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 journalArticlepeer-review

4 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

Bibliographical note

Funding Information:
Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for ‘NHLBI TOPMed: The Jackson Heart Study’ (phs000964.v1.p1) was performed at the University of Washington Northwest Genomics Center (HHSN268201100037C). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC and general study coordination were provided by the TOPMed Data Coordination

Funding Information:
Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for ‘NHLBI TOPMed: The Jackson Heart Study’ (phs000964.v1.p1) was performed at the University of Washington Northwest Genomics Center (HHSN268201100037C). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC and general study coordination were provided by the TOPMed Data Coordination Center (3R01HL-120393-02S1). We gratefully acknowledge the studies and Participants who provided biological samples and data for TOpMed. The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201300049C and HHSN268201300050C), Tougaloo College (HHSN268201300048C) and the University of Mississippi Medical Center (HHSN268201300046C and HHSN268201300047C) contracts from NHLBI and the National Institute for Minority Health and Health Disparities (NIMHD). The authors also wish to thank the staffs and participants of JHS. The Women’s Health Initiative (WHI) program is funded by NHLBI, the National Institutes of Health, the US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201-600004C. The authors thank the WHI investigators and staff for their dedication and the study participants for making the program possible. The Mount Sinai BioMe Biobank is supported by the Andrea and Charles Bronfman Philanthropies. P.L.A., A.P.R. and L.A.L. were supported by NHLBI R01HL132947. L.M.R. was supported by NHLBI T32 HL129982. R.J.F.L. was supported by National Institute of Health (R01DK110113, U01HG007417, R01DK107786, R01HL142302).

Funding Information:
Center (3R01HL-120393-02S1). We gratefully acknowledge the studies and Participants who provided biological samples and data for TOpMed. The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201300049C and HHSN268201300050C), Tougaloo College (HHSN268201300048C) and the University of Mississippi Medical Center (HHSN268201300046C and HHSN268201300047C) contracts from NHLBI and the National Institute for Minority Health and Health Disparities (NIMHD). The authors also wish to thank the staffs and participants of JHS. The Women’s Health Initiative (WHI) program is funded by NHLBI, the National Institutes of Health, the US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201-600004C. The authors thank the WHI investigators and staff for their dedication and the study participants for making the program possible. The Mount Sinai BioMe Biobank is supported by the Andrea and Charles Bronfman Philanthropies. P.L.A., A.P.R. and L.A.L. were supported by NHLBI R01HL132947. L.M.R. was supported by NHLBI T32 HL129982. R.J.F.L. was supported by National Institute of Health (R01DK110113, U01HG007417, R01DK107786, R01HL142302).

Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press. All rights reserved.

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