Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.
Strawbridge RJ., Dupuis J., Prokopenko I., Barker A., Ahlqvist E., Rybin D., Petrie JR., Travers ME., Bouatia-Naji N., Dimas AS., Nica A., Wheeler E., Chen H., Voight BF., Taneera J., Kanoni S., Peden JF., Turrini F., Gustafsson S., Zabena C., Almgren P., Barker DJP., Barnes D., Dennison EM., Eriksson JG., Eriksson P., Eury E., Folkersen L., Fox CS., Frayling TM., Goel A., Gu HF., Horikoshi M., Isomaa B., Jackson AU., Jameson KA., Kajantie E., Kerr-Conte J., Kuulasmaa T., Kuusisto J., Loos RJF., Luan J., Makrilakis K., Manning AK., Martínez-Larrad MT., Narisu N., Nastase Mannila M., Ohrvik J., Osmond C., Pascoe L., Payne F., Sayer AA., Sennblad B., Silveira A., Stancáková A., Stirrups K., Swift AJ., Syvänen A-C., Tuomi T., van 't Hooft FM., Walker M., Weedon MN., Xie W., Zethelius B., DIAGRAM Consortium None., GIANT Consortium None., MuTHER Consortium None., CARDIoGRAM Consortium None., C4D Consortium None., Ongen H., Mälarstig A., Hopewell JC., Saleheen D., Chambers J., Parish S., Danesh J., Kooner J., Ostenson C-G., Lind L., Cooper CC., Serrano-Ríos M., Ferrannini E., Forsen TJ., Clarke R., Franzosi MG., Seedorf U., Watkins H., Froguel P., Johnson P., Deloukas P., Collins FS., Laakso M., Dermitzakis ET., Boehnke M., McCarthy MI., Wareham NJ., Groop L., Pattou F., Gloyn AL., Dedoussis GV., Lyssenko V., Meigs JB., Barroso I., Watanabe RM., Ingelsson E., Langenberg C., Hamsten A., Florez JC.
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.