التفاصيل البيبلوغرافية
| العنوان: |
26-OR: Meta-analyses of Genome-Wide Association Studies for Proinsulin Provide Insight into Glycemic Trait Dysregulation. |
| المؤلفون: |
BROADAWAY, K. ALAINE, YIN, XIANYONOG, WILLIAMSON, ALICE, WILSON, EMMA, INVESTIGATORS, MAGIC |
| المصدر: |
Diabetes; 2021 Supplement 1, Vol. 70, pN.PAG-N.PAG, 1p |
| مستخلص: |
Proinsulin, a prohormone precursor to insulin, is synthesized and processed before secretion from pancreatic islet beta cells. Increased plasma proinsulin levels relative to insulin levels may predict insulin resistance and type 2 diabetes (T2D), and the genes involved in proinsulin processing are incompletely understood. Previous genome-wide association studies (GWAS) have identified 13 loci associated with proinsulin levels. To identify additional loci, we conducted a meta-analysis of GWAS results of fasting proinsulin from 16 European-ancestry studies of 45,826 individuals. Each cohort analysis controlled for age, sex, population structure, fasting insulin, and BMI. We identified 35 independent association signals at 30 loci (1 Mb, p<5E-8), including 22 signals not reported previously for proinsulin, 11 of which also were not reported in four recent large GWAS meta-analyses for T2D or four glycemic traits. We identified 14 additional nominally significant proinsulin signals (P<5E-5) that colocalized with at least one known glycemic trait signal. Using Bayesian colocalization methods and expression quantitative trait locus (eQTL) data from the InsPIRE islet eQTL consortium, we identified at least one gene colocalized with 17 proinsulin signals. One set of new loci may influence proinsulin processing, including signals near PCSK2, DLC1, and a low-frequency, missense variant at ELAPOR1, a transmembrane protein localized in the plasma membrane-late endosome-lysosome compartments. Another subset of new loci may influence proinsulin and insulin secretion, including TLE1, BCL11A, and RNF6. We further find a proinsulin-increasing allele at the SIX3 locus that has previously only been associated with glucose and T2D in East Asians, demonstrating that the glycemic trait associations at SIX3 are not population-specific. Our results provide additional insight into the biology underlying glycemic trait dysregulation and etiology of T2D. Disclosure: K. Broadaway: None. X. Yin: None. A. Williamson: None. E. Wilson: None. Magic investigators: n/a. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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