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@article{Yaghootkar:2014:10.2337/db14-0318,
author = {Yaghootkar, H and Scott, RA and White, CC and Zhang, W and Speliotes, E and Munroe, PB and Ehret, GB and Bis, JC and Fox, CS and Walker, M and Borecki, IB and Knowles, JW and Yerges-Armstrong, L and Ohlsson, C and Perry, JRB and Chambers, JC and Kooner, JS and Franceschini, N and Langenberg, C and Hivert, M-F and Dastani, Z and Richards, JB and Semple, RK and Frayling, TM},
doi = {10.2337/db14-0318},
journal = {Diabetes},
pages = {4369--4377},
title = {Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes},
url = {http://dx.doi.org/10.2337/db14-0318},
volume = {63},
year = {2014}
}

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TY  - JOUR
AB  - The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy—a reduction in subcutaneous adipose tissue—it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin–based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (β = 0.018; P = 4 × 10−29), lower HDL cholesterol (β = −0.020; P = 7 × 10−37), greater hepatic steatosis (β = 0.021; P = 3 × 10−4), higher alanine transaminase (β = 0.002; P = 3 × 10−5), lower sex-hormone-binding globulin (β = −0.010; P = 9 × 10−13), and lower adiponectin (β = −0.015; P = 2 × 10−26). The same risk alleles were associated with lower BMI (per-allele β = −0.008; P = 7 × 10−8) and increased visceral-to-subcutaneous adipose tissue ratio (β = −0.015; P = 6 × 10−7). Individuals carrying ≥17 fasting insulin–raising alleles (5.5% population) were slimmer (0.30 kg/m2) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5
AU  - Yaghootkar,H
AU  - Scott,RA
AU  - White,CC
AU  - Zhang,W
AU  - Speliotes,E
AU  - Munroe,PB
AU  - Ehret,GB
AU  - Bis,JC
AU  - Fox,CS
AU  - Walker,M
AU  - Borecki,IB
AU  - Knowles,JW
AU  - Yerges-Armstrong,L
AU  - Ohlsson,C
AU  - Perry,JRB
AU  - Chambers,JC
AU  - Kooner,JS
AU  - Franceschini,N
AU  - Langenberg,C
AU  - Hivert,M-F
AU  - Dastani,Z
AU  - Richards,JB
AU  - Semple,RK
AU  - Frayling,TM
DO  - 10.2337/db14-0318
EP  - 4377
PY  - 2014///
SN  - 0012-1797
SP  - 4369
TI  - Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes
T2  - Diabetes
UR  - http://dx.doi.org/10.2337/db14-0318
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000345335500045&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://diabetes.diabetesjournals.org/content/63/12/4369
VL  - 63
ER  -

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