Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

TY - JOUR

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 -