TY  - JOUR
AU  - Strawbridge, R.J.
AU  - et, al
TI  - Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes
JO  - Diabetes
VL  - 60
SN  - 0012-1797
CY  - Alexandria, Va
PB  - Assoc.
M1  - PreJuSER-17725
SP  - 2624 - 2634
PY  - 2011
N1  - Record converted from VDB: 12.11.2012
AB  - 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.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.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.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  - Diabetes Mellitus, Type 2: genetics
KW  - Diabetes Mellitus, Type 2: metabolism
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
KW  - Insulin (NLM Chemicals)
KW  - Proinsulin (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:21873549
C2  - pmc:PMC3178302
UR  - <Go to ISI:>//WOS:000295998700022
DO  - DOI:10.2337/db11-0415
UR  - https://juser.fz-juelich.de/record/17725
ER  -