Separating within and between effects in family studies: an application to the study of blood pressure in children.

In epidemiology the analyses of family or twin studies do not always fully exploit the data, as information on differences between siblings is often used while between-families effect are not considered. We show how cross-sectional time-series linear regression analysis can be easily implemented to estimate within- and between-families effects simultaneously and how these effects can then be compared using the Hausman test. We illustrate this approach with data from the Uppsala family study on blood pressure in children with age ranging from 5.5 to 12.3 years for the younger and from 7.5 to 13.8 years for the older siblings. Comparing the effect of differences in birth weight on blood pressure within-family (in full siblings) and between-families (in unrelated children) allows us to study the contributions of fixed and pregnancy-specific maternal effects on birth weight and consequently on blood pressure. Our data showed a 0.88 mmHg decrease (95 per cent confidence interval: -1.7 to -0.03 mmHg) in systolic blood pressure for one standard deviation increase in birth weight between siblings within a family and 0.88 mmHg (95 per cent confidence interval: -1.6 to -0.2 mmHg) decrease in systolic blood pressure for one standard deviation increase in birth weight between unrelated children. These estimates were controlled for sex, age, pubertal stage, body size and pulse rate of the children at examination and for maternal body size and systolic blood pressure. The within- and between-families effects were not significantly different, p = 0.19, suggesting that fixed and pregnancy-specific factors have similar effects on childhood systolic blood pressure

Reduced CD300LG mRNA tissue expression, increased intramyocellular lipid content and impaired glucose metabolism in healthy male carriers of Arg82Cys in CD300LG:a novel genometabolic cross-link between CD300LG and common metabolic phenotypes

BACKGROUND: CD300LG rs72836561 (c.313C>T, p.Arg82Cys) has in genetic-epidemiological studies been associated with the lipoprotein abnormalities of the metabolic syndrome. CD300LG belongs to the CD300-family of membrane-bound molecules which have the ability to recognize and interact with extracellular lipids. We tested whether this specific polymorphism results in abnormal lipid accumulation in skeletal muscle and liver and other indices of metabolic dysfunction. METHODS: 40 healthy men with a mean age of 55 years were characterized metabolically including assessment of insulin sensitivity by the hyperinsulinemic euglycemic clamp, intrahepatic lipid content (IHLC) and intramyocellular lipid content (IMCL) by MR spectroscopy, and β-cell function by an intravenous glucose tolerance test. Changes in insulin signaling and CD300LG mRNA expression were determined by western blotting and quantitative PCR in muscle and adipose tissue. RESULTS: Compared with the 20 controls (CC carriers), the 20 CT carriers (polymorphism carriers) had higher IMCL (p=0.045), a reduced fasting forearm glucose uptake (p=0.011), a trend toward lower M-values during the clamp; 6.0 mg/kg/min vs 7.1 (p=0.10), and higher IHLC (p=0.10). CT carriers had lower CD300LG mRNA expression and CD300LG expression in muscle correlated with IMCL (β=−0.35, p=0.046), forearm glucose uptake (β=0.37, p=0.03), and tended to correlate with the M-value (β=0.33, p=0.06), independently of CD300LG genotype. β-cell function was unaffected. CONCLUSIONS: The CD300LG polymorphism was associated with decreased CD300LG mRNA expression in muscle and adipose tissue, increased IMCL, and abnormalities of glucose metabolism. CD300LG mRNA levels correlated with IMCL and forearm glucose uptake. These findings link a specific CD300LG polymorphism with features of the metabolic syndrome suggesting a role for CD300LG in the regulation of common metabolic traits. TRIAL REGISTRATION NUMBER: NCT01571609

The type 2 diabetes risk allele of TMEM154-rs6813195 associates with decreased beta cell function in a study of 6,486 Danes

A trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified seven novel susceptibility variants in or near TMEM154, SSR1/RREB1, FAF1, POU5F1/TCF19, LPP, ARL15 and ABCB9/MPHOSPH9. The aim of our study was to investigate associations between these novel risk variants and type 2 diabetes and pre-diabetic traits in a Danish population-based study with measurements of plasma glucose and serum insulin after an oral glucose tolerance test in order to elaborate on the physiological impact of the variants.Case-control analyses were performed in up to 5,777 patients with type 2 diabetes and 7,956 individuals with normal fasting glucose levels. Quantitative trait analyses were performed in up to 5,744 Inter99 participants naïve to glucose-lowering medication. Significant associations between TMEM154-rs6813195 and the beta cell measures insulinogenic index and disposition index and between FAF1-rs17106184 and 2-hour serum insulin levels were selected for further investigation in additional Danish studies and results were combined in meta-analyses including up to 6,486 Danes.We confirmed associations with type 2 diabetes for five of the seven SNPs (TMEM154-rs6813195, FAF1-rs17106184, POU5F1/TCF19-rs3130501, ARL15-rs702634 and ABCB9/MPHOSPH9-rs4275659). The type 2 diabetes risk C-allele of TMEM154-rs6813195 associated with decreased disposition index (n=5,181, β=-0.042, p=0.012) and insulinogenic index (n=5,181, β=-0.032, p=0.043) in Inter99 and these associations remained significant in meta-analyses including four additional Danish studies (disposition index n=6,486, β=-0.042, p=0.0044; and insulinogenic index n=6,486, β=-0.037, p=0.0094). The type 2 diabetes risk G-allele of FAF1-rs17106184 associated with increased levels of 2-hour serum insulin (n=5,547, β=0.055, p=0.017) in Inter99 and also when combining effects with three additional Danish studies (n=6,260, β=0.062, p=0.0040).Studies of type 2 diabetes intermediary traits suggest the diabetogenic impact of the C-allele of TMEM154-rs6813195 is mediated through reduced beta cell function. The impact of the diabetes risk G-allele of FAF1-rs17106184 on increased 2-hour insulin levels is however unexplained

Studies of association of AGPAT6 variants with type 2 diabetes and related metabolic phenotypes in 12,068 Danes

BACKGROUND: Type 2 diabetes, obesity and insulin resistance are characterized by hypertriglyceridemia and ectopic accumulation of lipids in liver and skeletal muscle. AGPAT6 encodes a novel glycerol-3 phosphate acyltransferase, GPAT4, which catalyzes the first step in the de novo triglyceride synthesis. AGPAT6-deficient mice show lower weight and resistance to diet- and genetically induced obesity. Here, we examined whether common or low-frequency variants in AGPAT6 associate with type 2 diabetes or related metabolic traits in a Danish population. METHODS: Eleven variants selected by a candidate gene approach capturing the common and low-frequency variation of AGPAT6 were genotyped in 12,068 Danes from four study populations of middle-aged individuals. The case–control study involved 4,638 type 2 diabetic and 5,934 glucose-tolerant individuals, while studies of quantitative metabolic traits were performed in 5,645 non-diabetic participants of the Inter99 Study. RESULTS: None of the eleven AGPAT6 variants were robustly associated with type 2 diabetes in the Danish case–control study. Moreover, none of the AGPAT6 variants showed association with measures of obesity (waist circumference and BMI), serum lipid concentrations, fasting or 2-h post-glucose load levels of plasma glucose and serum insulin, or estimated indices of insulin secretion or insulin sensitivity. CONCLUSIONS: Common and low-frequency variants in AGPAT6 do not significantly associate with type 2 diabetes susceptibility, or influence related phenotypic traits such as obesity, dyslipidemia or indices of insulin sensitivity or insulin secretion in the population studied

Organization of Partner Knowledge: Relationship Outcomes and Longitudinal Change

This study examined the association between organization of knowledge about a romantic partner (partner structure) and relationship status (ongoing or ended) 1 year later. Ironically, partner structures that were associated with more positive feelings about one’s partner at Time 1 were associated with greater rates of breakup by Time 2. These results are interpreted in terms of the vulnerability of compartmentalized partner structures to shifts in the salience of negative beliefs and the hypothesized difficulty of maintaining integrative structures for an extended period of time. Change in partner structure during 1 year’s time was consistent with the predictions of the dynamic model that evaluative integration should increase when negative beliefs become salient. Such change (which may represent a transient shift) was associated with couples’ longevity when relationship conflict was low, supporting the view that integration reflects a struggle with negative attributes that may or may not be successful.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

A New Electronic Monitoring Device to Measure Medication Adherence: Usability of the Helping Hand™

The aim of this study was to test the user performance, satisfaction and acceptability of the Helping Hand™ (B&O Medicom) electronic medication adherence monitor. Using a mixed-method design, we studied 11 kidney transplant patients and 10 healthy volunteers during three weeks. Although testing showed positive usability aspects, several areas requiring technical improvement were identified: the most important obstacles to usability and acceptability were the weak sound signal, problems loading the medication, and the fact that only one medication could be used at a time

Stochastic semiclassical gravity

In the first part of this paper, we show that the semiclassical Einstein-Langevin equation, introduced in the framework of a stochastic generalization of semiclassical gravity to describe the back reaction of matter stress-energy fluctuations, can be formally derived from a functional method based on the influence functional of Feynman and Vernon. In the second part, we derive a number of results for background solutions of semiclassical gravity consisting of stationary and conformally stationary spacetimes and scalar fields in thermal equilibrium states. For these cases, fluctuation-dissipation relations are derived. We also show that particle creation is related to the vacuum stress-energy fluctuations and that it is enhanced by the presence of stochastic metric fluctuations.Comment: 26 pages, RevTeX, no figure

Isoenergetic penta- and hexanucleotide microarray probing and chemical mapping provide a secondary structure model for an RNA element orchestrating R2 retrotransposon protein function

LNA (locked nucleic acids, i.e. oligonucleotides with a methyl bridge between the 2′ oxygen and 4′ carbon of ribose) and 2,6-diaminopurine were incorporated into 2′-O-methyl RNA pentamer and hexamer probes to make a microarray that binds unpaired RNA approximately isoenergetically. That is, binding is roughly independent of target sequence if target is unfolded. The isoenergetic binding and short probe length simplify interpretation of binding to a structured RNA to provide insight into target RNA secondary structure. Microarray binding and chemical mapping were used to probe the secondary structure of a 323 nt segment of the 5′ coding region of the R2 retrotransposon from Bombyx mori (R2Bm 5′ RNA). This R2Bm 5′ RNA orchestrates functioning of the R2 protein responsible for cleaving the second strand of DNA during insertion of the R2 sequence into the genome. The experimental results were used as constraints in a free energy minimization algorithm to provide an initial model for the secondary structure of the R2Bm 5′ RNA