Dataset Information

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology.

ABSTRACT: Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10^-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r² > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10^-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

SUBMITTER: Spracklen CN

PROVIDER: S-EPMC6612516 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology.

Spracklen Cassandra N CN Karaderi Tugce T Yaghootkar Hanieh H Schurmann Claudia C Fine Rebecca S RS Kutalik Zoltan Z Preuss Michael H MH Lu Yingchang Y Wittemans Laura B L LBL Adair Linda S LS Allison Matthew M Amin Najaf N Auer Paul L PL Bartz Traci M TM Blüher Matthias M Boehnke Michael M Borja Judith B JB Bork-Jensen Jette J Broer Linda L Chasman Daniel I DI Chen Yii-Der Ida YI Chirstofidou Paraskevi P Demirkan Ayse A van Duijn Cornelia M CM Feitosa Mary F MF Garcia Melissa E ME Graff Mariaelisa M Grallert Harald H Grarup Niels N Guo Xiuqing X Haesser Jeffrey J Hansen Torben T Harris Tamara B TB Highland Heather M HM Hong Jaeyoung J Ikram M Arfan MA Ingelsson Erik E Jackson Rebecca R Jousilahti Pekka P Kähönen Mika M Kizer Jorge R JR Kovacs Peter P Kriebel Jennifer J Laakso Markku M Lange Leslie A LA Lehtimäki Terho T Li Jin J Li-Gao Ruifang R Lind Lars L Luan Jian'an J Lyytikäinen Leo-Pekka LP MacGregor Stuart S Mackey David A DA Mahajan Anubha A Mangino Massimo M Männistö Satu S McCarthy Mark I MI McKnight Barbara B Medina-Gomez Carolina C Meigs James B JB Molnos Sophie S Mook-Kanamori Dennis D Morris Andrew P AP de Mutsert Renee R Nalls Mike A MA Nedeljkovic Ivana I North Kari E KE Pennell Craig E CE Pradhan Aruna D AD Province Michael A MA Raitakari Olli T OT Raulerson Chelsea K CK Reiner Alex P AP Ridker Paul M PM Ripatti Samuli S Roberston Neil N Rotter Jerome I JI Salomaa Veikko V Sandoval-Zárate America A AA Sitlani Colleen M CM Spector Tim D TD Strauch Konstantin K Stumvoll Michael M Taylor Kent D KD Thuesen Betina B Tönjes Anke A Uitterlinden Andre G AG Venturini Cristina C Walker Mark M Wang Carol A CA Wang Shuai S Wareham Nicholas J NJ Willems Sara M SM Willems van Dijk Ko K Wilson James G JG Wu Ying Y Yao Jie J Young Kristin L KL Langenberg Claudia C Frayling Timothy M TM Kilpeläinen Tuomas O TO Lindgren Cecilia M CM Loos Ruth J F RJF Mohlke Karen L KL

American journal of human genetics 20190606 1

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10<sup>-7</sup>). Comparison ...[more]

PMID: 31178129

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Project description:BackgroundDyslipidemia is a major risk factor for cardiovascular disease, and diabetes impacts the lipid metabolism through multiple pathways. In addition to the standard lipid measurements, apolipoprotein concentrations provide added awareness of the burden of circulating lipoproteins. While common genetic variants modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesterolemia and other genetic disorders of lipid metabolism. We aimed to identify low-frequency protein-altering variants (PAVs) affecting lipoprotein and lipid traits.MethodsWe analyzed whole-exome (WES) and whole-genome sequencing (WGS) data of 481 and 474 individuals with type 1 diabetes, respectively. The phenotypic data consisted of 79 serum lipid and apolipoprotein phenotypes obtained with clinical laboratory measurements and nuclear magnetic resonance spectroscopy.ResultsThe single-variant analysis identified an association between the LIPC p.Thr405Met (rs113298164) and serum apolipoprotein A1 concentrations (p=7.8×10-8). The burden of PAVs was significantly associated with lipid phenotypes in LIPC, RBM47, TRMT5, GTF3C5, MARCHF10, and RYR3 (p<2.9×10-6). The RBM47 gene is required for apolipoprotein B post-translational modifications, and in our data, the association between RBM47 and apolipoprotein C-III concentrations was due to a rare 21 base pair p.Ala496-Ala502 deletion; in replication, the burden of rare deleterious variants in RBM47 was associated with lower triglyceride concentrations in WES of >170,000 individuals from multiple ancestries (p=0.0013). Two PAVs in GTF3C5 were highly enriched in the Finnish population and associated with cardiovascular phenotypes in the general population. In the previously known APOB gene, we identified novel associations at two protein-truncating variants resulting in lower serum non-HDL cholesterol (p=4.8×10-4), apolipoprotein B (p=5.6×10-4), and LDL cholesterol (p=9.5×10-4) concentrations.ConclusionsWe identified lipid and apolipoprotein-associated variants in the previously known LIPC and APOB genes, as well as PAVs in GTF3C5 associated with LDLC, and in RBM47 associated with apolipoprotein C-III concentrations, implicated as an independent CVD risk factor. Identification of rare loss-of-function variants has previously revealed genes that can be targeted to prevent CVD, such as the LDL cholesterol-lowering loss-of-function variants in the PCSK9 gene. Thus, this study suggests novel putative therapeutic targets for the prevention of CVD.

Project description:Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD) to "Cafeteria diets" (CAF) consisting of nutrient poor human junk food. Our previous work demonstrated the rapid and severe obesogenic and inflammatory consequences of CAF compared to HFD including rapid weight gain, markers of Metabolic Syndrome, multi-tissue lipid accumulation, and dramatic inflammation. To identify potential mediators of CAF-induced obesity and Metabolic Syndrome, we used metabolomic analysis to profile serum, muscle, and white adipose from rats fed CAF, HFD, or standard control diets. Principle component analysis identified elevations in clusters of fatty acids and acylcarnitines. These increases in metabolites were associated with systemic mitochondrial dysfunction that paralleled weight gain, physiologic measures of Metabolic Syndrome, and tissue inflammation in CAF-fed rats. Spearman pairwise correlations between metabolites, physiologic, and histologic findings revealed strong correlations between elevated markers of inflammation in CAF-fed animals, measured as crown like structures in adipose, and specifically the pro-inflammatory saturated fatty acids and oxidation intermediates laurate and lauroyl carnitine. Treatment of bone marrow-derived macrophages with lauroyl carnitine polarized macrophages towards the M1 pro-inflammatory phenotype through downregulation of AMPK and secretion of pro-inflammatory cytokines. Results presented herein demonstrate that compared to a traditional HFD model, the CAF diet provides a robust model for diet-induced human obesity, which models Metabolic Syndrome-related mitochondrial dysfunction in serum, muscle, and adipose, along with pro-inflammatory metabolite alterations. These data also suggest that modifying the availability or metabolism of saturated fatty acids may limit the inflammation associated with obesity leading to Metabolic Syndrome.

Dataset Information

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology.

Publications

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology.

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