Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes
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Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes. / Strawbridge, Rona J; Dupuis, Josée; Prokopenko, Inga; Barker, Adam; Ahlqvist, Emma; Rybin, Denis; Petrie, John R; Travers, Mary E; Bouatia-Naji, Nabila; Dimas, Antigone S; Nica, Alexandra; Wheeler, Eleanor; Chen, Han; Voight, Benjamin F; Taneera, Jalal; Kanoni, Stavroula; Peden, John F; Turrini, Fabiola; Gustafsson, Stefan; Zabena, Carina; Almgren, Peter; Barker, David J P; Barnes, Daniel; Dennison, Elaine M; Eriksson, Johan G; Eriksson, Per; Eury, Elodie; Folkersen, Lasse; Fox, Caroline S; Frayling, Timothy M; Goel, Anuj; Gu, Harvest F; Horikoshi, Momoko; Isomaa, Bo; Jackson, Anne U; Jameson, Karen A; Kajantie, Eero; Kerr-Conte, Julie; Kuulasmaa, Teemu; Kuusisto, Johanna; Loos, Ruth J F; Luan, Jian'an; Makrilakis, Konstantinos; Manning, Alisa K; Martínez-Larrad, María Teresa; Narisu, Narisu; Nastase Mannila, Maria; Ohrvik, John; Osmond, Clive; Pascoe, Laura; Payne, Felicity; Sayer, Avan A; Sennblad, Bengt; Silveira, Angela; Stancáková, Alena; Stirrups, Kathy; Swift, Amy J; Syvänen, Ann-Christine; Tuomi, Tiinamaija; van 't Hooft, Ferdinand M; Walker, Mark; Weedon, Michael N; Xie, Weijia; Zethelius, Björn; Ongen, Halit; Mälarstig, Anders; Hopewell, Jemma C; Saleheen, Danish; Chambers, John; Parish, Sarah; Danesh, John; Kooner, Jaspal; Ostenson, Claes-Göran; Lind, Lars; Cooper, Cyrus C; Serrano-Ríos, Manuel; Ferrannini, Ele; Forsen, Tom J; Clarke, Robert; Franzosi, Maria Grazia; Seedorf, Udo; Watkins, Hugh; Froguel, Philippe; Johnson, Paul; Deloukas, Panos; Collins, Francis S; Laakso, Markku; Dermitzakis, Emmanouil T; Boehnke, Michael; McCarthy, Mark I; Wareham, Nicholas J; Groop, Leif; Pattou, François; Gloyn, Anna L; Dedoussis, George V; Lyssenko, Valeriya; Meigs, James B; Barroso, Inês; Watanabe, Richard M; Ingelsson, Erik; Langenberg, Claudia; Hamsten, Anders; Florez, Jose C; DIAGRAM Consortium.
in: DIABETES, Jahrgang 60, Nr. 10, 10.2011, S. 2624-2634.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes
AU - Strawbridge, Rona J
AU - Dupuis, Josée
AU - Prokopenko, Inga
AU - Barker, Adam
AU - Ahlqvist, Emma
AU - Rybin, Denis
AU - Petrie, John R
AU - Travers, Mary E
AU - Bouatia-Naji, Nabila
AU - Dimas, Antigone S
AU - Nica, Alexandra
AU - Wheeler, Eleanor
AU - Chen, Han
AU - Voight, Benjamin F
AU - Taneera, Jalal
AU - Kanoni, Stavroula
AU - Peden, John F
AU - Turrini, Fabiola
AU - Gustafsson, Stefan
AU - Zabena, Carina
AU - Almgren, Peter
AU - Barker, David J P
AU - Barnes, Daniel
AU - Dennison, Elaine M
AU - Eriksson, Johan G
AU - Eriksson, Per
AU - Eury, Elodie
AU - Folkersen, Lasse
AU - Fox, Caroline S
AU - Frayling, Timothy M
AU - Goel, Anuj
AU - Gu, Harvest F
AU - Horikoshi, Momoko
AU - Isomaa, Bo
AU - Jackson, Anne U
AU - Jameson, Karen A
AU - Kajantie, Eero
AU - Kerr-Conte, Julie
AU - Kuulasmaa, Teemu
AU - Kuusisto, Johanna
AU - Loos, Ruth J F
AU - Luan, Jian'an
AU - Makrilakis, Konstantinos
AU - Manning, Alisa K
AU - Martínez-Larrad, María Teresa
AU - Narisu, Narisu
AU - Nastase Mannila, Maria
AU - Ohrvik, John
AU - Osmond, Clive
AU - Pascoe, Laura
AU - Payne, Felicity
AU - Sayer, Avan A
AU - Sennblad, Bengt
AU - Silveira, Angela
AU - Stancáková, Alena
AU - Stirrups, Kathy
AU - Swift, Amy J
AU - Syvänen, Ann-Christine
AU - Tuomi, Tiinamaija
AU - van 't Hooft, Ferdinand M
AU - Walker, Mark
AU - Weedon, Michael N
AU - Xie, Weijia
AU - Zethelius, Björn
AU - Ongen, Halit
AU - Mälarstig, Anders
AU - Hopewell, Jemma C
AU - Saleheen, Danish
AU - Chambers, John
AU - Parish, Sarah
AU - Danesh, John
AU - Kooner, Jaspal
AU - Ostenson, Claes-Göran
AU - Lind, Lars
AU - Cooper, Cyrus C
AU - Serrano-Ríos, Manuel
AU - Ferrannini, Ele
AU - Forsen, Tom J
AU - Clarke, Robert
AU - Franzosi, Maria Grazia
AU - Seedorf, Udo
AU - Watkins, Hugh
AU - Froguel, Philippe
AU - Johnson, Paul
AU - Deloukas, Panos
AU - Collins, Francis S
AU - Laakso, Markku
AU - Dermitzakis, Emmanouil T
AU - Boehnke, Michael
AU - McCarthy, Mark I
AU - Wareham, Nicholas J
AU - Groop, Leif
AU - Pattou, François
AU - Gloyn, Anna L
AU - Dedoussis, George V
AU - Lyssenko, Valeriya
AU - Meigs, James B
AU - Barroso, Inês
AU - Watanabe, Richard M
AU - Ingelsson, Erik
AU - Langenberg, Claudia
AU - Hamsten, Anders
AU - Florez, Jose C
AU - DIAGRAM Consortium
AU - Zeller, Tanja
PY - 2011/10
Y1 - 2011/10
N2 - 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.
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.
KW - Adult
KW - Diabetes Mellitus, Type 2/blood
KW - Fasting/blood
KW - Female
KW - Genetic Variation
KW - Genome, Human
KW - Genotype
KW - Humans
KW - Insulin/blood
KW - Male
KW - Polymorphism, Single Nucleotide/genetics
KW - Proinsulin/blood
U2 - 10.2337/db11-0415
DO - 10.2337/db11-0415
M3 - SCORING: Journal article
C2 - 21873549
VL - 60
SP - 2624
EP - 2634
JO - DIABETES
JF - DIABETES
SN - 0012-1797
IS - 10
ER -