, solid-phase 125 I RIA (Coat-A-Count, Diagnostic Products Corporation, Los Angeles, CA, USA).…”

Section: Laboratory Measurementsmentioning

confidence: 99%

“…It is well known that AITD clusters in families, and about 50% of patients with GH have a positive family history for AITDs (4,7). In view of genetic anticipation, one may presume that GH develops at a younger age in patients with a positive family history for AITD than in patients with a negative family history, and this was our second hypothesis.…”

Section: Introductionmentioning

confidence: 99%

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Variation in phenotypic appearance of Graves' disease: effect of genetic anticipation and duration of complaints

Vos¹,

Smit²,

Endert

et al. 2009

European Journal of Endocrinology

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Objective: Both genetic and environmental factors contribute to susceptibility of Graves' disease. In this study, we evaluated whether the duration of symptoms or a positive family history of autoimmune thyroid disease (AITD) are related to specific phenotypes in patients with a first episode of Graves' hyperthyroidism (GH). Design: Cross-sectional multicentre observational study. Patients: Two hundred and sixty-three consecutive untreated patients (mean age (GS.D.) 42.6G12.4 years; range 16-79 years) with a first episode of GH were included. Biochemical and clinical severity of GH was evaluated. Participants were asked to complete questionnaires about environmental factors (smoking behavior, use of estrogens, stress etc.), the duration of symptoms (interval between start of symptoms and date of referral) and family history for AITD. We ascertained the autoimmune nature of thyroid disease in affected relatives. Family history scores (FHS; high score indicating a close genetic relationship and/or a large number of affected relatives) were calculated for patients with a positive family history for AITD. Results: The peak incidence for the diagnosis of GH was 2-3 months after onset of symptoms (32% of patients). Duration of symptoms was negatively associated with age (P for trendZ0.04). A positive family history for AITD was present in 42.6% of patients. Patients with the highest FHS were more often male (PZ0.01) while age at onset was lower (PZ0.02) compared to patients with a lower FHS. Among patient groups with different FHS, no differences were found in exposure to environmental factors, nor in clinical or biochemical severity of hyperthyroidism. Conclusion: Our study does not support the hypothesis that a short duration of thyrotoxic symptoms until diagnosis is related to more severe hyperthyroidism in Graves' disease. We have found supporting evidence for the existence of genetic anticipation in Graves' disease by means of a lower age of onset in the group with the highest FHS.

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“…7 Control samples totaling 3446 were obtained from the 1958 British Birth cohort (http://www.b58cgene.sgul.ac.uk). The WTCCC had previously genotyped 900 GD patients and 1500 control subjects from these data sets in the 14 500 nsSNPs association scan.…”

Section: Materials and Methods Subjectsmentioning

confidence: 99%

Follow-up of potential novel Graves' disease susceptibility loci, identified in the UK WTCCC genome-wide nonsynonymous SNP study

et al. 2010

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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 (PX10 À3 ) 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 (P¼0.042-0.002) 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.

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

Abstract: 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.

Cited by 217 publications

References 33 publications

Association of NFKB1 −94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves' disease

Association of NFKB1 −94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves' disease

Variation in phenotypic appearance of Graves' disease: effect of genetic anticipation and duration of complaints

Follow-up of potential novel Graves' disease susceptibility loci, identified in the UK WTCCC genome-wide nonsynonymous SNP study

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