Fine mapping of quantitative trait loci for mastitis resistance on bovine chromosome 11

Quantitative trait loci (QTL) affecting clinical mastitis (CM) and somatic cell score (SCS) were mapped on bovine chromosome 11. The mapping population consisted of 14 grandsire families belonging to three Nordic red cattle breeds: Finnish Ayrshire (FA), Swedish Red and White (SRB) and Danish Red. The families had previously been shown to segregate for udder health QTL. A total of 524 progeny tested bulls were included in the analysis. A linkage map including 33 microsatellite and five SNP markers was constructed. We performed combined linkage disequilibrium and linkage analysis (LDLA) using the whole data set. Further analyses were performed for FA and SRB separately to study the origin of the identified QTL/haplotype and to examine if it was common in both populations. Finally, different two-trait models were fitted. These postulated either a pleiotropic QTL affecting both traits; two linked QTL, each affecting one trait; or one QTL affecting a single trait. A QTL affecting CM was fine-mapped. In FA, a haplotype having a strong association with a high negative effect on mastitis resistance was identified. The mapping precision of an earlier detected SCS-QTL was not improved by the LDLA analysis because of lack of linkage disequilibrium between the markers used and the QTL in the region.     

Leveraging related health phenotypes for polygenic prediction of impulsive choice,impulsive action,and impulsive personality traits in 1534 European ancestry community adults

Impulsivity refers to a number of conceptually related phenotypes reflecting self-regulatory capacity that are considered promising endophenotypes for mental and physical health. Measures of impulsivity can be broadly grouped into three domains, namely, impulsive choice, impulsive action, and impulsive personality traits. In a community-based sample of ancestral Europeans (n = 1534), we conducted genome-wide association studies (GWASs) of impulsive choice (delay discounting), impulsive action (behavioral inhibition), and impulsive personality traits (UPPS-P), and evaluated 11 polygenic risk scores (PRSs) of phenotypes previously linked to self-regulation. Although there were no individual genome-wide significant hits, the neuroticism PRS was positively associated with negative urgency (adjusted R² = 1.61%, p = 3.6 × 10⁻⁷) and the educational attainment PRS was inversely associated with delay discounting (adjusted R² = 1.68%, p = 2.2 × 10⁻⁷). There was also evidence implicating PRSs of attention-deficit/hyperactivity disorder, externalizing, risk-taking, smoking cessation, smoking initiation, and body mass index with one or more impulsivity phenotypes (adjusted R²s: 0.35%–1.07%; FDR adjusted ps = 0.05–0.0006). These significant associations between PRSs and impulsivity phenotypes are consistent with established genetic correlations. The combined PRS explained 0.91%–2.46% of the phenotypic variance for individual impulsivity measures, corresponding to 8.7%–32.5% of their reported single-nucleotide polymorphism (SNP)-based heritability, suggesting a non-negligible portion of the SNP-based heritability can be recovered by PRSs. These results support the predictive validity and utility of PRSs, even derived from related phenotypes, to inform the genetics of impulsivity phenotypes.     

Relationships between substance abuse/dependence and psychiatric disorders based on polygenic scores

Genetic susceptibility to substance use disorders (SUDs) is partially shared between substances. Heritability of any substance dependence, estimated as 54%, is partly explained by additive effects of common variants. Comorbidity between SUDs and other psychiatric disorders is frequent. The present study aims to analyze the additive role of common variants in this comorbidity using polygenic scores (PGSs) based on genome‐wide association study discovery samples of schizophrenia (SCZ), bipolar disorder, attention‐deficit/hyperactivity disorder, autism spectrum disorder, major depressive disorder and anxiety disorders, available from large consortia. PGSs were calculated for 534 patients meeting DSM‐IV criteria for dependence of a substance and abuse/dependence of another substance between alcohol, tobacco, cannabis, cocaine, opiates, hypnotics, stimulants, hallucinogens and solvents; and 587 blood donors from the same population, Iberians from Galicia, as controls. Significance of the PGS and percentage of variance explained were calculated by logistic regression. Using discovery samples of similar size, significant associations with SUDs were detected for SCZ PGS. SCZ PGS explained more variance in SUDs than in most psychiatric disorders. Cross‐disorder PGS based on five psychiatric disorders was significant after adjustment for the effect of SCZ PGS. SCZ PGS was significantly higher in women than in men abusing alcohol. Our findings indicate that SUDs share genetic susceptibility with SCZ to a greater extent than with other psychiatric disorders, including externalizing disorders such as attention‐deficit/hyperactivity disorder. Women have lower probability to develop substance abuse/dependence than men at similar PGS probably because of a higher social pressure against excessive drug use in women.     

Increasing temperature weakens the positive effect of genetic diversity on population growth

Genetic diversity and temperature increases associated with global climate change are known to independently influence population growth and extinction risk. Whether increasing temperature may influence the effect of genetic diversity on population growth, however, is not known. We address this issue in the model protist system Tetrahymena thermophila. We test the hypothesis that at temperatures closer to the species’ thermal optimum (i.e., the temperature at which population growth is maximal, or T _opt), genetic diversity should have a weaker effect on population growth compared to temperatures away from the thermal optimum. To do so, we grew populations of T. thermophila with varying levels of genetic diversity at increasingly warmer temperatures and quantified their intrinsic population growth rate, r. We found that genetic diversity increases population growth at cooler temperatures, but that as temperature increases, this effect weakens. We also show that a combination of changes in the amount of expressed genetic diversity (G) in r, plastic changes in population growth across temperatures (E), and strong G × E interactions underlie this temperature effect. Our results uncover important but largely overlooked temperature effects that have implications for the management of small populations with depauperate genetic stocks in an increasingly warming world.     

The effect of weight loss on serum concentration of interleukine-6 (IL-6) and insulin resistance

INTRODUCTION: Interleukine-6 (IL-6) is one of the cytokines, excreting by adipocytes, which increases in obesity. These cytokines participate in very complicated mechanisms of developing insulin resistance that accompany obesity. The aim of the study was to: 1) evaluate the influence of weight loss on insulin resistance and serum concentration of IL-6, 2) evaluate the hypothetical association between serum concentration of IL-6 and the improvement of insulin sensitivity in obese women after weight loss. MATERIAL AND METHODS: The study involved 27 obese women (age 40.3 +/- 11.1 year; BMI 37.4 +/- 5.2 kg/m(2)) with insulin resistance diagnosed using HOMA index, without concomitant diseases and without any medication. All the patients participated in complex weight reduction treatment (diet, physical activity and psychotherapy). Before and after weight reduction therapy weight and height were measured, body composition was determined using bioimpedance analysis. Serum concentration of glucose was determined by enzymatic procedure, serum concentration of insulin was measured by radioimmunoassay, serum concentration of IL-6 was measured by ELISA. HOMA index was calculated with formula. RESULTS: The mean weight loss after 3-month was 9.2 +/- 4.5 kg (approximately 10% of initial weight). After weight reduction significant decreases in HOMA index, insulin and IL-6 concentrations was observed. However, no correlations between changes in insulin concentrations, HOMA index and decrease of IL-6 concentration were showed. We observed significant correlations between DeltaHOMA and DeltaBMI (r = 0.48; p = 0.012) and Delta percentage fat mass (r = 0.39; p < 0.05). CONCLUSIONS: A moderate weight loss improves insulin sensitivity and decreases serum concentrations of IL-6. However improvement of insulin sensitivity is the effect of fat mass reduction and does not change serum concentration of IL-6.     

APOA5 polymorphisms influence plasma triglycerides in young, healthy African Americans and whites of the CARDIA Study

Genetic variation in the apolipoprotein A-V gene (APOA5) has been associated with variation in plasma triglyceride (TG) levels in African American and white females and males older than 40 years and/or at increased risk of coronary artery disease. We have examined whether plasma TG levels are associated with 16 APOA5 polymorphisms in young (18-30 years) African American (1,075 females and 783 males) and white (1,041 females and 932 males) individuals of the Coronary Artery Risk Development in Young Adults (CARDIA) Study selected without regard to health. Plasma TG was significantly (P < 0.01) associated with markers 27376 and 28837 (-3A/G) in both white females and males, with 27709 (-1131T/C) and 29085 in white males, with 29009 (S19W) in African American females and white males, and with 30966 in African American females. No statistically significant associations were observed in African American males. These six single-nucleotide polymorphisms individually accounted for 0-0.78% of lnTG variation among white females, 0-2.46% among white males, and 0-0.69% among African American females. The results of our study suggest a small but replicable context-dependent influence of the APOA5 gene region on plasma TG levels in young, healthy individuals.     

基于大豆胞囊线虫病抗性候选基因的SNP位点遗传变异分析

以我国363份栽培和野生大豆资源为材料, 对大豆胞囊线虫抗性候选基因(rhg1和Rhg4)的SNP位点(8个)进行遗传变异分析, 以期阐明野生和栽培大豆间遗传多样性及连锁不平衡水平差异。结果表明, 与野生大豆相比, 代表我国栽培大豆总体资源多样性的微核心种质及其补充材料的连锁不平衡水平较高(R²值为0.216)。在栽培大豆群体内, 基因内和基因间分别有100％和16.6％的SNP位点对连锁不平衡显著, 形成两个基因特异的连锁不平衡区间(Block)。在所有供试材料中共检测到单倍型46个, 野生大豆的单倍型数目(27)少于栽培大豆(31), 但单倍型多样性(0.916)稍高于栽培大豆(0.816)。单倍型大多数(67.4％)为群体所特有(31个), 其中15个为野生大豆特有单倍型。野生大豆的两个主要优势单倍型(Hap_10和Hap_11)在栽培大豆中的发生频率也明显下降, 推测野生大豆向栽培大豆进化过程中, 一方面形成了新的单倍型, 另一方面因为瓶颈效应部分单倍型的频率降低甚至消失。     

The effect of PPARgamma ligands on the adipose tissue in insulin resistance

Insulin resistance is frequently accompanied by obesity and both obesity and type 2 diabetes are associated with a mild chronic inflammation. Elevated levels of various cytokines, such as TNF-alpha and IL-6, are typically found in the adipose tissue in these conditions. It has been suggested that many cytokines produced in the adipose tissue are derived from infiltrated inflammatory cells. However, the adipose tissue itself has proven to be an important endocrine organ, secreting several hormones and cytokines, usually referred to as adipokines. Peroxisome proliferator-activated receptor (PPAR)gamma is essential for adipocyte proliferation and differentiation. In recent years, PPARgamma and its ligands, the thiazolidinediones (TZD), have achieved great attention due to their insulin sensitizing and anti-inflammatory properties. Treatment with TZDs result in improved insulin signaling and adipocyte differentiation, increased adipose tissue influx of free fatty acids and inhibition of cytokine expression and action. As a result, PPARgamma plays a central role in maintaining a functional and differentiated adipose tissue.     

Effects of anti-insulin serum, insulin, and glucose on output of triglycerides and on ketogenesis by the perfused rat liver.

The rate of change of the concentration of various metabolites in blood in vivo and of the metbolism of free fatty acids by the perfused liver in vitro was sutidied as a function of time after the induction of acute insulin deficiency in rats by administration of guinea pig anti-insulin serum; the rate of reversal of these changes afte treatment of the anti-insulinserum diabetic ratss with insulin was also investigated. The concentrations of blood glucose and ketonebodies, and plasma-free fatty acids increased rapidly after injection of anti-insuli serum, while plasma triglycerides increased more slowly. These alterations were restored rapidly toward normal after treatment of the diabetic animals with insulin...     

Genetic risk scores to predict the prognosis of chronic heart failure patients in Chinese Han

Chronic heart failure (CHF) has poor prognosis and polygenic heritability, and the genetic risk score (GRS) to predict CHF outcome has not yet been researched comprehensively. In this study, we sought to establish GRS to predict the outcomes of CHF. We re‐analysed the proteomics data of failing human heart and combined them to filter the data of high‐throughput sequencing in 1000 Chinese CHF cohort. Cox hazards models were used based on single nucleotide polymorphisms (SNPs) to estimate the association of GRS with the prognosis of CHF, and to analyse the difference between individual SNPs and tertiles of genetic risk. In the cohort study, GRS encompassing eight SNPs harboured in seven genes were significantly associated with the prognosis of CHF (P = 2.19 × 10^?10 after adjustment). GRS was used in stratifying individuals into significantly different CHF risk, with those in the top tertiles of GRS distribution having HR of 3.68 (95% CI: 2.40‐5.65 P = 2.47 × 10^?10) compared with those in the bottom. We developed GRS and demonstrated its association with first event of heart failure endpoint. GRS might be used to stratify individuals for CHF prognostic risk and to predict the outcomes of genomic screening as a complement to conventional risk and NT‐proBNP.     

Linkage of the hordein loci Hor1 and Hor2 with the powdery mildew resistance loci Ml-k and Ml-a on Barley chromosome 5

Summary The linkage relationship among the loci Hor1, Hor2, Ml-k and Ml-a on the short arm of chromosome 5 was studied by progeny testing the F₂ generation of two crosses. The loci Hor1 and Hor2 code for polypeptides of the storage protein hordein (prolamin) and the loci Ml-k and Ml-a determine the resistance reaction with some powdery mildew fungi cultures. The order of the loci is Ml-k, Hor1, Ml-a, and Hor2, the first named being nearest the centromere. The recombination percentage between Hor1 and Hor2 was determined in the F₁ and F₂ generations in both crosses, the combined estimate being 7.4±0.9 per cent. The recombination percentage estimated between Ml-k and Hor1 was 4.0±1.3, between Hor1 and Ml-a, 5.3±1.1, and between Ml-a and Hor2, 6.1±1.2. The estimates involving the Ml- loci were all probably a little too high.     

Quaternary conformational stability: The effect of reversible self‐association on the fibrillation of two insulin analogs

Under conditions relevant to the manufacturing of insulin (e.g., pH 3, room temperature), biosynthetic human insulin (BHI), and Lispro insulin (Lispro) require a nucleation step to initiate aggregation. However, upon seeding with preformed aggregates, both insulins rapidly aggregate into nonnative fibrils. Far ultraviolet circular dichroism (far‐UV CD) and second derivative Fourier transform infrared (2D‐FTIR) spectroscopic analyses show that the fibrillation process involves a change in protein secondary structure from α‐helical in native insulin to predominantly β‐sheet in the nonnative fibrils. After seeding, Lispro aggregates faster than BHI, likely because of a reduced propensity to reversibly self‐associate. Composition gradient multi‐angle light scattering (CG‐MALS) analyses show that Lispro is more monomeric than BHI, whereas their conformational stabilities measured by denaturant‐induced unfolding are statistically indistinguishable. For both BHI and Lispro, as the protein concentration increases, the apparent first‐order rate constant for soluble protein loss decreases. To explain these phenomena, we propose an aggregation model that assumes fibril growth through monomer addition with competitive inhibition by insulin dimers. Biotechnol. Bioeng. 2011;108: 2359–2370. © 2011 Wiley Periodicals, Inc.     

Genome-wide association study of the plasma triglyceride response to an n-3 polyunsaturated fatty acid supplementation

Studies have shown a large interindividual variability in plasma TG response to long-chain n-3 PUFA supplementation, which may likely be attributable to genetic variability within the populations studied. The objective is to compare the frequency of SNPs in a genome-wide association study between responders (reduction in plasma TG levels ≥0.01 mM) and nonresponders (increase in plasma TG of ≥0 mM) to supplementation. Genomic DNA from 141 subjects who completed a 2-week run-in period followed by 6-week supplementation with 5 g of fish oil daily (1.9–2.2 g EPA and 1.1 g DHA daily) were genotyped on Illumina HumanOmni-5-QuadBeadChip. Thirteen loci had frequency differences between responders and nonresponders (P < 1 × 10⁻⁵), including SNPs in or near IQCJ-SCHIP1, MYB, NELL1, NXPH1, PHF17, and SLIT2 genes. A genetic risk score (GRS) was constructed by summing the number of risk alleles. This GRS explained 21.53% of the variation in TG response to n-3 PUFA supplementation when adjusted for age, sex, and BMI (P = 0.0002). Using Fish Oil Intervention and Genotype as a replication cohort, the GRS was able to explain 2% of variation in TG response when adjusted. In conclusion, subjects who decrease their plasma TG levels following n-3 PUFA supplementation may have a different genetic profile than individuals who do not respond.     

Studies on the effect of 2-hydroxy-5-nitrobenzyl bromide on the mechanism of insulin.

The effects of HNB were tested on the binding of insulin to fat cells and fat cell membranes as well as the responsiveness of fat cells to insulin. Although metabolism was found to be inhibited, the reagent was found to stimulate the binding of insulin. The stimulatory effect on insulin binding as well as inhibitory effect on metabolism was reversed by free tryptophan consumption of the reagent. The results are discussed relative to these findings.     

益生菌对高脂饮食诱导的大鼠胰岛素抵抗的影响

目的 观察益生菌对高脂饲料喂养的SD大鼠胰岛素抵抗的影响.方法 30只雄性健康SD大鼠正常喂养1周后,随机分为正常对照组、高脂模型组、益生菌干预组[即在高脂饲料喂养的基础上给予培菲康210 mg/(只·d)灌胃].14周末,处死所有大鼠,测量大鼠体重,检测血清及肝匀浆液中脂质和葡萄糖的变化,评价胰岛素抵抗程度,并检测血浆内毒素水平.结果 (1)与对照组比较,模型组大鼠肝指数明显升高(P＜0.05);益生菌治疗后肝指数无明显降低(P＞0.05).(2)与对照组比较,模型组存在脂质代谢紊乱(P＜0.05),益生菌治疗后脂代谢紊乱明显改善(P＜0.05).(3)与对照组比较,模型组胰岛素抵抗指数明显升高(P＜0.05),胰岛素敏感指数明显降低(P＜0.05),存在胰岛素抵抗,益生菌治疗后胰岛素抵抗改善(P＜0.05).(4)与对照组比较,模型组血浆内毒素水平明显升高(P＜0.05),存在内毒素血症,益生菌治疗后内毒素血症减轻(P＜0.05).结论 益生菌可减轻内毒素血症,改善高脂饮食诱导的胰岛素抵抗.