Insulin-like growth factor binding protein 4 (IGFBP4) is involved in adipogenesis, and IGFBP4 null mice have decreased body fat through decreased PPAR-γ expression. In the current study, we assessed whether variation in the IGFBP4 coding region influences body mass index (BMI) in American Indians who are disproportionately affected by obesity. Whole exome sequence data from a population-based sample of 6779 American Indians with longitudinal measures of BMI were used to identify variation in IGFBP4 that associated with BMI. A novel variant that predicts a p.Ser76Thr in IGFBP4 (Thr-allele frequency = 0.02) was identified which associated with the maximum BMI measured during adulthood (BMI 39.8 kg/m2 for Thr-allele homozygotes combined with heterozygotes vs. 36.2 kg/m2 for Ser-allele homozygotes, β = 6.7% per Thr-allele, p = 8.0 × 10−5, adjusted for age, sex, birth-year and the first five genetic principal components) and the maximum age- and sex-adjusted BMI z-score measured during childhood/adolescence (z-score 0.70 SD for Thr-allele heterozygotes vs. 0.32 SD for Ser-allele homozygotes, β = 0.37 SD per Thr-allele, p = 8.8 × 10−6). In vitro functional studies showed that IGFBP4 with the Thr-allele (BMI-increasing) had a 55% decrease (p = 0.0007) in FOXO-induced transcriptional activity, reflecting increased activation of the PI3K/AKT pathway mediated through increased IGF signaling. Over-expression and knock-down of IGFBP4 in OP9 cells during differentiation showed that IGFBP4 upregulates adipogenesis through PPARγ, CEBPα, AGPAT2 and SREBP1 expression. We propose that this American Indian specific variant in IGFBP4 affects obesity via an increase of IGF signaling.
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Materials are available upon request. Individual-level data are not publicly available due to privacy concerns, but may be made available upon reasonable request—see dbGAP accession number phs002490.v1.p1 for details.
Analyses were conducted using available software applications, as described in the Methods.
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We thank the study participants as well as the clinical staff of the Phoenix Epidemiology and Clinical Research Branch for collecting phenotypes for the study. The opinions expressed in this paper are those of the authors, and do not necessarily reflect the views of the Indian Health Service.
This work was supported by the Intramural Research Programme of National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.
The authors declare that there is no conflict of interest. ARS or CVVH is or was full-time employees of the Regeneron Genetics Center from Regeneron Pharmaceuticals Inc. and receive or received stock options and restricted stock units as compensation.
These participants had provided written consent for DNA sequencing; and informed consent was obtained from all subjects. The consent was approved by the Institutional Review Board of the NIDDK and/or by the Phoenix Area Indian Health Service Institutional Review Board.
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Muller, Y.L., Saporito, M., Day, S. et al. Functional characterization of a novel p.Ser76Thr variant in IGFBP4 that associates with body mass index in American Indians. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01129-3