Influence of common and rare genetic variation on warfarin dose among African-Americans and European-Americans using the exome array

Nianjun Liu; Marguerite R Irvin; Degui Zhi; Amit Patki; T Mark Beasley; Deborah A Nickerson; Charles E Hill; Jinbo Chen; Stephen E Kimmel; Nita A Limdi

doi:10.2217/pgs-2017-0046

Influence of common and rare genetic variation on warfarin dose among African-Americans and European-Americans using the exome array

Pharmacogenomics. 2017 Jul;18(11):1059-1073. doi: 10.2217/pgs-2017-0046. Epub 2017 Jul 7.

Authors

Nianjun Liu¹, Marguerite R Irvin², Degui Zhi³, Amit Patki⁴, T Mark Beasley⁴, Deborah A Nickerson⁵, Charles E Hill⁶, Jinbo Chen⁷, Stephen E Kimmel^{7

8}, Nita A Limdi⁹

Affiliations

¹ Department of Epidemiology & Biostatistics, School of Public Health - Bloomington, Indiana University, Bloomington, IN 47405, USA.
² Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
³ School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁴ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
⁵ Department of Genome Sciences, School of Medicine, University of Washington, Seattle, WA 98195, USA.
⁶ Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁷ Department of Biostatistics & Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁹ Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Abstract

Aim: We conducted a genome-wide association study using the Illumina Exome Array to identify coding SNPs that may explain additional warfarin dose variability.

Patients & methods: Analysis was performed after adjustment for clinical variables and genetic factors known to influence warfarin dose among 1680 warfarin users (838 European-Americans and 842 African-Americans). Replication was performed in an independent sample.

Results: We confirmed the influence of known genetic variants on warfarin dose variability. Our study is the first to show the association between rs12772169 and warfarin dose in African-Americans. In addition, genes COX15 and FGF5 showed significant association in European-Americans.

Conclusion: We identified some novel genes/SNPs that underpin warfarin dose response. Further replication is needed to confirm our findings.

Keywords: CYP2C9; CYP4F2; VKORC1; exome array; genome-wide association study; prediction models; warfarin; warfarin dose.

MeSH terms

Anticoagulants / administration & dosage*
Black or African American / genetics*
Cytochrome P-450 CYP2C9 / genetics
Cytochrome P450 Family 4 / genetics
Exome / genetics
Genome-Wide Association Study
Humans
Linkage Disequilibrium
Pharmacogenomic Variants*
Polymorphism, Single Nucleotide*
Vitamin K Epoxide Reductases / genetics
Warfarin / administration & dosage*
White People / genetics*

Substances

Anticoagulants
Warfarin
CYP2C9 protein, human
Cytochrome P-450 CYP2C9
Cytochrome P450 Family 4
CYP4F2 protein, human
VKORC1 protein, human
Vitamin K Epoxide Reductases

Abstract

MeSH terms

Substances

Grants and funding