Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO) RAPIDO collaborative investigators; Bahadoer

Osteoarthritis [MIM 165720] is a common late-onset articular joint disease for which no pharmaceutical intervention is available to attenuate the cartilage degeneration. To identify a new osteoarthritis susceptibility locus, a genome-wide linkage scan and combined linkage association analysis were applied to 179 affected siblings and four trios with generalized osteoarthritis (The GARP study). We tested, for confirmation by association, 1478 subjects who required joint replacement and 734 controls in a UK population. Additional replication was tested in 1582 population-based females from the Rotterdam study that contained 94 cases with defined hip osteoarthritis and in 267 Japanese females with symptomatic hip osteoarthritis and 465 controls. Suggested evidence for linkage in the GARP study was observed on chromosome 14q32.11 (log of odds = 3.03, P = 1.9 x 10(-4)). Genotyping tagging single-nucleotide polymorphisms covering three important candidate genes revealed a common coding variant (rs225014; Thr92Ala) in the iodothyronine-deiodinase enzyme type 2 (D2) gene (DIO2 [MIM 601413]) which significantly explained the linkage signal (P = 0.006). Confirmation and replication by association in the additional osteoarthritis studies indicated a common DIO2 haplotype, exclusively containing the minor allele of rs225014 and common allele of rs12885300, with a combined recessive odds ratio of 1.79, 95% confidence interval (CI) 1.37-2.34 with P = 2.02 x 10(-5) in female cases with advanced/symptomatic hip osteoarthritis. The gene product of this DIO2 converts intracellular pro-hormone-3,3',5,5'-tetraiodothyronine (T4) into the active thyroid hormone 3,3',5-triiodothyronine (T3) thereby regulating intracellular levels of active T3 in target tissues such as the growth plate. Our results indicate a new susceptibility gene (DIO2) conferring risk to osteoarthritis.

Background: Overt and subclinical hyperthyroidism are both well-known independent risk factors for atrial fibrillation. We aimed to investigate the association of high-normal thyroid function with the development of atrial fibrillation in a prospective population-based study in the elderly. Methods: The association between thyroid-stimulating hormone (TSH) levels and atrial fibrillation was examined in 1426 subjects with TSH levels in the normal range (0.4-4.0 mU/L) and without atrial fibrillation at baseline. In 1177 of the 1426 persons in this group, we also examined the association between free thyroxine levels within the normal range (0.86-1.94 ng/dL [to convert to picomoles per liter, multiply by 12.871]) and atrial fibrillation. During a median follow-up of 8 years, 105 new cases of atrial fibrillation were identified. Hazard ratios (HRs) were calculated with 95% confidence intervals (CIs) using Cox proportional hazards models after adjustment for age, sex, current smoking, former smoking, body mass index, systolic blood pressure, hypertension, history of myocardial infarction, presence of heart failure, left ventricular hypertrophy on the electrocardiogram, diabetes mellitus, total cholesterol level, and time of the drawing of blood samples. Results: The risk of atrial fibrillation was associated with the TSH level. The multivariate adjusted HR was 1.94 (95% CI, 1.13-3.34, lowest vs highest quartile; P for trend, .02). The multivariate adjusted level of free thyroxine showed a graded association with risk of atrial fibrillation (HR, 1.62; 95% CI, 0.84-3.14, highest vs lowest quartile; P for trend, .06). Conclusion: Within the normal range of thyroid parameters, persons with high-normal thyroid function are at an increased risk of atrial fibrillation.

In line with the effect of TSH on bone in mice, serum TSH shows a positive trend with BMD in human subjects, a finding that is strengthened by the association between the TSHR-Asp727Glu polymorphism and femoral neck BMD. However, serum FT4 has a much greater influence on bone than TSH.

This is the first study to report an association of D1a-C/T and D1b-A/G polymorphisms with iodothyronine levels in the elderly. Polymorphisms in the DIO1 and DIO2 genes are not associated with early magnetic resonance imaging markers of AD. This suggests that the previously reported association between iodothyronine levels and brain atrophy reflects comorbidity or nonthyroidal illness rather than thyroid hormones being involved in developing AD.