Variance In Susceptibility Research Articles

Adaptive potential in the face of a transmissible cancer in Tasmanian devils.

Emerging infectious diseases (EIDs) not only cause catastrophic declines in wildlife populations but also generate selective pressures that may result in rapid evolutionary responses. One such EID is devil facial tumour disease (DFTD) in the Tasmanian devil. DFTD is almost always fatal and has reduced the average lifespan of individuals by around 2 years, likely causing strong selection for traits that reduce susceptibility to the disease, but population decline has also left Tasmanian devils vulnerable to inbreeding depression. We analysed 22 years of data from an ongoing study of a population of Tasmanian devils on Freycinet Peninsula, Tasmania, to (1) identify whether DFTD may be causing selection on body size, by estimating phenotypic and genetic correlations between DFTD and size traits, (2) estimate the additive genetic variance of susceptibility to DFTD, and (3) investigate whether size traits or susceptibility to DFTD were under inbreeding depression. We found a positive phenotypic relationship between head width and susceptibility to DFTD, but this was not underpinned by a genetic correlation. Conversely, we found a negative phenotypic relationship between body weight and susceptibility to DFTD, and there was evidence for a negative genetic correlation between susceptibility to DFTD and body weight. There was additive genetic variance in susceptibility to DFTD, head width and body weight, but there was no evidence for inbreeding depression in any of these traits. These results suggest that Tasmanian devils have the potential to respond adaptively to DFTD, although the realised evolutionary response will critically further depend on the evolution of DFTD itself.

C. elegans toxicant responses vary among genetically diverse individuals

The genetic variability of toxicant responses among indisviduals in humans and mammalian models requires practically untenable sample sizes to create comprehensive chemical hazard risk evaluations. To address this need, tractable model systems enable reproducible and efficient experimental workflows to collect high-replication measurements of exposure cohorts. Caenorhabditis elegans is a premier toxicology model that has revolutionized our understanding of cellular responses to environmental pollutants and boasts robust genomic resources and high levels of genetic variation across the species. In this study, we performed dose-response analysis across 23 environmental toxicants using eight C. elegans strains representative of species-wide genetic diversity. We observed substantial variation in EC10 estimates and slope parameter estimates of dose-response curves of different strains, demonstrating that genetic background is a significant driver of differential toxicant susceptibility. We also showed that, across all toxicants, at least one C. elegans strain exhibited a significantly different EC10 or slope estimate compared to the reference strain, N2 (PD1074), indicating that population-wide differences among strains are necessary to understand responses to toxicants. Moreover, we quantified the heritability of responses (phenotypic variance attributable to genetic differences between individuals) to each toxicant exposure and observed a correlation between the exposure closest to the species-agnostic EC10 estimate and the exposure that exhibited the most heritable response. At least 20% of the variance in susceptibility to at least one exposure level of each compound was explained by genetic differences among the eight C. elegans strains. Taken together, these results provide robust evidence that heritable genetic variation explains differential susceptibility across an array of environmental pollutants and that genetically diverse C. elegans strains should be deployed to aid high-throughput toxicological screening efforts.

Interactions of the bacteriome, virome, and immune system in the nose.

Emerging evidence suggests that the nasal microbiome may influence host susceptibility to initial development and severity of respiratory viral infections. While not as extensively studied as the microbiota of the alimentary tract, it is now clearly established that the microbial composition of this niche is influenced by medical, social and pharmacological influences, predisposing some sub-populations to respiratory infections. The resulting specific microbial profiles may explain variance in susceptibility to viral infection. This review summaries the evolution and constituents of the commensal nasal microbiome; the bacterial-virus, bacterial-host and interbacterial interactions which potentiate disease; and considers the effects of interventions such as vaccination and probiotics.

Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries.

Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.

Resistance status of one host tick Rhipicephalus microplus of arid and semi-arid region of Gujarat, India

Ticks cause various harmful effects on livestock with a combination of direct and indirect effects. Resistance status of one host tick Rhipicephalus microplus from two districts, Banaskantha (BK) and Patan (PN) of North Gujarat was tested against synthetic pyrethroids (deltamethrin and cypermethrin) by adult immersion test (AIT).Ticks were collected from six talukas each from BK and PN. Tick isolates from eight places showed resistance against deltamethrin having resistance factor ranging from 2.52–22.59. Further, isolates from six places, Ranuj, Dhanera, Radhanpur, Patan, Dhaneri and Kheda showed resistance against cypermethrin with resistance factor in range of 2.42–18.66. The results reveal a remarkable variance of susceptibility to deltamethrin and cypermethrin in the R. microplus populations studied. Isolates from PN district, from talukas Ranuj, Patan, Radhanpur, and Sidhpur were resistant to deltamethrin with resistance level II in all the places and resistance factors estimated were 16.73, 16.7, 9.64, and 7.25, respectively. Tick isolated from Patan, Radhanpur and Ranuj were resistant to cypermethrin with resistance level II, II and I, respectively with resistance factor of 11.74, 6.74 and 2.42, respectively. The slope and R2 values for deltamethrin resistant tick isolates were in the range of, 0.64 ± 0.33 to 2.28 ± 0.21 and 50.0 to 97.62; and that for cypermethrin resistant tick isolates was 0.64 ± 0.33 to 2.28 ± 0.21 and 46.53 to 88.26 respectively. The finding is significant, as it reports the development of resistance against most commonly used acaricides in very large area of North Gujarat and the data generated would be useful in formulation of effective control strategies against ticks of this large geographic region.

Consequences of Depletion of Susceptibles for Hazard Ratio Estimators Based on Propensity Scores

We use simulated data to examine the consequences of depletion of susceptibles for hazard ratio (HR) estimators based on a propensity score (PS). First, we show that the depletion of susceptibles attenuates marginal HRs toward the null by amounts that increase with the incidence of the outcome, the variance of susceptibility, and the impact of susceptibility on the outcome. If susceptibility is binary then the Bross bias multiplier, originally intended to quantify bias in a risk ratio from a binary confounder, also quantifies the ratio of the instantaneous marginal HR to the conditional HR as susceptibles are depleted differentially. Second, we show how HR estimates that are conditioned on a PS tend to be between the true conditional and marginal HRs, closer to the conditional HR if treatment status is strongly associated with susceptibility and closer to the marginal HR if treatment status is weakly associated with susceptibility. We show that associations of susceptibility with the PS matter to the marginal HR in the treated (ATT) though not to the marginal HR in the entire cohort (ATE). Third, we show how the PS can be updated periodically to reduce depletion-of-susceptibles bias in conditional estimators. Although marginal estimators can hit their ATE or ATT targets consistently without updating the PS, we show how their targets themselves can be misleading as they are attenuated toward the null. Finally, we discuss implications for the interpretation of HRs and their relevance to underlying scientific and clinical questions. See video Abstract: http://links.lww.com/EDE/B727.

The Susceptibles, Chancers, Pragmatists, and Fair Players: An Examination of the Sport Drug Control Model for Adolescent Athletes, Cluster Effects, and Norm Values Among Adolescent Athletes.

Although there are few high-profile cases of adolescent athletes being caught doping, up to a third of young athletes may dope. In order to generate a more accurate understanding of why adolescent athletes dope, it is important to validate models that help to explain this behavior. The aims of this study were 3-fold: firstly, to test the Sport Drug Control Model for Adolescent Athletes (SDCM-AA); secondly, to generate athlete profiles that would help quantify the proportion of athletes who are at risk of doping; and thirdly, to create norm values for the Adolescent Sport Doping Inventory (ASDI), which would allow national doping organizations, sporting organizations, and clubs to benchmark the scores of their athletes for key psycho-social variables linked to doping. A total of 2208 adolescent athletes from the United Kingdom, Australia, Hong Kong, and the United States completed the ASDI. The data presented an appropriate fit to the SDCM-AA model, in which 54% of the variance in susceptibility to doping was explained in the model, and 44.8% of attitudes toward doping was accounted for. Four distinct clusters of athletes emerged: the Susceptibles (i.e., identified with the benefits of doping, were willing to cheat, and viewed little threat), the Chancers (i.e., identified with the benefits of doping, scored high on willingness to cheat, and were highly influenced by their reference group, but had an average score for threat, self-esteem, and legitimacy), the Pragmatists (i.e., did not engage with any aspects of doping, but were more susceptible than the fair players), and Fair Players (i.e., high levels of sportspersonship, unwilling to cheat, and viewed doping as a threat). The revised SDCM-AA appears a valid model that helps explain the factors associated with doping attitudes and doping susceptibility. Adolescent athletes can be classified into one of four clusters, in relation to doping. Their cluster group could influence the content of the anti-doping education they receive.

Complex Coding and Regulatory Polymorphisms in a Restriction Factor Determine the Susceptibility of Drosophila to Viral Infection.

It is common to find that major-effect genes are an important cause of variation in susceptibility to infection. Here we have characterized natural variation in a gene called pastrel that explains over half of the genetic variance in susceptibility to the Drosophila C virus (DCV) in populations of Drosophila melanogaster. We found extensive allelic heterogeneity, with a sample of seven alleles of pastrel from around the world conferring four phenotypically distinct levels of resistance. By modifying candidate SNPs in transgenic flies, we show that the largest effect is caused by an amino acid polymorphism that arose when an ancestral threonine was mutated to alanine, greatly increasing resistance to DCV. Overexpression of the ancestral, susceptible allele provides strong protection against DCV; indicating that this mutation acted to improve an existing restriction factor. The pastrel locus also contains complex structural variation and cis-regulatory polymorphisms altering gene expression. We find that higher expression of pastrel is associated with increased survival after DCV infection. To understand why this variation is maintained in populations, we investigated genetic variation surrounding the amino acid variant that is causing flies to be resistant. We found no evidence of natural selection causing either recent changes in allele frequency or geographical variation in frequency, suggesting that this is an old polymorphism that has been maintained at a stable frequency. Overall, our data demonstrate how complex genetic variation at a single locus can control susceptibility to a virulent natural pathogen.

Association of Psoriasis With the Risk for Type 2 Diabetes Mellitus and Obesity.

Psoriasis has been shown to be associated with overweight and type 2 diabetes mellitus. The genetic association is unclear. To examine the association among psoriasis, type 2 diabetes mellitus, and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) in twins. This cross-sectional, population-based twin study included 34 781 Danish twins, 20 to 71 years of age. Data from a questionnaire on psoriasis was validated against hospital discharge diagnoses of psoriasis and compared with hospital discharge diagnoses of type 2 diabetes mellitus and self-reported BMI. Data were collected in the spring of 2002. Data were analyzed from January 1 to October 31, 2014. Crude and adjusted odds ratios (ORs) were calculated for psoriasis in relation to type 2 diabetes mellitus, increasing BMI, and obesity in the whole population of twins and in 449 psoriasis-discordant twins. Variance component analysis was used to measure genetic and nongenetic effects on the associations. Among the 34 781 questionnaire respondents, 33 588 with complete data were included in the study (15 443 men [46.0%]; 18 145 women [54.0%]; mean [SD] age, 44.5 [7.6] years). After multivariable adjustment, a significant association was found between psoriasis and type 2 diabetes mellitus (odds ratio [OR], 1.53; 95% CI, 1.03-2.27; P = .04) and between psoriasis and increasing BMI (OR, 1.81; 95% CI, 1.28-2.55; P = .001 in individuals with a BMI>35.0). Among psoriasis-discordant twin pairs, the association between psoriasis and obesity was diluted in monozygotic twins (OR, 1.43; 95% CI, 0.50-4.07; P = .50) relative to dizygotic twins (OR, 2.13; 95% CI, 1.03-4.39; P = .04). Variance decomposition showed that additive genetic factors accounted for 68% (95% CI, 60%-75%) of the variance in the susceptibility to psoriasis, for 73% (95% CI, 58%-83%) of the variance in susceptibility to type 2 diabetes mellitus, and for 74% (95% CI, 72%-76%) of the variance in BMI. The genetic correlation between psoriasis and type 2 diabetes mellitus was 0.13 (-0.06 to 0.31; P = .17); between psoriasis and BMI, 0.12 (0.08 to 0.19; P < .001). The environmental correlation between psoriasis and type 2 diabetes mellitus was 0.10 (-0.71 to 0.17; P = .63); between psoriasis and BMI, -0.05 (-0.14 to 0.04; P = .44). This study determines the contribution of genetic and environmental factors to the interaction between obesity, type 2 diabetes mellitus, and psoriasis. Psoriasis, type 2 diabetes mellitus, and obesity are also strongly associated in adults after taking key confounding factors, such as sex, age, and smoking, into account. Results indicate a common genetic etiology for psoriasis and obesity.

Breeding for better eye health in Finnish blue fox (Vulpes lagopus).

The frequency of eye infections in the Finnish blue fox population has increased during the past decade. Eye infection may incur economic losses to producers due to reduced selection intensity, but ethical aspects need to be considered as well because eye infection can be quite painful and reduce animal well-being. The purpose of this study was to determine the potential for genetic selection against susceptibility to eye infection. The data were collected from 2076 blue foxes at the MTT fur animal research station. Genetic parameters were estimated using single- and multiple-trait animal models. The heritability estimate for eye infection was analysed as a binary trait (EYE) and was moderate (0.24±0.07). EYE had a moderate antagonistic genetic correlation (-0.49±0.20) with grading density (thick underfur). The genetic correlation of EYE with grading size or body condition score was estimated without precision, but all size traits had a low antagonistic phenotypic correlation with EYE. Our results suggest that there is genetic variance in susceptibility to EYE, indicating that eye health can be improved through selection. The current recommendation is that the sick animals should be culled immediately. If more efficient selection is needed, the selection index and multiple-trait animal models can be applied in breeding for better eye health.

Suppression of ACSL6 in Skeletal Muscle Induces Alteration of Glucose Metabolism

Understanding the role of various sources of fatty acids and genes involved in fatty acid metabolism provide core information how nutrition therapy can be applied to the people who has different metabolic trait or genetic variance in susceptibility of metabolic diseases. Numerous isoforms of long chain acyl‐CoA synthetase (ACSL) mediate intracellular fatty acids channeling and regulate energy metabolism. However the role of these genes in skeletal muscle need to be identified in order to understand how they contribute to whole body energy metabolism. The purpose of this study was to identify a role of ACSL6 in skeletal muscle energy metabolism. C2C12 mouse myoblasts were cultured and expression of genes that involving glucose and fatty acids metabolism were analyzed. Also siRNA mediated knockdown of ACSL6 was performed to characterize the role of ACSL6 in skeletal muscle. In mouse skeletal muscle cells mRNA and protein expression of ACSL6 were increased over the time course of cellular differentiation. ACSL6 was up‐regulated by high‐glucose but its expression was not influenced by insulin treatment. Knockdown of ACSL6 decreased glucose without affecting insulin signaling or mitochondrial beta oxidation suggesting that ACSL6 is involved in glucose uptake or utilization independent of early stage of insulin signaling. On‐going study to investigate the effect of tissue specific knockdown of ACSL6 on glucose uptake and insulin signaling pathway in animal model will provide further insight into the role of ACSL6 in skeletal muscle.This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A1019253

The Role of Spectral Resolution, Working Memory, and Audibility in Explaining Variance in Susceptibility to Temporal Envelope Distortion

Several studies have shown that hearing thresholds alone cannot adequately predict listeners' success with hearing-aid amplification. Furthermore, previous studies have shown marked differences in listeners' susceptibility to distortions introduced by certain nonlinear amplification parameters. The purpose of this study was to examine the role of spectral resolution, working memory, and audibility in explaining perceptual susceptibility to temporal envelope and other hearing-aid compression-induced distortions for listeners with mild to moderate and moderate to severe hearing loss. A between-subjects repeated-measures design was used to compare speech recognition scores with linear versus compression amplification, for listeners with mild to moderate and moderate to severe hearing loss. The study included 15 adult listeners with mild to moderate hearing loss and 13 adults with moderate to severe hearing loss. Speech recognition scores were measured for vowel-consonant-vowel syllables processed with linear, moderate compression, and extreme compression amplification. Perceptual susceptibility to compression-induced temporal envelope distortion was defined as the difference in scores between linear and compression amplification. Both overall scores and consonant feature scores (i.e., place, manner, and voicing) were analyzed. Narrowband spectral resolution was measured using individual measures of auditory filter bandwidth at 2000 Hz. Working memory was measured using the reading span test. Signal audibility was quantified using the Aided Audibility Index. Multiple linear regression was used to determine the predictive role of spectral resolution, working memory, and audibility benefit on listeners' susceptibility to compression-induced distortions. For all listeners, spectral resolution, working memory, and audibility benefit were significant predictors of overall distortion scores. For listeners with moderate to severe hearing loss, spectral resolution and audibility benefit predicted distortion scores for consonant place and manner of articulation features, and audibility benefit predicted distortion scores for consonant voicing features. For listeners with mild to moderate hearing loss, the model did not predict distortion scores for overall or consonant feature scores. The results from this study suggest that when audibility is adequately controlled, measures of spectral resolution may identify the listeners who are most susceptible to compression-induced distortions. Working memory appears to modulate the negative effect of these distortions for listeners with moderate to severe hearing loss.

Population variation in and selection for resistance to pyrethroid-neonicotinoid insecticides in the bed bug

Pyrethroid resistance in bed bugs, Cimex lectularius, has prompted a change to combination products that include a pyrethroid and a neonicotinoid. Ten populations of bed bugs were challenged with two combination products (Temprid SC and Transport GHP). Susceptibility of these populations varied, with the correlated response of the two products indicating cross resistance. We imposed selection on three populations using label rate Temprid, and then reared progeny from unselected and selected strains. All selected strains were significantly less susceptible to Temprid SC than unselected strains. Temprid selected strains were also less susceptible to Transport. The pyrethroid component of Temprid showed a significantly higher LD50 in selected strains, but susceptibility to the neonicotinoid remained unchanged. Taken together these results indicate resistance to combination insecticides is present in field populations at levels that should be of concern, and that short-term selection affecting existing variance in susceptibility can quickly increase resistance.

A twin study of early-childhood asthma in Puerto Ricans.

BackgroundThe relative contributions of genetics and environment to asthma in Hispanics or to asthma in children younger than 3 years are not well understood.ObjectiveTo examine the relative contributions of genetics and environment to early-childhood asthma by performing a longitudinal twin study of asthma in Puerto Rican children ≤3 years old.Methods678 twin infants from the Puerto Rico Neo-Natal Twin Registry were assessed for asthma at age 1 year, with follow-up data obtained for 624 twins at age 3 years. Zygosity was determined by DNA microsatellite profiling. Structural equation modeling was performed for three phenotypes at ages 1 and 3 years: physician-diagnosed asthma, asthma medication use in the past year, and ≥1 hospitalization for asthma in the past year. Models were additionally adjusted for early-life environmental tobacco smoke exposure, sex, and age.ResultsThe prevalences of physician-diagnosed asthma, asthma medication use, and hospitalization for asthma were 11.6%, 10.8%, 4.9% at age 1 year, and 34.1%, 40.1%, and 8.5% at 3 years, respectively. Shared environmental effects contributed to the majority of variance in susceptibility to physician-diagnosed asthma and asthma medication use in the first year of life (84%–86%), while genetic effects drove variance in all phenotypes (45%–65%) at age 3 years. Early-life environmental tobacco smoke, sex, and age contributed to variance in susceptibility.ConclusionOur longitudinal study in Puerto Rican twins demonstrates a changing contribution of shared environmental effects to liability for physician-diagnosed asthma and asthma medication use between ages 1 and 3 years. Early-life environmental tobacco smoke reduction could markedly reduce asthma morbidity in young Puerto Rican children.

Abundance of Three Sap Sucking Pests on Three Eggplant Cultivars With Utilization of Phytoseiulus persimilis Athias-Henriot against Tetnlnychus urticae Koch

Abundance and fluctuation of Tetranychus urticae Koch, Aphis gossypii Glover and Bemisia tabaci (Gann.) were studied on three eggplant cultivars (i.e. Baladi-White, Florida Market and Baladi-Black) during 2009 and 2010 successive seasons. T. urticae occurrence continued almost all the season and reached its maximum at the end of June or the beginning of July. A gossypii reaching the highest abundance in the middle of September while B. tabaci reached its maximum abundance at the end of July and first half of August. Variance in susceptibility among tested cultivars was recorded based on the abundance averages overall the two seasons. Florida Market, Baladi-White and Baladi-Black recorded the lowest abundance of T. urticae, A gossypii and B. tabaci, respectively. Phytoseiulus persimilis proved to be a good biocontrol agent against T. urticae at release ratios of 1 :5 and 1:10 predator : prey. A reduction appeared one week after release, generally it revealed 68.60 and 88.20 % mean reduction for both release ratios, respectively.

The genetic architecture of insecticide resistance within a natural population of &amp;lt;i&amp;gt;Drosophila melanogaster&amp;lt;/i&amp;gt;

The dynamics of genetic variation in susceptibility to insecticides within a natural population of Drosophila melanogaster (Meigen) at Katsunuma (Yamanashi Prefecture, Japan) was examined. Two resistance factors for three organophosphate insecticides (OPs), a resistant-type acetylcholinesterase (AChE) and a cytochrome P450 monooxygenase (cytochrome P450), have already been suggested to be involved within the Katsunuma population. In this study, genetic variances were estimated for susceptibility to other classes of chemicals than OPs, permethrin (a pyrethroid) and dichloro-diphenyl-trichloroethane (DDT; an organo-chlorine), which existed simultaneously with genetic variances for susceptibility to OPs. Analyses of variance for susceptibility to permethrin and DDT showed highly significant variation among isofemale lines from the Katsunuma population, and the genetic variances for susceptibility to each insecticide fluctuated differently during this period. The impacts of fluctuations of genetic variation in susceptibility to one class of insecticides on genetic variation in susceptibility to other classes of insecticides existing simultaneously within the natural population were discussed.

The Influence of Mapped Hazards on Risk Beliefs: A Proximity‐Based Modeling Approach

Interview findings suggest perceived proximity to mapped hazards influences risk beliefs when people view environmental hazard maps. For dot maps, four attributes of mapped hazards influenced beliefs: hazard value, proximity, prevalence, and dot patterns. In order to quantify the collective influence of these attributes for viewers' perceived or actual map locations, we present a model to estimate proximity-based hazard or risk (PBH) and share study results that indicate how modeled PBH and map attributes influenced risk beliefs. The randomized survey study among 447 university students assessed risk beliefs for 24 dot maps that systematically varied by the four attributes. Maps depicted water test results for a fictitious hazardous substance in private residential wells and included a designated "you live here" location. Of the nine variables that assessed risk beliefs, the numerical susceptibility variable was most consistently and strongly related to map attributes and PBH. Hazard value, location in or out of a clustered dot pattern, and distance had the largest effects on susceptibility. Sometimes, hazard value interacted with other attributes, for example, distance had stronger effects on susceptibility for larger than smaller hazard values. For all combined maps, PBH explained about the same amount of variance in susceptibility as did attributes. Modeled PBH may have utility for studying the influence of proximity to mapped hazards on risk beliefs, protective behavior, and other dependent variables. Further work is needed to examine these influences for more realistic maps and representative study samples.

The etiology of preeclampsia: the role of the father

Preeclampsia is often considered as simply a maternal disease with variable degrees of fetal involvement. More and more the unique immunogenetic maternal-paternal relationship is appreciated, and also the specific 'genetic conflict' that is characteristic of haemochorial placentation. From that perspective, pre-eclampsia can be seen as a disease of an individual couple with primarily maternal and fetal manifestations. The maternal and fetal genomes perform different roles during development. Heritable paternal, rather than maternal, imprinting of the genome is necessary for normal trophoblast development. Large population studies have estimated that 35% of the variance in susceptibility to preeclampsia is attributable to maternal genetic effects; 20% to fetal genetic effects (with similar contributions of both parents), 13% to the couple effect, less than 1% to the shared sibling environment and 32% to unmeasured factors. Not one of these large population studies focussed on the paternal contribution to preeclampsia, which is demonstrated by (1) the effect of the length of the sexual relationship; (2) the concept of primipaternity versus primigravidity; and (3) the existence of the so-called 'dangerous' father, as demonstrated in various large population studies. It is currently unknown how the father exerts this effect. Possible mechanisms include seminal cytokine levels and their effect on maternal immune deviation, specific paternal HLA characteristics and specific paternal single nucleotide polymorphisms (SNPs), in particular in the paternally expressed genes affecting placentation. Several large cohort studies, including the large international SCOPE consortium, have identified paternal SNPs with strong associations with preeclampsia.

Biological research into depression: a clinician's commentary

This commentary presents a clinician‘s view of biological research into depression. It seeks to demonstrate the shortcomings of correlating highly sophisticated biological research with simple and questionable DSM diagnoses of depression. In his wide-ranging review of the patho- physiology of depression, G. Hasler repeatedly stresses that depression is heterogeneous. It is in fact striking how great is the discrepancy between the simplistic DSM-IV clinical diagnosis of major depressive disorder (applying a top-down approach), on the one hand, and the battery of highly sophisticated, expensive biological research techniques (bottom-up approach) which are used in order to study the disorder‘s pathophysiology, on the other. In view of this methodological incongruence, it is hardly surprising that biological research contributes very little to the early recognition, clinical application and treatment of depression. A clinical bottom-up approach would be more promising. It would consist of: a) a careful, exhaustive psychopathological description of all depressive, including somatic, symptoms; b) a syndromal diagnosis (e.g., retarded, agitated, hypochondriacal, somatic, atypical, neurasthenic, mood-congruent and mood-incongruent psychotic depression); and c) a more sophisticated subclassification of major depressive disorder, duly identifying the large subgroup with hidden subthreshold bipolarity, which is an important element of the diagnostic mood spectrum extending from depression, via several subgroups of bipolar disorder, to pure mania 1. As a first, and feasible, step in the right direction, all biological studies on depression should be checked for a diagnosis of subthreshold bipolarity of major depressive disorder, and the biological data re-analysed. There is convergent evidence from three epidemiological investigations 2,3,4 that 40% to 50% of subjects diagnosed as suffering from DSM-IV major depressive disorder are subthreshold bipolars. These epidemiological findings are confirmed by the international BRIDGE study on 5,635 patients with major depressive episodes 5. This study also demonstrates that the DSM exclusion criterion of an antidepressant-induced switch to hypomania is misleading: in fact, patients in whom switches are observed differ greatly from other major depressives in terms of a positive family history of mania and of course characteristics distinguishing bipolar from unipolar depression. Moreover, recent reviews found no sound evidence that patients who switch to hypomania under treatment with placebo differ from those who switch under antidepressants 6,7. Hasler also summarizes the evidence for important gender differences in the biological findings on depressive patients. The prevalence of major depressive disorder among women is about twice that among men, whereas in bipolar disorder there is only a slight female preponderance. The Zurich epidemiological data suggest that certain components or subtypes of major depression, namely somatic items of DSM-IV atypical depression 8 and somatic depression 9, may explain those differences. Clearly, biological research should take such findings into account. In addition, there are marked gender differences in childhood adversity which can create biological and psychological vulnerability to stressors in adolescence and adulthood 10. Hasler states that 60% to 70% of the variance in susceptibility to depression is non-genetic. This leaves promising space for epigenetic and environmental research, which should at the same time also consider gender differences. Findings from the prospective Zurich study confirmed childhood adversity as being associated in both women and men with an earlier onset of depression and bipolar disorder, but also with a more frequent chronicity of the disorders. The risk may be partially mediated by anxious personality traits, poor coping and low self-esteem. Sexual trauma in childhood/adolescence (mainly in females) and conduct problems (mainly in males) were not related to chronicity 10. As Hasler points out, depression is currently considered to be one of the most important causes of disability worldwide. But, would that conclusion still hold true if subthreshold bipolar depressives were correctly diagnosed and identified as bipolars? The review of Pini et al 11 suggests that bipolar disorder carries an equally high if not higher burden compared to major depressive disorder. The above-mentioned epidemiological studies 3,4,5 have shown that, when bipolars are properly identified, there is a major shift of comorbidity from the depressive to the bipolar group; for instance, alcohol use disorders and some anxiety disorders become much more strongly associated with bipolarity than with pure depression. The resulting reduced prevalence rates and comorbidity will probably show pure depression to be less of a burden than bipolar disorders, and the estimates of the World Health Organization 12 may need to be considerably revised.

M7.4 Uncovering the metabolomic signature of intrauterine growth restriction in early pregnancy: search, discovery and validation

M7.3 – Table 1. Log2 (EXP) fold change data shown asmedian ratio (IQR) for each sample compared to the reference sample. Proteins A-C cannot be named in the abstract for confidentiality reasons Protein Technical replicate Control Control PE PE Control PE 22/40 22/40 22/40 22/40 26/40 26/40 Fibrinogen alpha 0.92 (0.64-1.31) 0.42 (0.23-0.75) 0.37 (0.22-0.64) 1.33 (0.76-2.34) 1.21 (0.69-2.12) 0.44 (0.27-0.73) 0.76 (0.41-1.41) Apo E 1.00 (0.70-1.42) 0.48 (0.31-0.72) 0.53 (0.32-0.86) 0.76 (0.54-1.09) 0.77 (0.52-1.14) 0.56 (0.39-0.81) 1.14 (0.70-1.87) PAPP-A 1.04 (0.82-1.33) 0.71 (0.44-1.15) 0.72 (0.41-1.27) 0.58 (0.36-0.92) 0.63 (0.49-0.82) 1.07 (0.74-1.55) 1.09 (0.74-1.59) Apo C3 0.89 (0.51-1.57) 0.28 (0.15-0.51) 0.28 (0.16-0.48) 0.49 (0.19-1.26) 0.39 (0.27-0.56) 0.50 (0.31-0.82) 1.13 (0.76-1.66) Apo C2 0.89 (0.51-1.57) 0.28 (0.15-0.51) 0.28 (0.16-0.48) 0.49 (0.19-1.26) 0.39 (0.27-0.56) 0.50 (0.31-0.82) 1.13 (0.76-1.66) Protein A 1.02 (0.85-1.21) 0.79 (0.70-0.90) 0.69 (0.90-0.54) 1.15 (0.99-1.34) 1.15 (0.95-1.38) 0.61 (0.48-0.79) 1.20 (0.96-1.50) Protein B 0.83 (0.61-1.13) 0.56 (0.36-0.86) 0.44 (0.33-0.59) 0.89 (0.54-1.49) 0.92 (0.45-1.86) 0.53 (0.43-0.64) 1.46 (0.69-3.08) Protein C 0.94 (0.75-1.17) 0.59 (0.49-0.71) 0.56 (0.35-0.89) 0.94 (0.72-1.23) 0.98 (0.85-1.14) 0.60 (0.50-0.72) 1.03 (0.77-1.38) in three independent studies (a) venous cord blood plasma from normal babies and babies with IUGR, (b) plasma from a rat model of fetal growth restriction: reduced uterine perfusion pressure (RUPP) rat, (c) plasma samples obtained at 15±1 weeks gestation from women who subsequently delivered an IUGR baby and matched controls. All samples were analyzed using Ultra Performance Liquid Chromatography coupled to a LTQ-Orbitrap Mass Spectrometer. In both the cord blood and RUPP studies there was comprehensive disruption of plasma metabolism due to IUGR. Multivariate predictive models gave area under the Receiver Operator Characteristic (AuROC) curve of 1 in both cases. Disruption was specific to lipid and amino acid metabolism. When the time-of-disease biomarker signature of cord blood was validated using the pre-symptomatic 15-week maternal blood, a multivariate predictive model with AuROC of 0.96 was produced. This is the first time any clear biomarkers for IUGR have been discovered using any technology. A pre-symptomatic predictive test at 15 weeks gestation will have a significant impact on clinical care, allowing scarce resources to be concentrated on those at greatest risk. M9.1 Paternal factors involved in the causation of preeclampsia Gus Dekker1,2 , Claire Roberts2, Denise Furness2, Prabha Andraweera2. 1Lyell McEwin Hospital 2Robinson Institute, University of Adelaide, Australia Preeclampsia is often considered as just a maternal disease with variable degrees of fetal involvement. More and more the unique immunogenetic maternal-paternal relationship is appreciated, and as such also the specific “genetic conflict” that is characteristic of haemochorial placentation. From that perspective, preeclampsia can also be seen as a disease of an individual couple with primarily maternal and fetal manifestations. The maternal and fetal genomes perform different roles during development. Heritable paternal, rather than maternal, imprinting of the genome is necessary for normal trophoblast development. Large population studies have estimated that 35% of the variance in susceptibility to preeclampsia was attributable to maternal genetic effects, 20% to fetal genetic effects (with similar contributions of both parents), 13% to the couple effect, less than 1% to shared sibling environment and 32% to unmeasured factors. Not one of these large population studies involved a real focus on the paternal contribution to preeclampsia which is demonstrated by: 1. The effect of the length of sexual relationship. 2. The concept of primipaternity versus primigravidity. 3. Existence of the so-called ’dangerous’ father which has been demonstrated in various large population studies. It is currently unknown how the father exerts this effect. Possible mechanisms include seminal cytokine levels and their effect on maternal immune deviation, specific paternal HLA characteristics and specific paternal SNP’s (in particular in the paternally expressed genes affecting placentation). Several large cohort studies, including the large international SCOPE consortium, have identified several paternal SNP’s with strong associations with preeclampsia