The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection

Research output: Contribution to journalJournal articleResearchpeer-review


  • Fulltext

    Final published version, 10.2 MB, PDF document

The intestinal hormone, glucose-dependent insulinotropic polypeptide (GIP), is involved in important physiological functions, including postprandial blood glucose homeostasis, bone remodeling, and lipid metabolism. While mutations leading to physiological changes can be identified in large-scale sequencing, no systematic investigation of GIP missense variants has been performed. Here, we identified 168 naturally occurring missense variants in the human GIP genes from three independent cohorts comprising ~720,000 individuals. We examined amino acid changing variants scattered across the pre-pro-GIP peptide using in silico effect predictions, which revealed that the sequence of the fully processed GIP hormone is more protected against mutations than the rest of the precursor protein. Thus, we observed a highly species-orthologous and population-specific conservation of the GIP peptide sequence, suggestive of evolutionary constraints to preserve the GIP peptide sequence. Elucidating the mutational landscape of GIP variants and how they affect the structural and functional architecture of GIP can aid future biological characterization and clinical translation.

Original languageEnglish
Article number891586
JournalFrontiers in Endocrinology
Number of pages14
Publication statusPublished - 2022

Bibliographical note

Publisher Copyright:
Copyright © 2022 Lindquist, Gasbjerg, Mokrosinski, Holst, Hauser and Rosenkilde.

    Research areas

  • GIP - glucose-dependent insulinotropic peptide, GIPR, GPCR (G protein coupled receptor), missense variants, pharmacogenomics, UK Biobank

Number of downloads are based on statistics from Google Scholar and

No data available

ID: 314837894