Extensive alterations of the whole-blood transcriptome are associated with body mass index: results of an mRNA profiling study involving two large population-based cohorts

TY - JOUR

T1 - Extensive alterations of the whole-blood transcriptome are associated with body mass index: results of an mRNA profiling study involving two large population-based cohorts

AU - Homuth, Georg

AU - Wahl, Simone

AU - Müller, Christian

AU - Schurmann, Claudia

AU - Mäder, Ulrike

AU - Blankenberg, Stefan

AU - Carstensen, Maren

AU - Dörr, Marcus

AU - Endlich, Karlhans

AU - Englbrecht, Christian

AU - Felix, Stephan B

AU - Gieger, Christian

AU - Grallert, Harald

AU - Herder, Christian

AU - Illig, Thomas

AU - Kruppa, Jochen

AU - Marzi, Carola S

AU - Mayerle, Julia

AU - Meitinger, Thomas

AU - Metspalu, Andres

AU - Nauck, Matthias

AU - Peters, Annette

AU - Rathmann, Wolfgang

AU - Reinmaa, Eva

AU - Rettig, Rainer

AU - Roden, Michael

AU - Schillert, Arne

AU - Schramm, Katharina

AU - Steil, Leif

AU - Strauch, Konstantin

AU - Teumer, Alexander

AU - Völzke, Henry

AU - Wallaschofski, Henri

AU - Wild, Philipp S

AU - Ziegler, Andreas

AU - Völker, Uwe

AU - Prokisch, Holger

AU - Zeller, Tanja

PY - 2015/10/15

Y1 - 2015/10/15

N2 - BACKGROUND: Obesity, defined as pathologically increased body mass index (BMI), is strongly related to an increased risk for numerous common cardiovascular and metabolic diseases. It is particularly associated with insulin resistance, hyperglycemia, and systemic oxidative stress and represents the most important risk factor for type 2 diabetes (T2D). However, the pathophysiological mechanisms underlying these associations are still not completely understood. Therefore, in order to identify potentially disease-relevant BMI-associated gene expression signatures, a transcriptome-wide association study (TWAS) on BMI was performed.METHODS: Whole-blood mRNA levels determined by array-based transcriptional profiling were correlated with BMI in two large independent population-based cohort studies (KORA F4 and SHIP-TREND) comprising a total of 1977 individuals.RESULTS: Extensive alterations of the whole-blood transcriptome were associated with BMI: More than 3500 transcripts exhibited significant positive or negative BMI-correlation. Three major whole-blood gene expression signatures associated with increased BMI were identified. The three signatures suggested: i) a ratio shift from mature erythrocytes towards reticulocytes, ii) decreased expression of several genes essentially involved in the transmission and amplification of the insulin signal, and iii) reduced expression of several key genes involved in the defence against reactive oxygen species (ROS).CONCLUSIONS: Whereas the first signature confirms published results, the other two provide possible mechanistic explanations for well-known epidemiological findings under conditions of increased BMI, namely attenuated insulin signaling and increased oxidative stress. The putatively causative BMI-dependent down-regulation of the expression of numerous genes on the mRNA level represents a novel finding. BMI-associated negative transcriptional regulation of insulin signaling and oxidative stress management provide new insights into the pathogenesis of metabolic syndrome and T2D.

AB - BACKGROUND: Obesity, defined as pathologically increased body mass index (BMI), is strongly related to an increased risk for numerous common cardiovascular and metabolic diseases. It is particularly associated with insulin resistance, hyperglycemia, and systemic oxidative stress and represents the most important risk factor for type 2 diabetes (T2D). However, the pathophysiological mechanisms underlying these associations are still not completely understood. Therefore, in order to identify potentially disease-relevant BMI-associated gene expression signatures, a transcriptome-wide association study (TWAS) on BMI was performed.METHODS: Whole-blood mRNA levels determined by array-based transcriptional profiling were correlated with BMI in two large independent population-based cohort studies (KORA F4 and SHIP-TREND) comprising a total of 1977 individuals.RESULTS: Extensive alterations of the whole-blood transcriptome were associated with BMI: More than 3500 transcripts exhibited significant positive or negative BMI-correlation. Three major whole-blood gene expression signatures associated with increased BMI were identified. The three signatures suggested: i) a ratio shift from mature erythrocytes towards reticulocytes, ii) decreased expression of several genes essentially involved in the transmission and amplification of the insulin signal, and iii) reduced expression of several key genes involved in the defence against reactive oxygen species (ROS).CONCLUSIONS: Whereas the first signature confirms published results, the other two provide possible mechanistic explanations for well-known epidemiological findings under conditions of increased BMI, namely attenuated insulin signaling and increased oxidative stress. The putatively causative BMI-dependent down-regulation of the expression of numerous genes on the mRNA level represents a novel finding. BMI-associated negative transcriptional regulation of insulin signaling and oxidative stress management provide new insights into the pathogenesis of metabolic syndrome and T2D.

KW - Aged

KW - Aged, 80 and over

KW - Blood/metabolism

KW - Body Mass Index

KW - Cohort Studies

KW - Female

KW - Gene Expression Profiling

KW - Humans

KW - Insulin/metabolism

KW - Male

KW - Middle Aged

KW - Oxidative Stress/genetics

KW - RNA, Messenger/genetics

KW - Reactive Oxygen Species/metabolism

KW - Reticulocytes/metabolism

KW - Signal Transduction/genetics

U2 - 10.1186/s12920-015-0141-x

DO - 10.1186/s12920-015-0141-x

M3 - SCORING: Journal article

C2 - 26470795

VL - 8

SP - 65

JO - BMC MED GENOMICS

JF - BMC MED GENOMICS

SN - 1755-8794

ER -