Functional analysis of RYR1 variants in patients with confirmed susceptibility to malignant hyperthermia.

BACKGROUND: A major bottleneck to the introduction of noninvasive presymptomatic diagnostic tests for the pharmacogenetic disorder malignant hyperthermia is the lack of functional data for associated variants. METHODS: We screened 50 genes having a potential role in skeletal muscle calcium homeostasis using the HaloPlex™ (Agilent Technologies, Santa Clara, CA, USA) target enrichment system and next-generation sequencing. Twenty-one patients with a history of a clinical malignant hyperthermia reaction together with a positive in vitro contracture test were included. Eight variants in RYR1 were subsequently introduced into the cDNA for the human ryanodine receptor gene and tested in cultured human embryonic kidney (HEK293) cells for their effect on calcium release from intracellular stores in response to the ryanodine receptor-1 agonist 4-chloro-m-cresol using fura-2 as calcium indicator. Each variant was subjected to in silico curation using the European Malignant Hyperthermia Group scoring matrix and ClinGen RYR1 variant curation expert panel guidelines. RESULTS: Potentially causative RYR1 variants were identified in 15 patients. Of these, two families carried two RYR1 variants, five variants had been previously reported as 'pathogenic', two variants had been previously reported as 'likely benign', and eight were of 'uncertain significance'. Of these eight variants, four showed hypersensitivity to 4-chloro-m-cresol. Three variants were reclassified as either 'pathogenic' or 'likely pathogenic'. Two were classified as 'benign', whilst three remained of 'uncertain significance'. CONCLUSIONS: Three (p.Tyr1711Cys, p.Val2280Ile, and p.Arg4737Gln) additional variants can be added to the list of RYR1 disease-associated variants managed by the European Malignant Hyperthermia Group. These can therefore be used diagnostically in the future. Three variants (p.Glu2348Gly, p.Asn2634Lys, and p.Arg3629Trp) that remained classified as of uncertain significance require further family studies or a different functional test to determine clinical relevance in malignant hyperthermia.

Emphasizing appeal over health promotes preference for nutritious foods in people of low socioeconomic status.

People of low socioeconomic status (SES) have disproportionately poorer dietary health despite efforts to improve access and highlight the health benefits of nutritious foods. While health-focused labels and advertisements make healthier options easier to recognize, they can prime a number of negative associations about healthy foods (e.g., taste, satiety, cost), which may be particularly aversive for low SES groups. This within-subjects study recruited people of low and high SES (those without and with a college degree) and compared their product expectations, experiences, satiety, and choice when consuming a bottled fruit and vegetable smoothie promoted as pleasurable ("Crave") or as healthy ("Nutralean"). Relative to Nutralean, Crave improved product expectations and behavioral measures of satiety across all participants. However, Crave enhanced expectations, experiences, and product choice more for low SES than high SES participants. Importantly, improvements were achieved without deception of nutritional facts and without decreasing perceived healthiness or increasing perceived cost. These findings identify SES as an important moderator in health-focused promotion and suggest how the rapidly growing healthy food industry can more effectively appeal to low SES groups, contexts which the majority of Americans navigate.

Language in popular American culture constructs the meaning of healthy and unhealthy eating: Narratives of craveability, excitement, and social connection in movies, television, social media, recipes, and food reviews.

Many people want to eat healthier but struggle to do so, in part due to a dominant perception that healthy foods are at odds with hedonic goals. Is the perception that healthy foods are less appealing than unhealthy foods represented in language across popular entertainment media and social media? Six studies analyzed dialogue about food in six cultural products - creations of a culture that reflect its perspectives - including movies, television, social media posts, food recipes, and food reviews. In Study 1 (N = 617 movies) and Study 2 (N = 27 television shows), healthy foods were described with fewer appealing descriptions (e.g., "couldn't stop eating"; d = 0.59 and d = 0.37, respectively) and more unappealing descriptions (e.g., "I hate peas"; d = -.57 and d = -.63, respectively) than unhealthy foods in characters' speech from the film and television industries. Using sources with richer descriptive language, Studies 3-6 analyzed popular American restaurants' Facebook posts (Study 3, N = 2275), recipe descriptions from Allrecipes.com (Study 4, N = 1000), Yelp reviews from six U.S. cities (Study 5, N = 4403), and Twitter tweets (Study 6, N = 10,000) for seven specific themes. Meta-analytic results across Studies 3-6 showed that healthy foods were specifically described as less craveworthy (d = 0.51, 95% CI: 0.44-0.59), less exciting (d = 0.40, 95% CI: 0.31-0.49), and less social (d = 0.36, 95% CI: 0.04-0.68) than unhealthy foods. Machine learning methods further generalized patterns across 1.6 million tweets spanning 42 different foods representing a range of nutritional quality. These data suggest that strategies to encourage healthy choices must counteract pervasive narratives that dissociate healthy foods from craveability, excitement, and social connection in individuals' everyday lives.

Increasing Vegetable Intake by Emphasizing Tasty and Enjoyable Attributes: A Randomized Controlled Multisite Intervention for Taste-Focused Labeling.

Healthy food labels tout health benefits, yet most people prioritize tastiness in the moment of food choice. In a preregistered intervention, we tested whether taste-focused labels compared with health-focused labels increased vegetable intake at five university dining halls throughout the United States. Across 137,842 diner decisions, 185 days, and 24 vegetable types, taste-focused labels increased vegetable selection by 29% compared with health-focused labels and by 14% compared with basic labels. Vegetable consumption also increased. Supplementary studies further probed the mediators, moderators, and boundaries of these effects. Increased expectations of a positive taste experience mediated the effect of taste-focused labels on vegetable selection. Moderation tests revealed greater effects in settings that served tastier vegetable recipes. Taste-focused labels outperformed labels that merely contained positive words, fancy words, or lists of ingredients. Together, these studies show that emphasizing tasty and enjoyable attributes increases vegetable intake in real-world settings in which vegetables compete with less healthy options.

Evaluation of Cancer-Based Criteria for Use in Mainstream BRCA1 and BRCA2 Genetic Testing in Patients With Breast Cancer.

Importance: Increasing BRCA1 and BRCA2 (collectively termed herein as BRCA) gene testing is required to improve cancer management and prevent BRCA-related cancers. Objective: To evaluate mainstream genetic testing using cancer-based criteria in patients with cancer. Design, Setting, and Participants: A quality improvement study and cost-effectiveness analysis of different BRCA testing selection criteria and access procedures to evaluate feasibility, acceptability, and mutation detection performance was conducted at the Royal Marsden National Health Service Foundation Trust as part of the Mainstreaming Cancer Genetics (MCG) Programme. Participants included 1184 patients with cancer who were undergoing genetic testing between September 1, 2013, and February 28, 2017. Main Outcomes and Measures: Mutation rates, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios were the primary outcomes. Results: Of the 1184 patients (1158 women [97.8%]) meeting simple cancer-based criteria, 117 had a BRCA mutation (9.9%). The mutation rate was similar in retrospective United Kingdom (10.2% [235 of 2294]) and prospective Malaysian (9.7% [103 of 1061]) breast cancer studies. If traditional family history criteria had been used, more than 50% of the mutation-positive individuals would have been missed. Of the 117 mutation-positive individuals, 115 people (98.3%) attended their genetics appointment and cascade to relatives is underway in all appropriate families (85 of 85). Combining with the equivalent ovarian cancer study provides 5 simple cancer-based criteria for BRCA testing with a 10% mutation rate: (1) ovarian cancer; (2) breast cancer diagnosed when patients are 45 years or younger; (3) 2 primary breast cancers, both diagnosed when patients are 60 years or younger; (4) triple-negative breast cancer; and (5) male breast cancer. A sixth criterion-breast cancer plus a parent, sibling, or child with any of the other criteria-can be added to address family history. Criteria 1 through 5 are considered the MCG criteria, and criteria 1 through 6 are considered the MCGplus criteria. Testing using MCG or MCGplus criteria is cost-effective with cost-effectiveness ratios of $1330 per discounted QALYs and $1225 per discounted QALYs, respectively, and appears to lead to cancer and mortality reductions (MCG: 804 cancers, 161 deaths; MCGplus: 1020 cancers, 204 deaths per year over 50 years). Use of MCG or MCGplus criteria might allow detection of all BRCA mutations in patients with breast cancer in the United Kingdom through testing one-third of patients. Feedback questionnaires from 259 patients and 23 cancer team members (12 oncologists, 8 surgeons, and 3 nurse specialists) showed acceptability of the process with 100% of patients pleased they had genetic testing and 100% of cancer team members confident to approve patients for genetic testing. Use of MCGplus criteria also appeared to be time and resource efficient, requiring 95% fewer genetic consultations than the traditional process. Conclusions and Relevance: This study suggests that mainstream testing using simple, cancer-based criteria might be able to efficiently deliver consistent, cost-effective, patient-centered BRCA testing.

Identification of new Wilms tumour predisposition genes: an exome sequencing study.

BACKGROUND: Wilms tumour is the most common childhood renal cancer and is genetically heterogeneous. While several Wilms tumour predisposition genes have been identified, there is strong evidence that further predisposition genes are likely to exist. Our study aim was to identify new predisposition genes for Wilms tumour. METHODS: In this exome sequencing study, we analysed lymphocyte DNA from 890 individuals with Wilms tumour, including 91 affected individuals from 49 familial Wilms tumour pedigrees. We used the protein-truncating variant prioritisation method to prioritise potential disease-associated genes for further assessment. We evaluated new predisposition genes in exome sequencing data that we generated in 334 individuals with 27 other childhood cancers and in exome data from The Cancer Genome Atlas obtained from 7632 individuals with 28 adult cancers. FINDINGS: We identified constitutional cancer-predisposing mutations in 33 individuals with childhood cancer. The three identified genes with the strongest signal in the protein-truncating variant prioritisation analyses were TRIM28, FBXW7, and NYNRIN. 21 of 33 individuals had a mutation in TRIM28; there was a strong parent-of-origin effect, with all ten inherited mutations being maternally transmitted (p=0·00098). We also found a strong association with the rare epithelial subtype of Wilms tumour, with 14 of 16 tumours being epithelial or epithelial predominant. There were no TRIM28 mutations in individuals with other childhood or adult cancers. We identified truncating FBXW7 mutations in four individuals with Wilms tumour and a de-novo non-synonymous FBXW7 mutation in a child with a rhabdoid tumour. Biallelic truncating mutations in NYNRIN were identified in three individuals with Wilms tumour, which is highly unlikely to have occurred by chance (p<0·0001). Finally, we identified two de-novo KDM3B mutations, supporting the role of KDM3B as a childhood cancer predisposition gene. INTERPRETATION: The four new Wilms tumour predisposition genes identified-TRIM28, FBXW7, NYNRIN, and KDM3B-are involved in diverse biological processes and, together with the other 17 known Wilms tumour predisposition genes, account for about 10% of Wilms tumour cases. The overlap between these 21 constitutionally mutated predisposition genes and 20 genes somatically mutated in Wilms tumour is limited, consisting of only four genes. We recommend that all individuals with Wilms tumour should be offered genetic testing and particularly, those with epithelial Wilms tumour should be offered TRIM28 genetic testing. Only a third of the familial Wilms tumour clusters we analysed were attributable to known genes, indicating that further Wilms tumour predisposition factors await discovery. FUNDING: Wellcome Trust.

Changing Patient Mindsets about Non-Life-Threatening Symptoms During Oral Immunotherapy: A Randomized Clinical Trial.

BACKGROUND: Oral immunotherapy (OIT) can lead to desensitization to food allergens, but patients can experience treatment-related symptoms of allergic reactions that cause anxiety and treatment dropout. Interventions to improve OIT for patients are needed. OBJECTIVE: To determine whether fostering the mindset that non-life-threatening symptoms during OIT can signal desensitization improves treatment experience and outcomes. METHODS: In a randomized, blinded, controlled phase II study, 50 children/adolescents (28% girls, aged 7-17 years, M = 10.82, standard deviation = 3.01) completed 6-month OIT for peanut allergies. Patients and their parent(s) had monthly clinic visits at the Sean N. Parker Center for Allergy and Asthma Research between January 5, 2017, and August 3, 2017. All families received identical symptom management training. In a 1:1 approach, 24 patients and their families were informed that non-life-threatening symptoms during OIT were unfortunate side effects of treatment, and 26 patients and their families were informed that non-life-threatening symptoms could signal desensitization. Families participated in activities to reinforce these symptom mindsets. RESULTS: Compared with families informed that symptoms are side effects, families informed that symptoms can signal desensitization were less anxious (B = -0.46, 95% confidence interval [CI]: -0.76 to -0.16; P = .003), less likely to contact staff about symptoms (5/24 [9.4%] vs 27/154 [17.5%] instances; P = .036), experienced fewer non-life-threatening symptoms as doses increased (BInteraction = -0.54, 95% CI: -0.83 to -0.27; P < .001), less likely to skip/reduce doses (1/26 [4%] vs 5/24 [21%] patients; P = .065), and showed a greater increase in patient peanut-specific blood IgG4 levels (BInteraction = 0.76, 95% CI: 0.36 to 1.17; P < .001). CONCLUSIONS: Fostering the mindset that symptoms can signal desensitization improves OIT experience and outcomes. Changing how providers inform patients about non-life-threatening symptoms is a promising avenue for improving treatment.

Road to Home Program: A Performance Improvement Initiative to Increase Family and Nurse Satisfaction With the Discharge Education Process for Newly Diagnosed Pediatric Oncology Patients [Formula: see text].

Families of children, adolescents, and young adults with a new oncology diagnosis must absorb knowledge and skills needed to care for their child at home during a period of emergent hospitalizations and intense medical interventions. Effective nurse-led teaching and discharge planning begun at diagnosis can prepare families to safely care for their child following discharge, and be a source of satisfaction. The objective of this performance improvement initiative was to increase family and nurse satisfaction with new diagnosis education and discharge. Using standard performance improvement techniques, family and nursing stakeholder satisfaction with current processes was assessed. Working from established best practice and literature review; The Road to Home was designed and implemented. This novel, comprehensive program includes a visual, interactive display of required education based on the Children's Oncology Group Family Handbook© and hospital specific discharge materials; standardized teaching, tools and documentation for nursing; and caregiver discharge tool kits. Stakeholder input guided improvement strategies throughout the phases of implementation. Sustained increases in family and nurse satisfaction resulted from each phase. The Road to Home program is established for all families of newly diagnosed oncology patients and is meeting goals of increased family and nurse satisfaction with discharge education.

A Standardized Education Checklist for Parents of Children Newly Diagnosed With Cancer: A Report From the Children's Oncology Group.

Parents of children newly diagnosed with cancer must acquire new knowledge and skills in order to safely care for their child at home. Institutional variation exists in the methods and content used by nurses in providing the initial education. The goal of this project was to develop a checklist, standardized across institutions, to guide nursing education provided to parents of children newly diagnosed with cancer. A team of 21 members (19 nurses and 2 parent advocates) used current hospital educational checklists, expert consensus recommendations, and a series of iterative activities and discussions to develop one standardized checklist. The final checklist specifies primary topics that are essential to teach prior to the initial hospital discharge, secondary topics that should be discussed within the first month after the cancer diagnosis, and tertiary topics that should be discussed prior to completion of therapy. This checklist is designed to guide education and will set the stage for future studies to identify effective teaching strategies that optimize the educational process for parents of children newly diagnosed with cancer.

Multi-stage genome-wide association study identifies new susceptibility locus for testicular germ cell tumour on chromosome 3q25.

Recent genome-wide association studies (GWAS) and subsequent meta-analyses have identified over 25 SNPs at 18 loci, together accounting for >15% of the genetic susceptibility to testicular germ cell tumour (TGCT). To identify further common SNPs associated with TGCT, here we report a three-stage experiment, involving 4098 cases and 18 972 controls. Stage 1 comprised previously published GWAS analysis of 307 291 SNPs in 986 cases and 4946 controls. In Stage 2, we used previously published customised Illumina iSelect genotyping array (iCOGs) data across 694 SNPs in 1064 cases and 10 082 controls. Here, we report new genotyping of eight SNPs showing some evidence of association in combined analysis of Stage 1 and Stage 2 in an additional 2048 cases of TGCT and 3944 controls (Stage 3). Through fixed-effects meta-analysis across three stages, we identified a novel locus at 3q25.31 (rs1510272) demonstrating association with TGCT [per-allele odds ratio (OR) = 1.16, 95% confidence interval (CI) = 1.06-1.27; P = 1.2 × 10(-9)].

Germline mutations in the PAF1 complex gene CTR9 predispose to Wilms tumour.

Wilms tumour is a childhood kidney cancer. Here we identify inactivating CTR9 mutations in 3 of 35 Wilms tumour families, through exome and Sanger sequencing. By contrast, no similar mutations are present in 1,000 population controls (P<0.0001). Each mutation segregates with Wilms tumour in the family and a second mutational event is present in available tumours. CTR9 is a key component of the polymerase-associated factor 1 complex which has multiple roles in RNA polymerase II regulation and is implicated in embryonic organogenesis and maintenance of embryonic stem cell pluripotency. These data establish CTR9 as a Wilms tumour predisposition gene and suggest it acts as a tumour suppressor gene.

Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer.

Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.

A genome-wide association study identifies susceptibility loci for Wilms tumor.

Wilms tumor is the most common renal malignancy of childhood. To identify common variants that confer susceptibility to Wilms tumor, we conducted a genome-wide association study in 757 individuals with Wilms tumor (cases) and 1,879 controls. We evaluated ten SNPs in regions significantly associated at P < 5 × 10(-5) in two independent replication series from the UK (769 cases and 2,814 controls) and the United States (719 cases and 1,037 controls). We identified clear significant associations at 2p24 (rs3755132, P = 1.03 × 10(-14); rs807624, P = 1.32 × 10(-14)) and 11q14 (rs790356, P = 4.25 × 10(-15)). Both regions contain genes that are plausibly related to Wilms tumorigenesis. We also identified candidate association signals at 5q14, 22q12 and Xp22.

Gene-gene interactions in breast cancer susceptibility.

There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10(-4); ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 × 10(-4); CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation.

Germline mutations in RAD51D confer susceptibility to ovarian cancer.

Recently, RAD51C mutations were identified in families with breast and ovarian cancer. This observation prompted us to investigate the role of RAD51D in cancer susceptibility. We identified eight inactivating RAD51D mutations in unrelated individuals from 911 breast-ovarian cancer families compared with one inactivating mutation identified in 1,060 controls (P = 0.01). The association found here was principally with ovarian cancer, with three mutations identified in the 59 pedigrees with three or more individuals with ovarian cancer (P = 0.0005). The relative risk of ovarian cancer for RAD51D mutation carriers was estimated to be 6.30 (95% CI 2.86-13.85, P = 4.8 × 10(-6)). By contrast, we estimated the relative risk of breast cancer to be 1.32 (95% CI 0.59-2.96, P = 0.50). These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. Moreover, we show that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers.

Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion.

The main histological abnormality in congenital fiber type disproportion (CFTD) is hypotrophy of type 1 (slow twitch) fibers compared to type 2 (fast twitch) fibers. To investigate whether mutations in RYR1 are a cause of CFTD we sequenced RYR1 in seven CFTD families in whom the other known causes of CFTD had been excluded. We identified compound heterozygous changes in the RYR1 gene in four families (five patients), consistent with autosomal recessive inheritance. Three out of five patients had ophthalmoplegia, which may be the most specific clinical indication of mutations in RYR1. Type 1 fibers were at least 50% smaller, on average, than type 2 fibers in all biopsies. Recessive mutations in RYR1 are a relatively common cause of CFTD and can be associated with extreme fiber size disproportion.

Mutation and association analysis of GEN1 in breast cancer susceptibility.

GEN1 was recently identified as a key Holliday junction resolvase involved in homologous recombination. Somatic truncating GEN1 mutations have been reported in two breast cancers. Together these data led to the proposition that GEN1 is a breast cancer predisposition gene. In this article we have formally investigated this hypothesis. We performed full-gene mutational analysis of GEN1 in 176 BRCA1/2-negative familial breast cancer samples and 159 controls. We genotyped six SNPs tagging the 30 common variants in the transcribed region of GEN1 in 3,750 breast cancer cases and 4,907 controls. Mutation analysis revealed one truncating variant, c.2515_2519delAAGTT, which was present in 4% of cases and 4% of controls. We identified control individuals homozygous for the deletion, demonstrating that the last 69 amino acids of GEN1 are dispensable for its function. We identified 17 other variants, but their frequency did not significantly differ between cases and controls. Analysis of 3,750 breast cancer cases and 4,907 controls demonstrated no evidence of significant association with breast cancer for six SNPs tagging the 30 common GEN1 variants. These data indicate that although it also plays a key role in double-strand DNA break repair, GEN1 does not make an appreciable contribution to breast cancer susceptibility by acting as a high- or intermediate-penetrance breast cancer predisposition gene like BRCA1, BRCA2, CHEK2, ATM, BRIP1 and PALB2 and that common GEN1 variants do not act as low-penetrance susceptibility alleles analogous to SNPs in FGFR2. Furthermore, our analyses demonstrate the importance of undertaking appropriate genetic investigations, typically full gene screening in cases and controls together with large-scale case-control association analyses, to evaluate the contribution of genes to cancer susceptibility.

Genome-wide association study identifies five new breast cancer susceptibility loci.

Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls. We identified five new susceptibility loci, on chromosomes 9, 10 and 11 (P = 4.6 x 10(-7) to P = 3.2 x 10(-15)). We also identified SNPs in the 6q25.1 (rs3757318, P = 2.9 x 10(-6)), 8q24 (rs1562430, P = 5.8 x 10(-7)) and LSP1 (rs909116, P = 7.3 x 10(-7)) regions that showed more significant association with risk than those reported previously. Previously identified breast cancer susceptibility loci were also found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the disease.

Randomized controlled trial of the effect of selenium supplementation on thyroid function in the elderly in the United Kingdom.

BACKGROUND: Thyroid function depends on the essential trace mineral selenium, which is at the active center of the iodothyronine deiodinase enzymes that catalyze the conversion of the prohormone thyroxine (T(4)) to the active form of thyroid hormone, triiodothyronine (T(3)). OBJECTIVE: Because selenium intake in the United Kingdom has fallen during the past 25 y, we wanted to determine whether current selenium status might be limiting conversion of T(4) to T(3) in the elderly, in whom marginal hypothyroidism is relatively common. DESIGN: We investigated the effect of selenium supplementation in a double-blind, placebo-controlled trial in 501 elderly UK volunteers. Similar numbers of men and women from each of 3 age groups, 60-64 y, 65-69 y, and 70-74 y, were randomly allocated to receive 100, 200, or 300 microg Se/d as high-selenium yeast or placebo yeast for 6 mo. As part of the study, plasma selenium, thyroid-stimulating hormone, and total and free T(3) and T(4) were measured. Data from 368 euthyroid volunteers who provided blood samples at baseline and 6 mo were analyzed. RESULTS: Although selenium status at baseline correlated weakly with free T(4) (r = -0.19, P < 0.001) and with the ratio of free T(3) to free T(4) (r = 0.12, P = 0.02), we found no evidence of any effect of selenium supplementation on thyroid function, despite significant increases in plasma selenium. However, baseline plasma selenium in our study (x: 91 microg/L) was somewhat higher than in previous supplementation studies in which apparently beneficial effects were seen. CONCLUSION: We found no indication for increasing selenium intake to benefit T(4) to T(3) conversion in the elderly UK population.