Imperial College London
Alternate

ProfessorAlexBlakemore

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 3313 2156a.blakemore

 
 
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Location

 

Commonwealth Building, 6N2BHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Strawbridge:2011:10.2337/db11-0415,
author = {Strawbridge, RJ and Dupuis, J and Prokopenko, I and Barker, A and Ahlqvist, E and Rybin, D and Petrie, JR and Travers, ME and Bouatia-Naji, N and Dimas, AS and Nica, A and Wheeler, E and Chen, H and Voight, BF and Taneera, J and Kanoni, S and Peden, JF and Turrini, F and Gustafsson, S and Zabena, C and Almgren, P and Barker, DJP and Barnes, D and Dennison, EM and Eriksson, JG and Eriksson, P and Eury, E and Folkersen, L and Fox, CS and Frayling, TM and Goel, A and Gu, HF and Horikoshi, M and Isomaa, B and Jackson, AU and Jameson, KA and Kajantie, E and Kerr-Conte, J and Kuulasmaa, T and Kuusisto, J and Loos, RJF and Luan, J and Makrilakis, K and Manning, AK and Teresa, Martinez-Larrad M and Narisu, N and Mannila, MN and Ohrvik, J and Osmond, C and Pascoe, L and Payne, F and Sayer, AA and Sennblad, B and Silveira, A and Stancakova, A and Stirrups, K and Swift, AJ and Syvanen, A-C and Tuomi, T and van, 't Hooft FM and Walker, M and Weedon, MN and Xie, W and Zethelius, B and Ongen, H and },
doi = {10.2337/db11-0415},
journal = {Diabetes},
pages = {2624--2634},
title = {Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes},
url = {http://dx.doi.org/10.2337/db11-0415},
volume = {60},
year = {2011}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
AU  - Strawbridge,RJ
AU  - Dupuis,J
AU  - Prokopenko,I
AU  - Barker,A
AU  - Ahlqvist,E
AU  - Rybin,D
AU  - Petrie,JR
AU  - Travers,ME
AU  - Bouatia-Naji,N
AU  - Dimas,AS
AU  - Nica,A
AU  - Wheeler,E
AU  - Chen,H
AU  - Voight,BF
AU  - Taneera,J
AU  - Kanoni,S
AU  - Peden,JF
AU  - Turrini,F
AU  - Gustafsson,S
AU  - Zabena,C
AU  - Almgren,P
AU  - Barker,DJP
AU  - Barnes,D
AU  - Dennison,EM
AU  - Eriksson,JG
AU  - Eriksson,P
AU  - Eury,E
AU  - Folkersen,L
AU  - Fox,CS
AU  - Frayling,TM
AU  - Goel,A
AU  - Gu,HF
AU  - Horikoshi,M
AU  - Isomaa,B
AU  - Jackson,AU
AU  - Jameson,KA
AU  - Kajantie,E
AU  - Kerr-Conte,J
AU  - Kuulasmaa,T
AU  - Kuusisto,J
AU  - Loos,RJF
AU  - Luan,J
AU  - Makrilakis,K
AU  - Manning,AK
AU  - Teresa,Martinez-Larrad M
AU  - Narisu,N
AU  - Mannila,MN
AU  - Ohrvik,J
AU  - Osmond,C
AU  - Pascoe,L
AU  - Payne,F
AU  - Sayer,AA
AU  - Sennblad,B
AU  - Silveira,A
AU  - Stancakova,A
AU  - Stirrups,K
AU  - Swift,AJ
AU  - Syvanen,A-C
AU  - Tuomi,T
AU  - van,'t Hooft FM
AU  - Walker,M
AU  - Weedon,MN
AU  - Xie,W
AU  - Zethelius,B
AU  - Ongen,H
AU  - Malarstig,A
AU  - Hopewell,JC
AU  - Saleheen,D
AU  - Chambers,J
AU  - Parish,S
AU  - Danesh,J
AU  - Kooner,J
AU  - Ostenson,C-G
AU  - Lind,L
AU  - Cooper,CC
AU  - Serrano-Rios,M
AU  - Ferrannini,E
AU  - Forsen,TJ
AU  - Clarke,R
AU  - Franzosi,MG
AU  - Seedorf,U
AU  - Watkins,H
AU  - Froguel,P
AU  - Johnson,P
AU  - Deloukas,P
AU  - Collins,FS
AU  - Laakso,M
AU  - Dermitzakis,ET
AU  - Boehnke,M
AU  - McCarthy,MI
AU  - Wareham,NJ
AU  - Groop,L
AU  - Pattou,F
AU  - Gloyn,AL
AU  - Dedoussis,GV
AU  - Lyssenko,V
AU  - Meigs,JB
AU  - Barroso,I
AU  - Watanabe,RM
AU  - Ingelsson,E
AU  - Langenberg,C
AU  - Hamsten,A
AU  - Florez,JC
DO  - 10.2337/db11-0415
EP  - 2634
PY  - 2011///
SN  - 0012-1797
SP  - 2624
TI  - Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes
T2  - Diabetes
UR  - http://dx.doi.org/10.2337/db11-0415
UR  - http://hdl.handle.net/10044/1/28755
VL  - 60
ER  -
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