Common Physiological Processes Research Articles

Common biological processes and mutual crosstalk mechanisms between cardiovascular disease and cancer.

Cancer and cardiovascular disease (CVD) are leading causes of mortality and thus represent major health challenges worldwide. Clinical data suggest that cancer patients have an increased likelihood of developing cardiovascular disease, while epidemiologic studies have shown that patients with cardiovascular disease are also more likely to develop cancer. These observations underscore the increasing importance of studies exploring the mechanisms underlying the interaction between the two diseases. We review their common physiological processes and potential pathophysiological links. We explore the effects of chronic inflammation, oxidative stress, and disorders of fatty acid metabolism in CVD and cancer, and also provide insights into how cancer and its treatments affect heart health, as well as present recent advances in reverse cardio-oncology using a new classification approach.

The genetic regulation of the gastric transcriptome is associated with metabolic and obesity-related traits and diseases.

Tissue-specific gene expression and gene regulation lead to a better understanding of tissue-specific physiology and pathophysiology. We analyzed the transcriptome and genetic regulatory profiles of two distinct gastric sites, corpus and antrum, to identify tissue-specific gene expression and its regulation. Gastric corpus and antrum mucosa biopsies were collected during routine gastroscopies from up to 431 healthy individuals. We obtained genotype and transcriptome data and performed transcriptome profiling and expression quantitative trait locus (eQTL) studies. We further used data from genome-wide association studies (GWAS) of various diseases and traits to partition their heritability and to perform transcriptome-wide association studies (TWAS). The transcriptome data from corpus and antral mucosa highlights the heterogeneity of gene expression in the stomach. We identified enriched pathways revealing distinct and common physiological processes in gastric corpus and antrum. Furthermore, we found an enrichment of the single nucleotide polymorphism (SNP)-based heritability of metabolic, obesity-related, and cardiovascular traits and diseases by considering corpus- and antrum-specifically expressed genes. Particularly, we could prioritize gastric-specific candidate genes for multiple metabolic traits, like NQO1 which is involved in glucose metabolism, MUC1 which contributes to purine and protein metabolism or RAB27B being a regulator of weight and body composition. Our findings show that gastric corpus and antrum vary in their transcriptome and genetic regulatory profiles indicating physiological differences which are mostly related to digestion and epithelial protection. Moreover, our findings demonstrate that the genetic regulation of the gastric transcriptome is linked to biological mechanisms associated with metabolic, obesity-related, and cardiovascular traits and diseases. NEW & NOTEWORTHY We analyzed the transcriptomes and genetic regulatory profiles of gastric corpus and for the first time also of antrum mucosa in 431 healthy individuals. Through tissue-specific gene expression and eQTL analyses, we uncovered unique and common physiological processes across both primary gastric sites. Notably, our findings reveal that stomach-specific eQTLs are enriched in loci associated with metabolic traits and diseases, highlighting the pivotal role of gene expression regulation in gastric physiology and potential pathophysiology.

Functional Relationship between Leptin and Nitric Oxide in Metabolism.

Leptin, the product of the ob gene, was originally described as a satiety factor, playing a crucial role in the control of body weight. Nevertheless, the wide distribution of leptin receptors in peripheral tissues supports that leptin exerts pleiotropic biological effects, consisting of the modulation of numerous processes including thermogenesis, reproduction, angiogenesis, hematopoiesis, osteogenesis, neuroendocrine, and immune functions as well as arterial pressure control. Nitric oxide (NO) is a free radical synthesized from L-arginine by the action of the NO synthase (NOS) enzyme. Three NOS isoforms have been identified: the neuronal NOS (nNOS) and endothelial NOS (eNOS) constitutive isoforms, and the inducible NOS (iNOS). NO mediates multiple biological effects in a variety of physiological systems such as energy balance, blood pressure, reproduction, immune response, or reproduction. Leptin and NO on their own participate in multiple common physiological processes, with a functional relationship between both factors having been identified. The present review describes the functional relationship between leptin and NO in different physiological processes.

Energetic trade-offs and feedbacks between behavior and metabolism influence correlations between pace-of-life attributes

Correlations between behavioral, physiological, and morphological traits linked to life history have been given the label “pace-of-life syndrome” (POLS), hypothesized to arise through variation in the resolution of a trade-off between present and future reproduction. However, other trade-offs over energy allocation may also have effects and influence the present-future trade-off. We analyzed an optimality model of basal metabolic rate (BMR) across variation in food availability and two types of mortality. The model contained three major features: (1) feedback between activity and energy acquisition, (2) links between BMR and the use of energy for other traits, and (3) allocation trade-offs between BMR and all other traits, between activity and defense, and between defense against activity-related risk and activity-independent risk. The model produced an intermediate optimal BMR that was usually highest at an intermediate level of food availability. Food availability and both types of mortality risk interacted to influence the exact value of optimal BMR. Trait correlations expected in the POLS existed under some environmental conditions, but these correlations flipped sign under different conditions and were not always strong. Our model reproduces trait correlations consistent with the POLS, but also generated a “sloppy” syndrome with considerable non-POLS-like variation. In addition, among-individual, non-adaptive variation in BMR produced adjustments of the other traits. These fit a best-of-a-bad job strategy, and the adjustments further weakened trait correlations. The results emphasize that variation in resources and mortality risk creates a diversity of correlation structures. This complexity means the POLS is likely to be a variable construct. Many attributes important for reproduction and survival are associated. Such associations may arise through common physiological processes and correlated selection. We modeled metabolic rate within a system in which foraging behavior both depended on and mediated the acquisition of resources necessary for metabolism, while energy was allocated among multiple attributes. Variation in several environmental variables (food availability and two types of mortality risk) influenced basal metabolic rate, activity, and defenses against mortality risk. This variation affected the correlations between the traits in complex ways. When basal metabolic rate was non-optimal, evolution of the allocation of energy to other traits partially compensated, but this further eroded consistent trait correlations. Our results indicate that complexity in how energy is acquired and used can potentially disrupt trait correlations normally associated with the pace-of-life syndrome.

Hypothetical orchestrated cooperation between dopaminergic and kinin receptors for the regulation of common functions.

The G protein-coupled receptors (GPCRs), one of the largest protein families, are essential components of the most commonly used signal-transduction systems in cells. These receptors, often using common pathways, may cooperate in the regulation of signal transmission to the cell nucleus. Recent scientific interests increasingly focus on the cooperation between these receptors, particularly in a context of their oligomerization, e.g. the formation of dimers that are able to change characteristic signaling of each receptor. Numerous studies on kinin and dopamine receptors which belong to this family of receptors have shown new facts demonstrating their direct interactions with other GPCRs. In this review, current knowledge on signaling pathways and oligomerization of these receptors has been summarized. Owing to the fact that kinin and dopamine receptors are widely expressed in cell membranes where they act as mediators of numerous common physiological processes, the information presented here sheds new light on a putative crosstalk of these receptors and provides more comprehensive understanding of possible direct interactions that may change their functions. The determination of such interactions may be useful for the development of new targeted therapeutic strategies against many disorders in which kinin and dopamine receptors are involved.

Quantitative resistance to biotrophic filamentous plant pathogens: concepts, misconceptions, and mechanisms.

Quantitative resistance (QR) refers to a resistance that is phenotypically incomplete and is based on the joined effect of several genes, each contributing quantitatively to the level of plant defense. Often, QR remains durably effective, which is the primary driver behind the interest in it. The various terms that are used to refer to QR, such as field resistance, adult plant resistance, and basal resistance, reflect the many properties attributed to it. In this article, we discuss aspects connected to those attributions, in particular the hypothesis that much of the QR to biotrophic filamentous pathogens is basal resistance, i.e., poor suppression of PAMP-triggered defense by effectors. We discuss what role effectors play in suppressing defense or improving access to nutrients. Based on the functions of the few plant proteins identified as involved in QR, vesicle trafficking and protein/metabolite transportation are likely to be common physiological processes relevant to QR.

Soft Bodies, Hard Jaws: An Introduction to the Symposium, with Rotifers as Models of Jaw Diversity.

Jaws have evolved numerous times in the animal kingdom and they display a wide variety of structural, compositional, and functional characteristics that reflect their polyphyletic origins. Among soft-bodied invertebrates, jaws are known from annelids, chaetognaths, flatworms, gnathostomulids, micrognathozoans, mollusks, rotifers, and several ecdysozoans. Depending on the taxon, jaws may function in the capture of prey (e.g., chaetognaths and flatworms), processing of prey (e.g., gnathostomulids and onychophorans), or both (e.g., rotifers). Although structural diversity among invertebrates’ jaws is becoming better characterized with the use of electron microscopy, many details remain poorly described, including neuromuscular control, elemental composition, and physical characteristics, such as hardness and resistance to wear. Unfortunately, absence of relevant data has impeded understanding of their functional diversity and evolutionary origins. With this symposium, we bring together researchers of disparately jawed taxa to draw structural and mechanistic comparisons among species to determine their commonalities. Additionally, we show that rotifers’ jaws, which are perhaps the best-characterized jaws among invertebrates, are still enigmatic with regard to their origins and mechanics. Nevertheless, technologies such as energy dispersive X-ray spectroscopy (EDX) and 3D modeling are being used to characterize their chemical composition and to develop physical models that allow exploration of their mechanical properties, respectively. We predict that these methods can also be used to develop biomimetic and bioinspired constructs based on the full range of the complexity of jaws, and that such constructs also can be developed from other invertebrate taxa. These approaches may also shed light on common developmental and physiological processes that facilitate the evolution of invertebrates’ jaws.

Situation-Specific Disease and Dispositional Function

In ( Kingma [2010] ), I argued that Boorse's ([1977], [1997]) biostatistical theory of health (BST) is unable to accommodate diseases that are the normal result of harmful environments. Hausman ( [2011] ) disagrees: if the BST compares normal dispositional function against the whole population or reference class, rather than against organisms in similar circumstances as I proposed, then my ( [2010] ) challenge can be avoided. In this paper, I argue that Hausman's response fails: his proposal cannot accommodate a series of common physiological processes, such as sleep and those involved in reproduction. In the course of this argument, I also offer a detailed discussion of the concept of functional efficiency ( Hausman [2011] , [2012] ), and reveal a link between the problem of environments ( Kingma [2010] ) and that of reference classes ( Kingma [2007] ). 1 Introduction 2 Kingma on Boorse 3 Hausman on Kingma 4 Response to Hausman 5 Three Possible Replies 5.1 Reference classes 5.2 Temporary pathologies 5.3 Adequacy of function 6 Concluding Discussion

Treatment of insulin resistance in the neurodegeneration.

The association between diabetes and neurodegenerative diseases is increasing with aging. Several common mechanisms are involved in both these diseases. The endothelial cells of the blood brain barrier, neurons and glia express typical and different receptors of the glucose metabolism (glucose transporters, insulin receptors and glucagon-like peptide-1 receptors). The impairment in insulin signaling leads to an impairment of neuronal function and increases neurodegeneration, and, conversely, neurodegeneration causes a reduction of insulin signaling on neurons. Increased detailed knowledge of common physiological processes opens up the opportunities for developing new treatments that may prevent or reduce the onset of neurodegenerative diseases. The aim of the review is to discuss the potential neuroprotective effects of the antidiabetic drugs. The article presents some promising patents on the treatment of insulin resistance in the neurodegeneration.

Association of DAPK1 genetic variations with Alzheimer's disease in Han Chinese

Apoptosis and autophagy are common physiological and pathological processes in the human body. Death-associated kinase protein 1 (DAPK1), which participates in the process of cell death, has attracted people's attention for its potential risk with late-onset Alzheimer's disease (LOAD). A recent study identified two single nucleotide polymorphisms (SNPs) in DAPK1 that show significant association with LOAD in Caucasians. In order to clarify the role of these genetic variations in Chinese population, we examined the genetic variations of DAPK1/rs4877365 and DAPK1/rs4878104 in a group of 400 LOAD patients and 400 healthy controls. All samples were recruited from Northern Han Chinese population. Data collected from this study showed that there were significant differences in genotype (P=0.02) and allele (P=0.007) frequencies of DAPK1/rs4878104 but not in DAPK1/rs4877365 between LOAD patients and controls. The “C” allele of rs4878104 worked as a protective factor of LOAD (P=0.0026, odds ratio/OR=0.75) in Han Chinese. Logistic regression analysis revealed that homozygosity was strongly associated with LOAD under a recessive model (P=0.003, OR=0.23). No significant association was observed between rs4877365 and LOAD. Haplotype analysis identified the G/T haplotype as a risk factor for LOAD (P=0.007, OR=1.33, 95% CI=1.08–1.64). This study provides the evidence that variation in DAPK1 gene influences susceptibility to LOAD in the Northern Han Chinese population.

Costs of venom production in the common death adder ( Acanthophis antarcticus)

The utilization of venom in predatory and defensive contexts is associated with benefits regarding minimization of energetic expenditure on hunting, maximization of success in prey acquisition and avoidance of injury from dangerous prey and aggressors. Multiple characteristics suggest that venom is quite expensive to produce, thereby creating a tradeoff between advantages and disadvantages associated with its possession. The metabolic costs of venom production have rarely been studied and no information on the detailed metabolic processes during venom replenishment exists. Where costs of venom production have been studied they are often not in context with other components of the energy budget of the study organism. Using flow-through respirometry, we examined changes in metabolic rate in the Australian elapid Acanthophis antarcticus after venom expenditure and feeding as well as during preparation for shedding to establish a comparison of the magnitude of energetic expenditure during venom replenishment and other common physiological processes. We also defined the temporal pattern of metabolic processes during venom replenishment at a higher resolution than has previously been attempted in snakes. Our results suggest that total costs of venom replenishment are relatively small when compared to costs of digestion and shedding. We conclude that, in spite of the manifold factors suggesting a high cost of venom in snakes, its production is less energetically costly than often assumed. Until further research can clarify the reasons for this more caution should therefore be applied when assuming that costs of venom production exert strong selection pressures on the ecology, behavior and evolution of venomous taxa.

OsGSR1 is involved in crosstalk between gibberellins and brassinosteroids in rice

Gibberellins (GAs) and brassinosteroids (BRs), two growth-promoting phytohormones, regulate many common physiological processes. Their interactions at the molecular level remain unclear. Here, we demonstrate that OsGSR1, a member of the GAST (GA-stimulated transcript) gene family, is induced by GA and repressed by BR. RNA interference (RNAi) transgenic rice plants with reduced OsGSR1 expression show phenotypes similar to plants deficient in BR, including short primary roots, erect leaves and reduced fertility. The OsGSR1 RNAi transgenic rice shows a reduced level of endogenous BR, and the dwarf phenotype could be rescued by the application of brassinolide. The yeast two-hybrid assay revealed that OsGSR1 interacts with DIM/DWF1, an enzyme that catalyzes the conversion from 24-methylenecholesterol to campesterol in BR biosynthesis. These results suggest that OsGSR1 activates BR synthesis by directly regulating a BR biosynthetic enzyme at the post-translational level. Furthermore, OsGSR1 RNAi plants show a reduced sensitivity to GA treatment, an increased expression of the GA biosynthetic gene OsGA20ox2, which is feedback inhibited by GA signaling, and an elevated level of endogenous GA: together, these suggest that OsGSR1 is a positive regulator of GA signaling. These results demonstrate that OsGSR1 plays important roles in both BR and GA pathways, and also mediates an interaction between the two signaling pathways.

Unraveling the Molecular Mechanisms Behind the Metabolic Basis of Sporadic Alzheimer's Disease

Peripheral insulin resistance is associated with hyperinsulinemia, which may be associated with brain insulin deficiency that is characteristic of sporadic Alzheimer's disease (sAD). Oxidative insult, which is the result of insulin associated disordered brain energy metabolism, is a significant early event in the pathological cascade of sAD. Aggregation of disease-specific proteins such as amyloid-beta and tau may act as a compensatory response against the oxidative insult at the early periods. In the later stages, oxidative stress stimulates c-Jun N-terminal kinase (JNK) activation. The deficient insulin signaling is ultimately linked to protein kinase B (Akt) pathway and subsequently glycogen synthase kinase-3 (GSK3) and forkhead transcription factors (FOXO). Peripheral insulin resistance related intense interactions between JNK, GSK3, FOXO factors, and p53, which may lead to apoptotic neuronal death, are outlined in a postulate. In light of this postulate, the importance of detailed knowledge of these common physiological processes for the opportunities of treatment that could prevent or reduce the onset of sAD is discussed as well.

High-Resolution Dendrochemical Analysis of Flood-Affected Oaks using Laser Ablation Icp-Mass Spectrometry

Dendrochemical analysis was conducted on Quercus macrocarpa Michx. (bur oak) growing within the floodplain of the Red River, Canada, to determine if xylem formed during severe floods contained significantly perturbed chemistry. Wood samples were taken from five living trees in the same stand and from three timbers from a 19th-century building. Laser ablation ICP-mass spectrometry was used to determine the trace element chemistry in the earlywood and latewood of rings formed before, during and after major floods. Between-tree correlations were significant (p < 0.05) for Hg, Mg, Mn, Sr and Zn, suggesting that changes in the abundance of these elements over time might reflect common physiological processes or environmental signals. Mg, Mn and Sr concentrations were higher in the earlywood than in the latewood for both living and historical samples. These intra-annual shifts may reflect varying rates of uptake driven by seasonal changes in anatomical development, as well as stability of these elements after their initial deposition. Although no chemical anomalies are associated with 20th-century floods, earlywood coinciding with an extreme flood in 1826 contained low levels of Mg, Mn and Sr. These elemental anomalies might represent an independent biochemical flood signature but it is also possible they are a secondary expression of wood formation disrupted by flooding. In either case, elemental analysis does not provide any information beyond that obtained from studying anatomical features, and does not appear to be a viable tool to identify the occurrence of past floods.

Nitric Oxide Production and Nitric Oxide Synthase Activity in Malaria-Exposed Papua New Guinean Children and Adults Show Longitudinal Stability and No Association with Parasitemia

Individuals in areas of intense malaria transmission exhibit resistance (or tolerance) to levels of parasitemia in their blood that would normally be associated with febrile illness in malaria-naive subjects. The resulting level of parasitemia associated with illness (the pyrogenic threshold) is highest in childhood and lowest in adulthood. Clinical parallels between malarial and bacterial endotoxin tolerance have led to the supposition that both share common physiological processes, with nitric oxide (NO) proposed as a candidate mediator. The hypotheses that NO mediates tolerance and blood stage parasite killing in vivo were tested by determining its relationship to age and parasitemia cross-sectionally and longitudinally in a population of 195 children and adults from Papua New Guinea encountering intense malaria exposure. Despite pharmacological clearance of asymptomatic parasitemia, NO production and mononuclear cell NO synthase (NOS) activity were remarkably stable within individuals over time, were not influenced by parasitemia, and varied little with age. These results contrast with previous smaller cross-sectional studies. Baseline NO production and NOS activity did not protect against recurrent parasitemia, consistent with previous data suggesting that NO does not have antiparasitic effects against blood stage infection in vivo. The NO indices studied were markedly higher in specimens from study subjects than in samples from Australian controls, and NOS activity was significantly associated with plasma immunoglobulin E levels, consistent with induction of NO by chronic exposure to other infections and/or host genetic factors. These results suggest that NO is unlikely to mediate killing of blood stage parasites in this setting and is unlikely to be the primary mediator in the acquisition or maintenance of malarial tolerance.

Sitosterolemia; of mice and man

Investigation and study of rare genetic disorders can lead to considerable and rapid advancements into understanding common and basic physiological processes. One such case is the study of the rare human disorder of sitosterolemia. This autosomal recessive disorder is characterized by the accumulation of plant sterols in the blood and tissues. The identification of the molecular defect(s) responsible for causing sitosterolemia has not only advanced our understanding of how we normally regulate dietary sterol entry, but may have also led to the identification of the long sought after transporters responsible for secretion of cholesterol (and other sterols) into bile. This review will summarize the history and current knowledge of how the genetic defects identified have improved our understanding of these important processes.

Evaluation of common gene expression patterns in the rat nervous system.

In the postgenomic era, integrating data obtained from array technologies (e.g., oligonucleotide microarrays) with published information on eukaryotic genomes is beginning to yield biomarkers and therapeutic targets that are key for the diagnosis and treatment of disease. Nevertheless, identifying and validating these drug targets has not been a trivial task. Although a plethora of bioinformatics tools and databases are available, major bottlenecks for this approach reside in the interpretation of vast amounts of data, its integration into biologically representative models, and ultimately the identification of pathophysiologically and therapeutically useful information. In the field of neuroscience, accomplishing these goals has been particularly challenging because of the complex nature of nerve tissue, the relatively small adaptive nature of induced-gene expression changes, as well as the polygenic etiology of most neuropsychiatric diseases. This report combines published data sets from multiple transcript profiling studies that used GeneChip microarrays to illustrate a postanalysis approach for the interpretation of data from neuroscience microarray studies. By defining common gene expression patterns triggered by diverse events (administration of psychoactive drugs and trauma) in different nerve tissues (telencephalic brain areas and spinal cord), we broaden the conclusions derived from each of the original studies. In addition, the evaluation of the identified overlapping gene lists provides a foundation for generating hypotheses relating alterations in specific sets of genes to common physiological processes. Our approach demonstrates the significance of interpreting transcript profiling data within the context of common pathways and mechanisms rather than specific to a given tissue or stimulus. We also highlight the use of gene expression patterns in predictive biology (e.g., in toxicogenomics) as well as the utility of combining data derived from multiple microarray studies that examine diverse biological events for a broader interpretation of data from a particular microarray study.

Spatial memory and path integration studied by self-driven passive linear displacement. I. Basic properties.

According to path integration, the brain is able to compute the distance of a traveled path. In this research we applied our previously reported method for studying memory of linear distance, a crucial mechanism in path integration; our method is based on the overt reconstruction of a passive transport. Passive transport is a special case of navigation in which no active control is performed. Blindfolded subjects were first asked to travel 2 m forward, in darkness, by driving with a joystick the robot on which they were seated. The results show that all subjects but two undershot this distance, i.e., overestimated their own displacement. Then, subjects were submitted to a passive linear forward displacement along 2, 4, 6, 8, or 10 m, and had to reproduce the same distance, still blindfolded. The results show that the distance of the stimulus was accurately reproduced, as well as stimulus duration, peak velocity, and velocity profile. In this first condition, the imposed velocity profile was triangular and therefore stimulus distance and duration were correlated. In a second condition, it was shown that distance was correctly reproduced also when the information about stimulus duration was kept constant. Here, different velocity profiles were used as stimuli, and most subjects also reproduced the velocity profile. Statistical analyses indicated that distance was not reproduced as a consequence of duration, peak velocity, or velocity profile reproduction, but was uniquely correlated to stimulus distance. The previous hypothesis of a double integration of the otolith signal to provide a distance estimate can explain our results. There was a large discrepancy between the accuracy with which the subjects matched the velocity profiles and that of distance reproduction. It follows that, whereas the dynamics of passive motion are stored and available to further use, distance is independently estimated. It is concluded that vestibular and somatosensory signals excited by passive transport can be used to build a dynamic as well as a static representation of the traveled path. We found a close quantitative similarity between the present findings on distance reproduction and those obtained from active locomotion experiments in which the same paradigm was used. This resemblance suggests that the two types of navigation tasks draw on common physiological processes and extends the relevance of our results to naturally occurring path integration.

Heritability and repeatability of behavioural attributes affecting foraging success and fitness in water striders

Abstract. Heritabilities and repeatabilities are presented for various behavioural attributes affecting foraging performance and fitness in Aquarius (Gerris) remigis (Heteroptera: Gerridae) females. These behavioural attributes were patch choice, foraging success, capture accuracy, and measures of mobility, activity, skittishness and aggressiveness. Most heritabilities were not significantly different from zero, which may be related to the low sample size. Conclusions as to the potential of direct selection on behaviour in this species were consequently limited. In contrast, with a few exceptions (capture accuracy, foraging success), most repeatabilities were significant and at times high (range=0·22-0·79), indicating consistent, stereotypical individual behaviour. The life history or reproductive state of the daughter generation individuals significantly affected the magnitude of the repeatabilities as well as the mean values of many of the variables (notably mobility and aggressiveness), the latter in a manner consistent with field observations. This indicates that the state of the organism affects the general environmental variance, thus contributing to the discrepancies between the repeatabilities and the heritabilities obtained. It is suggested that common physiological processes (e.g. hormones) may underlie several of the behavioural attributes examined, resulting in possible pleiotropic effects and constraints on selection in a heterogeneous environment. It is further suggested that field studies of selection on behavioural attributes may be a more fruitful approach in this species, whose suitability for genetic analysis is limited.

Genome-wide association test of multiple continuous traits using imputed SNPs.

More and more large cohort studies have conducted or are conducting genome-wide association studies (GWAS) to reveal the genetic components of many complex human diseases. These large cohort studies often collected a broad array of correlated phenotypes that reflect common physiological processes. By jointly analyzing these correlated traits, we can gain more power by aggregating multiple weak effects and shed light on the mechanisms underlying complex human diseases. The majority of existing multi-trait association test methods are based on jointly modeling the multivariate traits conditional on the genotype as covariate, and can readily accommodate the imputed SNPs by using their imputed dosage as a covariate. An alternative class of multi-trait association tests is based on the inverted regression, which models the distribution of genotypes conditional on the covariate and multivariate traits, and has been shown to have competitive performance. To our knowledge, all existing inverted regression approaches have implicitly used the "best-guess" genotypes, which is not efficient and known to lead to dramatic power loss, and there have not been any proposed methods of incorporating imputation uncertainty into inverted regressions. In this work, we propose a general and efficient framework that can account for the imputation uncertainty to further improve the association test power of inverted regression models for imputed SNPs. We demonstrate through extensive numerical studies that the proposed method has competitive performance. We further illustrate its usefulness by application to association test of diabetes-related glycemic traits in the Atherosclerosis Risk in Communities (ARIC) Study.