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000017725 0247_ $$2DOI$$a10.2337/db11-0415
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000017725 041__ $$aeng
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000017725 084__ $$2WoS$$aEndocrinology & Metabolism
000017725 1001_ $$0P:(DE-HGF)0$$aStrawbridge, R.J.$$b0
000017725 245__ $$aGenome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes
000017725 260__ $$aAlexandria, Va$$bAssoc.$$c2011
000017725 300__ $$a2624 - 2634
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000017725 440_0 $$025006$$aDiabetes$$v60$$y10
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000017725 520__ $$aProinsulin 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.
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000017725 650_2 $$2MeSH$$aAdult
000017725 650_2 $$2MeSH$$aDiabetes Mellitus, Type 2: blood
000017725 650_2 $$2MeSH$$aDiabetes Mellitus, Type 2: genetics
000017725 650_2 $$2MeSH$$aDiabetes Mellitus, Type 2: metabolism
000017725 650_2 $$2MeSH$$aFasting: blood
000017725 650_2 $$2MeSH$$aFemale
000017725 650_2 $$2MeSH$$aGenetic Variation
000017725 650_2 $$2MeSH$$aGenome, Human
000017725 650_2 $$2MeSH$$aGenotype
000017725 650_2 $$2MeSH$$aHumans
000017725 650_2 $$2MeSH$$aInsulin: blood
000017725 650_2 $$2MeSH$$aMale
000017725 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide: genetics
000017725 650_2 $$2MeSH$$aProinsulin: blood
000017725 650_7 $$00$$2NLM Chemicals$$aInsulin
000017725 650_7 $$09035-68-1$$2NLM Chemicals$$aProinsulin
000017725 650_7 $$2WoSType$$aJ
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000017725 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178302
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000017725 9141_ $$y2011
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