Fine Mapping of the 1p36 Deletion Syndrome Identifies Mutation of PRDM16 as a Cause of Cardiomyopathy

Deletion 1p36 syndrome is recognized as the most common terminal deletion syndrome. Here, we describe the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and we confirm its role in nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). With our own data and publically available data from array comparative genomic hybridization (aCGH), we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome that included only the terminal 14 exons of the transcription factor PRDM16 (PR domain containing 16), a gene that had previously been shown to direct brown fat determination and differentiation. Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with LVNC detected three mutations, including one truncation mutant, one frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported nonsynonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in more than 6,400 controls. PRDM16 has not previously been associated with cardiac disease but is localized in the nuclei of cardiomyocytes throughout murine and human development and in the adult heart. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in both contractile dysfunction and partial uncoupling of cardiomyocytes and also revealed evidence of impaired cardiomyocyte proliferative capacity. In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36 deletion syndrome as well as a proportion of nonsyndromic LVNC and DCM

Rare variants in NR2F2 cause congenital heart defects in humans

Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Nonsyndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2, a very significant enrichment (p = 7.7 × 10?7) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in NR2F2 including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3 bp duplication that cosegregated in a multiplex family. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. Via luciferase assays, we showed that all six coding sequence variants observed in individuals significantly alter the activity of NR2F2 on target promoters

Folate, vitamin B12 and postmenopausal breast cancer in a prospective study of French women.

International audienceOBJECTIVE: Adequate folate intake may be important for breast cancer prevention. Its protective effect may be influenced by factors associated with folate metabolism. We sought to evaluate folate intake in relation to breast cancer risk and examine whether the relation is affected by alcohol and intake of vitamin B(2) and B(12). METHODS: A prospective cohort analysis of folate intake was conducted among 62,739 postmenopausal women in the French E3N cohort who had completed a validated food frequency questionnaire in 1993. During nine years' follow-up, 1,812 cases of pathology-confirmed breast cancer were documented through follow-up questionnaires. Nutrients were categorized in quintiles and energy-adjusted using the regression-residual method. Cox model-derived relative risks (RRs) were adjusted for known breast cancer determinants. RESULTS: The multivariate RR for extreme quintiles of folate intake was 0.78 (95% CI: 0.67-0.90; p-trend = 0.001) [Median intake for Q(1) = 296 microg/day and Q(5) = 522 microg/day]. There was no evidence to support effect modification by alcohol or B(2) intake. The decreasing trend was most marked in women with higher folate and vitamin B(12 )intake. However, test for interaction was not statistically significant (p = 0.29). CONCLUSIONS: High folate intake was associated with decreased breast cancer risk. Vitamin B(12) intake may modify this association

Posting point-of-purchase nutrition information in university canteens does not influence meal choice and nutrient intake

BACKGROUND: Growing concern over the relation between out-of-home eating and overweight has triggered the use of point-of-purchase (POP) nutrition information when eating out of the home. In canteens that offer various unhealthy choices, the posting of POP nutrition information has the potential to improve meal choices and dietary intakes. OBJECTIVE: The objective of this study was to increase the proportion of consumed meals that comply with recommendations for energy, saturated fat, sodium, and vegetable content by 5%. DESIGN: A one-group pretest-posttest design was used. A total of 224 customers of 2 university canteens completed a questionnaire used for consumer profiling and 3-d food records to assess their meal choices and nutrient intakes. The 12 best meal combinations received star ratings and descriptors for nutrients or food groups that did not comply. RESULTS: Reported meal choices in canteens and nutrient intakes did not improve after the intervention (P > 0.05). The nutritional profile of the meal choice, obtained from a qualitative and quantitative nutritional assessment of meals, mirrored the nutritional profile of all meals offered (P > 0.05) and not that of the recommended meals offered (P 0.05). The healthiest choices were made by participants with greater objective nutrition knowledge, stronger health and weight-control motives, and a greater openness to change meal choices at baseline (P < 0.05). CONCLUSIONS: The posting of nutrition information in university canteens did not effectively change meal choices and nutrient intakes. Despite the intervention, meal choices were largely determined by meals offered. Therefore, nutrition-information interventions in canteens may be more effective with a healthier meal supply. This trial was registered at clinicaltrials.gov as NCT01249508

The Perils of Marketing Weight-Management Remedies and the Role of Health Literacy

This research explores the impact of weight-management remedy marketing on healthy lifestyle behaviors. Three studies demonstrate that exposure to drug (but not supplement) marketing for weight management encourages unhealthy consumer behavior as a result of consumers' reliance on erroneous beliefs about health remedies. The authors explore the possible mitigating role of two dimensions of healthy literacy: nutrition knowledge and remedy knowledge. Whether measured or manipulated, the results show remedy knowledge to be more effective than nutrition knowledge at lessening the effect of weight-management drug marketing on unhealthy behavior. The authors close with a discussion of the theoretical and substantive implications of this research for consumer welfare