A distinct adipose tissue gene expression response to caloric restriction predicts 6-mo weight maintenance in obese subjects

BACKGROUND: Weight loss has been shown to reduce risk factors associated with cardiovascular disease and diabetes; however, successful maintenance of weight loss continues to pose a challenge. OBJECTIVE: The present study was designed to assess whether changes in subcutaneous adipose tissue (scAT) gene expression during a low-calorie diet (LCD) could be used to differentiate and predict subjects who experience successful short-term weight maintenance from subjects who experience weight regain. DESIGN: Forty white women followed a dietary protocol consisting of an 8-wk LCD phase followed by a 6-mo weight-maintenance phase. Participants were classified as weight maintainers (WMs; 0-10% weight regain) and weight regainers (WRs; 50-100% weight regain) by considering changes in body weight during the 2 phases. Anthropometric measurements, bioclinical variables, and scAT gene expression were studied in all individuals before and after the LCD. Energy intake was estimated by using 3-d dietary records. RESULTS: No differences in body weight and fasting insulin were observed between WMs and WRs at baseline or after the LCD period. The LCD resulted in significant decreases in body weight and in several plasma variables in both groups. WMs experienced a significant reduction in insulin secretion in response to an oral-glucose-tolerance test after the LCD; in contrast, no changes in insulin secretion were observed in WRs after the LCD. An ANOVA of scAT gene expression showed that genes regulating fatty acid metabolism, citric acid cycle, oxidative phosphorylation, and apoptosis were regulated differently by the LCD in WM and WR subjects. CONCLUSION: This study suggests that LCD-induced changes in insulin secretion and scAT gene expression may have the potential to predict successful short-term weight maintenanc

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Importance Of Toll-Like Receptors For B Lymphocyte Survival In Primary Sjögren’s Syndrome

The Sjögren's syndrome is a systemic autoimmune disease characterized by lymphocytic infiltration of the glands responsible for mouth and eyes dryness. A minority of infiltrating B cells is organized as germinal centers while the majority is aggregated into clusters of transitional and marginal zone B cells. The Toll-like receptor 9 (TLR9) recognizes microbial DNA but also, sometimes, the self DNA. It appears to be a key determinant of the survival and differentiation of B lymphocytes. After laser micro-dissection of B cells from salivary glands, analyses by quantitative RT-PCR showed that transitional B cells express high level of TLR9 mRNA unlike B cells from germinal centers. B lymphocytes from healthy donors were sorted by flow cytometry and stimulated in vitro with their TLR9. It induces survival, activation and proliferation associated with phenotypic changes. Transitional B cells exhibited characteristics of the marginal zone, whereas mature B cells expressed follicular germinal center specificities. Finally, IgM and IgG were secreted by both population, but with elevated production of autoantibodies by the transitional B cells. Increased expression of TLR9 by transitional B cells suggests that they may be highly sensitive to differentiate into autoantibody secreting cells through maturation into the marginal zone into the salivary glands. TLR9 might be a target for forthcoming biotherapies. Le syndrome de Gougerot-Sjögren est une maladie autoimmune systémique caractérisée par une infiltration lymphocytaire des glandes responsable d'une sécheresse buccale et oculaire. Une minorité des lymphocytes B infiltrants est organisée en centres germinatifs tandis que la majorité est regroupée en agrégats de lymphocytes B transitionnels et de la zone marginale. Le Toll-like receptor 9 (TLR9) reconnaît l'ADN microbien mais aussi, parfois, l'ADN du soi. Il apparaît donc comme un élément déterminant de la survie et la différenciation des lymphocytes B. Après micro-dissection laser des lymphocytes B des glandes salivaires, une analyse par RT-PCR quantitative a montré que les lymphocytes B transitionnels expriment fortement l'ARNm de TLR9 contrairement à ceux des centres germinatifs. Des lymphocytes B de donneurs sains ont été triés par cytométrie en flux puis stimulés in vitro par leur TLR9. Il s’ensuit une survie, une activation et une prolifération associées à des modifications phénotypiques. Les lymphocytes B transitionnels présentent des caractéristiques de la zone marginale, tandis que les lymphocytes B matures expriment des spécificités folliculaires des centres germinatifs. Enfin, des IgM et des IgG sont sécrétées par les deux types de population, mais avec une production d'auto-anticorps plus élevée issue de la différenciation des lymphocytes B transitionnels. L’expression accrue de TLR9 par les lymphocytes B transitionnels suggère qu'ils pourraient être particulièrement sensibles à une différenciation en cellules sécrétrices d'auto-anticorps par une maturation vers la zone marginale au sein des glandes salivaires. Le TLR9 pourrait bien devenir la cible des futures biothérapies.The Sjögren's syndrome is a systemic autoimmune disease characterized by lymphocytic infiltration of the glands responsible for mouth and eyes dryness. A minority of infiltrating B cells is organized as germinal centers while the majority is aggregated into clusters of transitional and marginal zone B cells. The Toll-like receptor 9 (TLR9) recognizes microbial DNA but also, sometimes, the self DNA. It appears to be a key determinant of the survival and differentiation of B lymphocytes. After laser micro-dissection of B cells from salivary glands, analyses by quantitative RT-PCR showed that transitional B cells express high level of TLR9 mRNA unlike B cells from germinal centers. B lymphocytes from healthy donors were sorted by flow cytometry and stimulated in vitro with their TLR9. It induces survival, activation and proliferation associated with phenotypic changes. Transitional B cells exhibited characteristics of the marginal zone, whereas mature B cells expressed follicular germinal center specificities. Finally, IgM and IgG were secreted by both population, but with elevated production of autoantibodies by the transitional B cells. Increased expression of TLR9 by transitional B cells suggests that they may be highly sensitive to differentiate into autoantibody secreting cells through maturation into the marginal zone into the salivary glands. TLR9 might be a target for forthcoming biotherapies. Le syndrome de Gougerot-Sjögren est une maladie autoimmune systémique caractérisée par une infiltration lymphocytaire des glandes responsable d'une sécheresse buccale et oculaire. Une minorité des lymphocytes B infiltrants est organisée en centres germinatifs tandis que la majorité est regroupée en agrégats de lymphocytes B transitionnels et de la zone marginale. Le Toll-like receptor 9 (TLR9) reconnaît l'ADN microbien mais aussi, parfois, l'ADN du soi. Il apparaît donc comme un élément déterminant de la survie et la différenciation des lymphocytes B. Après micro-dissection laser des lymphocytes B des glandes salivaires, une analyse par RT-PCR quantitative a montré que les lymphocytes B transitionnels expriment fortement l'ARNm de TLR9 contrairement à ceux des centres germinatifs. Des lymphocytes B de donneurs sains ont été triés par cytométrie en flux puis stimulés in vitro par leur TLR9. Il s’ensuit une survie, une activation et une prolifération associées à des modifications phénotypiques. Les lymphocytes B transitionnels présentent des caractéristiques de la zone marginale, tandis que les lymphocytes B matures expriment des spécificités folliculaires des centres germinatifs. Enfin, des IgM et des IgG sont sécrétées par les deux types de population, mais avec une production d'auto-anticorps plus élevée issue de la différenciation des lymphocytes B transitionnels. L’expression accrue de TLR9 par les lymphocytes B transitionnels suggère qu'ils pourraient être particulièrement sensibles à une différenciation en cellules sécrétrices d'auto-anticorps par une maturation vers la zone marginale au sein des glandes salivaires. Le TLR9 pourrait bien devenir la cible des futures biothérapies

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

BACKGROUND: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data was donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

The impact of low-frequency and rare variants on lipid levels

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P&lt;10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P&lt;5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health