Whole genome sequence association with E-selectin levels reveals loss-of-function variant in African Americans

Linda M. Polfus, Laura M. Raffield, Marsha M. Wheeler, Russell P. Tracy, Leslie A. Lange, Guillaume Lettre, Amanda Miller, Adolfo Correa, Russell P. Bowler, Joshua C. Bis, Shabnam Salimi, Nancy Swords Jenny, Nathan Pankratz, Biqi Wang, Michael H. Preuss, Lisheng Zhou, Arden Moscati, Girish N. Nadkarni, Ruth J.F. Loos, Xue ZhongBingshan Li, Jill M. Johnsen, Deborah A. Nickerson, Alex P. Reiner, Paul L. Auer

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

E-selectin mediates the rolling of circulating leukocytes during inflammatory processes. Previous genome-wide association studies in European and Asian individuals have identified the ABO locus associated with E-selectin levels. Using Trans-Omics for Precision Medicine whole genome sequencing data in 2249 African Americans (AAs) from the Jackson Heart Study, we examined genome-wide associations with soluble E-selectin levels. In addition to replicating known signals at ABO, we identified a novel association of a common loss-of-function, missense variant in Fucosyltransferase 6 (FUT6; rs17855739,p.Glu274Lys, P = 9.02 × 10−24) with higher soluble E-selectin levels. This variant is considerably more common in populations of African ancestry compared to non-African ancestry populations.We replicated the association of FUT6 p.Glu274Lys with higher soluble E-selectin in an independent population of 748 AAs from the Women’s Health Initiative and identified an additional pleiotropic association with vitamin B12 levels. Despite the broad role of both selectins and fucosyltransferases in various inflammatory, immune and cancer-related processes, we were unable to identify any additional disease associations of the FUT6 p.Glu274Lys variant in an electronic medical record-based phenome-wide association scan of over 9000 AAs.

Original languageEnglish (US)
Pages (from-to)515-523
Number of pages9
JournalHuman molecular genetics
Volume28
Issue number3
DOIs
StatePublished - Feb 1 2019

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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    Polfus, L. M., Raffield, L. M., Wheeler, M. M., Tracy, R. P., Lange, L. A., Lettre, G., Miller, A., Correa, A., Bowler, R. P., Bis, J. C., Salimi, S., Jenny, N. S., Pankratz, N., Wang, B., Preuss, M. H., Zhou, L., Moscati, A., Nadkarni, G. N., Loos, R. J. F., ... Auer, P. L. (2019). Whole genome sequence association with E-selectin levels reveals loss-of-function variant in African Americans. Human molecular genetics, 28(3), 515-523. https://doi.org/10.1093/hmg/ddy360