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 Zhong; Bingshan Li; Jill M Johnsen; Deborah A Nickerson; Alex P Reiner; Paul L Auer; NHLBI Trans-Omics for Precision Medicine Consortium

doi:10.1093/hmg/ddy360

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

Hum Mol Genet. 2019 Feb 1;28(3):515-523. doi: 10.1093/hmg/ddy360.

Authors

Linda M Polfus¹, Laura M Raffield², Marsha M Wheeler³, Russell P Tracy^{4

5}, Leslie A Lange⁶, Guillaume Lettre^{7

8}, Amanda Miller⁹, Adolfo Correa¹⁰, Russell P Bowler¹¹, Joshua C Bis¹², Shabnam Salimi¹³, Nancy Swords Jenny⁴, Nathan Pankratz¹⁴, Biqi Wang¹⁵, Michael H Preuss^{16

17}, Lisheng Zhou¹⁶, Arden Moscati¹⁶, Girish N Nadkarni¹⁶, Ruth J F Loos^{16

17

18}, Xue Zhong¹⁹, Bingshan Li¹⁹, Jill M Johnsen^{20

21}, Deborah A Nickerson³, Alex P Reiner^{22

23}, Paul L Auer⁹; NHLBI Trans-Omics for Precision Medicine Consortium

Affiliations

¹ Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
² Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
³ Department of Genome Sciences, University of Washington Center for Mendelian Genomics, Seattle, WA, USA.
⁴ Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
⁵ Department of Biochemistry, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
⁶ Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
⁷ Department of Medicine, Université de Montréal, Montréal, QC, Canada.
⁸ Montreal Heart Institute, Montréal, QC, Canada.
⁹ Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
¹⁰ Department of Pediatrics and Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
¹¹ Department of Medicine, National Jewish Health, Denver, CO, USA.
¹² Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
¹³ School of Medicine, University of Maryland, Baltimore, MD, USA.
¹⁴ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
¹⁵ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁶ Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁷ Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁸ Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁹ Vanderbilt Genetics Institute, Nashville, TN, USA.
²⁰ Bloodworks Northwest Research Institute, Seattle, WA, USA.
²¹ Department of Medicine, University of Washington, Seattle, WA, USA.
²² Department of Epidemiology, University of Washington, Seattle, WA, USA.
²³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

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.

Publication types

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

MeSH terms

Adult
Black or African American / genetics*
E-Selectin / genetics*
Female
Fucosyltransferases / genetics*
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Polymorphism, Single Nucleotide
Whole Genome Sequencing / methods

Substances

E-Selectin
SELE protein, human
Fucosyltransferases
FUT6 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding