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Comparative Analyses of QTLs Influencing Obesity and Metabolic Phenotypes in Pigs and Humans.

ABSTRACT: The pig is a well-known animal model used to investigate genetic and mechanistic aspects of human disease biology. They are particularly useful in the context of obesity and metabolic diseases because other widely used models (e.g. mice) do not completely recapitulate key pathophysiological features associated with these diseases in humans. Therefore, we established a F2 pig resource population (n = 564) designed to elucidate the genetics underlying obesity and metabolic phenotypes. Segregation of obesity traits was ensured by using breeds highly divergent with respect to obesity traits in the parental generation. Several obesity and metabolic phenotypes were recorded (n = 35) from birth to slaughter (242 ± 48 days), including body composition determined at about two months of age (63 ± 10 days) via dual-energy x-ray absorptiometry (DXA) scanning. All pigs were genotyped using Illumina Porcine 60k SNP Beadchip and a combined linkage disequilibrium-linkage analysis was used to identify genome-wide significant associations for collected phenotypes. We identified 229 QTLs which associated with adiposity- and metabolic phenotypes at genome-wide significant levels. Subsequently comparative analyses were performed to identify the extent of overlap between previously identified QTLs in both humans and pigs. The combined analysis of a large number of obesity phenotypes has provided insight in the genetic architecture of the molecular mechanisms underlying these traits indicating that QTLs underlying similar phenotypes are clustered in the genome. Our analyses have further confirmed that genetic heterogeneity is an inherent characteristic of obesity traits most likely caused by segregation or fixation of different variants of the individual components belonging to cellular pathways in different populations. Several important genes previously associated to obesity in human studies, along with novel genes were identified. Altogether, this study provides novel insight that may further the current understanding of the molecular mechanisms underlying human obesity.

SUBMITTER: Pant SD

PROVIDER: S-EPMC4562524 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Comparative Analyses of QTLs Influencing Obesity and Metabolic Phenotypes in Pigs and Humans.

Pant Sameer D SD Karlskov-Mortensen Peter P Jacobsen Mette J MJ Cirera Susanna S Kogelman Lisette J A LJ Bruun Camilla S CS Mark Thomas T Jørgensen Claus B CB Grarup Niels N Appel Emil V R EV Galjatovic Ehm A A EA Hansen Torben T Pedersen Oluf O Guerin Maryse M Huby Thierry T Lesnik Philipppe P Meuwissen Theo H E TH Kadarmideen Haja N HN Fredholm Merete M

PloS one 20150908 9

The pig is a well-known animal model used to investigate genetic and mechanistic aspects of human disease biology. They are particularly useful in the context of obesity and metabolic diseases because other widely used models (e.g. mice) do not completely recapitulate key pathophysiological features associated with these diseases in humans. Therefore, we established a F2 pig resource population (n = 564) designed to elucidate the genetics underlying obesity and metabolic phenotypes. Segregation ...[more]

PMID: 26348622

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Project description:BackgroundInnate monocytes can adopt dynamic "memory" states ranging from low-grade inflammation to pathogenic exhaustion, dependent upon signal strength and history of challenges. Low-grade inflammatory monocytes facilitate the pathogenesis of chronic inflammatory diseases, while exhausted monocytes drive the pathogenesis of severe sepsis. Although clinical and basic studies suggest the conservation of key features of exhausted monocytes from human and murine sepsis, systems analyses of monocyte exhaustion among human and murine monocytes are lacking.MethodsWe performed cross examination of septic monocytes scRNAseq data recently collected from human sepsis patients as well as experimental septic mice, in reference to monocytes experimentally exhausted in vitro. Furthermore, we performed pseudo-time analyses of in vitro programmed monocytes following prolonged challenges causing either low-grade inflammation or exhaustion. Additional comparative analyses of low-grade inflammatory monocytes were performed with scRNAseq data from selected human patients with chronic low-grade inflammatory diseases.ResultsOur systems analyses reveal key features of monocyte exhaustion including reduced differentiation, pathogenic inflammation and immune suppression that are highly conserved in human and murine septic monocytes, and captured by in vitro experimental exhaustion. Pseudo-time analyses reveal that monocytes initially transition into a less-differentiated state with proliferative potential. The expansion of proliferative monocytes can be observed not only in experimentally challenged monocytes, but also in tissues of murine sepsis and human septic blood. We observed that monocytes similarly transition into the less-differentiated state when challenged with a subclinical dose endotoxin under chronic inflammatory conditions. Instead of being exhausted, monocytes with prolonged challenges with super-low dose endotoxin bifurcate into the low-grade inflammatory immune-enhancing or the chemotactic/adhesive state, often see in atherosclerosis or auto-immune diseases.ConclusionsKey features of monocyte memory dynamics are identified and conserved in human and murine monocytes, which can be captured by prolonged challenges of innate signals with varying signal strength.

Dataset Information

Comparative Analyses of QTLs Influencing Obesity and Metabolic Phenotypes in Pigs and Humans.

Publications

Comparative Analyses of QTLs Influencing Obesity and Metabolic Phenotypes in Pigs and Humans.

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