Association between variations in the TLR4 gene and incident type 2 diabetes is modified by the ratio of total cholesterol to HDL-cholesterol

<p>Abstract</p> <p>Background</p> <p>Toll-like receptor 4 (TLR4), the signaling receptor for lipopolysaccharides, is an important member of the innate immunity system. Since several studies have suggested that type 2 diabetes might be associated with changes in the innate immune response, we sought to investigate the association between genetic variants in the <it>TLR4 </it>gene and incident type 2 diabetes.</p> <p>Methods</p> <p>A case-cohort study was conducted in initially healthy, middle-aged subjects from the MONICA/KORA Augsburg studies including 498 individuals with incident type 2 diabetes and 1,569 non-cases. Seven SNPs were systematically selected in the <it>TLR4 </it>gene and haplotypes were reconstructed.</p> <p>Results</p> <p>The effect of <it>TLR4 </it>SNPs on incident type 2 diabetes was modified by the ratio of total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C). In men, four out of seven <it>TLR4 </it>variants showed significant interaction with TC/HDL-C after correction for multiple testing (p < 0.01). The influence of the minor alleles of those variants on the incidence of type 2 diabetes was observed particularly for male patients with high values of TC/HDL-C. Consistent with these findings, haplotype-based analyses also revealed that the effect of two haplotypes on incident type 2 diabetes was modified by TC/HDL-C in men (p < 10^-3). However, none of the investigated variants or haplotypes was associated with type 2 diabetes in main effect models without assessment of effect modifications.</p> <p>Conclusion</p> <p>We conclude that minor alleles of several <it>TLR4 </it>variants, although not directly associated with type 2 diabetes might increase the risk for type 2 diabetes in subjects with high TC/HDL-C. Additionally, our results confirm previous studies reporting sex-related dissimilarities in the development of type 2 diabetes.</p

Unexpected diversity in socially synchronized rhythms of shorebirds

The behavioural rhythms of organisms are thought to be under strong selection, influenced by the rhythmicity of the environment. Such behavioural rhythms are well studied in isolated individuals under laboratory conditions, but free-living individuals have to temporally synchronize their activities with those of others, including potential mates, competitors, prey and predators. Individuals can temporally segregate their daily activities (for example, prey avoiding predators, subordinates avoiding dominants) or synchronize their activities (for example, group foraging, communal defence, pairs reproducing or caring for offspring). The behavioural rhythms that emerge from such social synchronization and the underlying evolutionary and ecological drivers that shape them remain poorly understood. Here we investigate these rhythms in the context of biparental care, a particularly sensitive phase of social synchronization where pair members potentially compromise their individual rhythms. Using data from 729 nests of 91 populations of 32 biparentally incubating shorebird species, where parents synchronize to achieve continuous coverage of developing eggs, we report remarkable within-and between-species diversity in incubation rhythms. Between species, the median length of one parent's incubation bout varied from 1-19 h, whereas period length-the time in which a parent's probability to incubate cycles once between its highest and lowest value-varied from 6-43 h. The length of incubation bouts was unrelated to variables reflecting energetic demands, but species relying on crypsis (the ability to avoid detection by other animals) had longer incubation bouts than those that are readily visible or who actively protect their nest against predators. Rhythms entrainable to the 24-h light-dark cycle were less prevalent at high latitudes and absent in 18 species. Our results indicate that even under similar environmental conditions and despite 24-h environmental cues, social synchronization can generate far more diverse behavioural rhythms than expected from studies of individuals in captivity. The risk of predation, not the risk of starvation, may be a key factor underlying the diversity in these rhythms.</p

An epigenome-wide association study of total serum immunoglobulin E concentration

Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever and allergic asthma. Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation. We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations-with a meta-analysis false discovery rate less than 10(-4)-between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies. This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases

Unexpected diversity in socially synchronized rhythms of shorebirds

The behavioural rhythms of organisms are thought to be under strong selection, influenced by the rhythmicity of the environment1, 2, 3, 4. Such behavioural rhythms are well studied in isolated individuals under laboratory conditions1, 5, but free-living individuals have to temporally synchronize their activities with those of others, including potential mates, competitors, prey and predators6, 7, 8, 9, 10. Individuals can temporally segregate their daily activities (for example, prey avoiding predators, subordinates avoiding dominants) or synchronize their activities (for example, group foraging, communal defence, pairs reproducing or caring for offspring)6, 7, 8, 9, 11. The behavioural rhythms that emerge from such social synchronization and the underlying evolutionary and ecological drivers that shape them remain poorly understood5, 6, 7, 9. Here we investigate these rhythms in the context of biparental care, a particularly sensitive phase of social synchronization12 where pair members potentially compromise their individual rhythms. Using data from 729 nests of 91 populations of 32 biparentally incubating shorebird species, where parents synchronize to achieve continuous coverage of developing eggs, we report remarkable within- and between-species diversity in incubation rhythms. Between species, the median length of one parent’s incubation bout varied from 1–19 h, whereas period length—the time in which a parent’s probability to incubate cycles once between its highest and lowest value—varied from 6–43 h. The length of incubation bouts was unrelated to variables reflecting energetic demands, but species relying on crypsis (the ability to avoid detection by other animals) had longer incubation bouts than those that are readily visible or who actively protect their nest against predators. Rhythms entrainable to the 24-h light–dark cycle were less prevalent at high latitudes and absent in 18 species. Our results indicate that even under similar environmental conditions and despite 24-h environmental cues, social synchronization can generate far more diverse behavioural rhythms than expected from studies of individuals in captivity5, 6, 7, 9. The risk of predation, not the risk of starvation, may be a key factor underlying the diversity in these rhythms

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities

Production of maternal-zygotic mutant zebrafish by germ-line replacement

We report a generally applicable strategy for transferring zygotic lethal mutations through the zebrafish germ line. By using a morpholino oligonucleotide that blocks primordial germ cell (PGC) development, we generate embryos devoid of endogenous PGCs to serve as hosts for the transplantation of germ cells derived from homozygous mutant donors. Successful transfers are identified by the localization of specifically labeled donor PGCs to the region of the developing gonad in chimeric embryos. This strategy, which results in the complete replacement of the host germ line with donor PGCs, was validated by the generation of maternal and maternal-zygotic mutants for the miles apart locus. This germ-line replacement technique provides a powerful tool for studying the maternal effects of zygotic lethal mutations. Furthermore, the ability to generate large clutches of purely mutant embryos will greatly facilitate embryological, genetic, genomic, and biochemical studies

Zebrafish Staufen1 and Staufen2 are required for the survival and migration of primordial germ cells

10.1016/j.ydbio.2006.01.014Developmental Biology2922393-406DEBI

Breastfeeding behavior is not associated with health literacy: evidence from the German KUNO-Kids birth cohort study

Purpose!#!Despite the health benefits of full breastfeeding for both infants and mothers, less than 50% of mothers in Germany practice this method for at least 4 months after childbirth. Because of the growing importance of health literacy to improve public health, we investigated the role of maternal health literacy in breastfeeding behavior.!##!Methods!#!We analyzed the data of 1172 mother-child dyads of the KUNO-Kids health study of the University Children's and Maternity Hospital Regensburg. Maternal health literacy was assessed with the HLS-EU-Q47 questionnaire (sub-index health care) up to 48 h after childbirth. Outcome was analyzed 6 months after childbirth and categorized into full breastfeeding for less than 4 months or for at least 4 months. The association between breastfeeding and maternal health literacy was calculated with univariable and multivariable logistic regression analyses.!##!Results!#!38.8% of mothers showed inadequate or limited health literacy. 75.9% of mothers had fully breastfed their child for at least 4 months. Univariable logistic regression analysis showed that health literacy and full breastfeeding for at least 4 months were not associated (OR = 0.995 [CI 0.977-1.015], p = 0.60). After adjusting for all potentially confounding variables with a significant association (p ≤ 0.05) on both health literacy and breastfeeding, the multivariable model showed no association between health literacy and breastfeeding (OR = 0.984 [CI 0.963-1.007], p = 0.170).!##!Conclusion!#!Surprisingly, we found no association between health literacy and breastfeeding behavior in our study. Therefore, future research with comparable measurements of health literacy and breastfeeding is required to validate this result and to identify reasons for early breastfeeding cessation