Genetic variants linked to warfarin-related bleeding in patients of African descent

Single-nucleotide polymorphisms linked to increased bleeding risk have been identified in patients of African descent taking warfarin, investigators have reported.

Four single-nucleotide polymorphisms (SNPs) were associated with increased major bleeding risk in African Americans at an international normalized ratio (INR) of less than 4, according to results of their preliminary, retrospective study.

The preliminary findings could have implications for patients of African descent, but independent validation of the study results are needed, according to Minoli A. Perera, PharmD, PhD, of Northwestern University, Chicago, and her coauthors.

“Identifying these variants may help physicians make safer choices in anticoagulation therapy for this understudied patient population,” Dr. Perera and her colleagues wrote in JAMA.

Most prior studies looking at warfarin-related bleeding risk have included predominantly white patients and don’t account for differences in warfarin responsiveness between ethnic groups, they wrote.

Moreover, bleeding-associated SNPs have been identified, but in populations of European ancestry, they added.

The report covered results of a discovery cohort based on African American patients from a genome-wide study conducted at the University of Chicago, and a replication cohort based on patients who self-identified as African American and had routinely received care at University of Chicago hospitals.

The discovery cohort included 31 patients with major bleeding that occurred at an INR less than 4 and 184 controls with no documented history of bleeding related to warfarin.

In that cohort, Dr. Perera and her coinvestigators found four SNPs in linkage disequilibrium on chromosome 6 associated with warfarin-related bleeding, including rs115112393, rs16871327, rs78132896, and rs114504854. In particular, the rs78132896 SNP was found in 35.5% of cases (n = 11) and just 4.9% of controls (n = 9), with an odds ratio of 8.31 (95% confidence interval, 3.2-21.5).

The replication cohort, including 40 cases and 148 warfarin-treated controls, was genotyped specifically for rs78132896. That SNP was similarly found in 35.0% of cases (n = 14) and 4.8% of controls (n = 7), with an odds ratio of 8.24 (95% CI, 3.1-25.3).

“Genome-wide significance of this cohort was achieved when the cohorts were combined via meta-analysis,” said the investigators, who reported an odds ratio of 8.27 for that analysis (95% CI, 4.18-16.38).

Compared with wild-type alleles, the rs16871327 and rs78132896 risk alleles increased EPHA7 gene transcription, results of gene assay analyses further showed.

Expression of the EPHA7 gene on vascular endothelial cells and peripheral lymphocytes is increased during inflammation, according to Dr. Perera and her coauthors. Increased EPHA7 expression might lead to bleeding in patients who are taking warfarin.

“This haplotype might also have potential implications for bleeding risk with direct oral anticoagulants,” they said.

Dr. Perera and her coauthors reported no conflicts of interest related to their work on this study, which was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of General Medicine; the National Institutes of Health; and the American Heart Association Midwest Affiliate; as well as a research award from the University of Illinois at Chicago College of Pharmacy.

SOURCE: Perera MA et al. JAMA. 2018 Oct 23. doi: 10.1001/jama.2018.14955.

Single-nucleotide polymorphisms linked to increased bleeding risk have been identified in patients of African descent taking warfarin, investigators have reported.

Four single-nucleotide polymorphisms (SNPs) were associated with increased major bleeding risk in African Americans at an international normalized ratio (INR) of less than 4, according to results of their preliminary, retrospective study.

The preliminary findings could have implications for patients of African descent, but independent validation of the study results are needed, according to Minoli A. Perera, PharmD, PhD, of Northwestern University, Chicago, and her coauthors.

“Identifying these variants may help physicians make safer choices in anticoagulation therapy for this understudied patient population,” Dr. Perera and her colleagues wrote in JAMA.

Most prior studies looking at warfarin-related bleeding risk have included predominantly white patients and don’t account for differences in warfarin responsiveness between ethnic groups, they wrote.

Moreover, bleeding-associated SNPs have been identified, but in populations of European ancestry, they added.

The report covered results of a discovery cohort based on African American patients from a genome-wide study conducted at the University of Chicago, and a replication cohort based on patients who self-identified as African American and had routinely received care at University of Chicago hospitals.

The discovery cohort included 31 patients with major bleeding that occurred at an INR less than 4 and 184 controls with no documented history of bleeding related to warfarin.

In that cohort, Dr. Perera and her coinvestigators found four SNPs in linkage disequilibrium on chromosome 6 associated with warfarin-related bleeding, including rs115112393, rs16871327, rs78132896, and rs114504854. In particular, the rs78132896 SNP was found in 35.5% of cases (n = 11) and just 4.9% of controls (n = 9), with an odds ratio of 8.31 (95% confidence interval, 3.2-21.5).

The replication cohort, including 40 cases and 148 warfarin-treated controls, was genotyped specifically for rs78132896. That SNP was similarly found in 35.0% of cases (n = 14) and 4.8% of controls (n = 7), with an odds ratio of 8.24 (95% CI, 3.1-25.3).

“Genome-wide significance of this cohort was achieved when the cohorts were combined via meta-analysis,” said the investigators, who reported an odds ratio of 8.27 for that analysis (95% CI, 4.18-16.38).

Compared with wild-type alleles, the rs16871327 and rs78132896 risk alleles increased EPHA7 gene transcription, results of gene assay analyses further showed.

Expression of the EPHA7 gene on vascular endothelial cells and peripheral lymphocytes is increased during inflammation, according to Dr. Perera and her coauthors. Increased EPHA7 expression might lead to bleeding in patients who are taking warfarin.

“This haplotype might also have potential implications for bleeding risk with direct oral anticoagulants,” they said.

Dr. Perera and her coauthors reported no conflicts of interest related to their work on this study, which was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of General Medicine; the National Institutes of Health; and the American Heart Association Midwest Affiliate; as well as a research award from the University of Illinois at Chicago College of Pharmacy.

SOURCE: Perera MA et al. JAMA. 2018 Oct 23. doi: 10.1001/jama.2018.14955.

Single-nucleotide polymorphisms linked to increased bleeding risk have been identified in patients of African descent taking warfarin, investigators have reported.

Four single-nucleotide polymorphisms (SNPs) were associated with increased major bleeding risk in African Americans at an international normalized ratio (INR) of less than 4, according to results of their preliminary, retrospective study.

The preliminary findings could have implications for patients of African descent, but independent validation of the study results are needed, according to Minoli A. Perera, PharmD, PhD, of Northwestern University, Chicago, and her coauthors.

“Identifying these variants may help physicians make safer choices in anticoagulation therapy for this understudied patient population,” Dr. Perera and her colleagues wrote in JAMA.

Most prior studies looking at warfarin-related bleeding risk have included predominantly white patients and don’t account for differences in warfarin responsiveness between ethnic groups, they wrote.

Moreover, bleeding-associated SNPs have been identified, but in populations of European ancestry, they added.

The report covered results of a discovery cohort based on African American patients from a genome-wide study conducted at the University of Chicago, and a replication cohort based on patients who self-identified as African American and had routinely received care at University of Chicago hospitals.

The discovery cohort included 31 patients with major bleeding that occurred at an INR less than 4 and 184 controls with no documented history of bleeding related to warfarin.

In that cohort, Dr. Perera and her coinvestigators found four SNPs in linkage disequilibrium on chromosome 6 associated with warfarin-related bleeding, including rs115112393, rs16871327, rs78132896, and rs114504854. In particular, the rs78132896 SNP was found in 35.5% of cases (n = 11) and just 4.9% of controls (n = 9), with an odds ratio of 8.31 (95% confidence interval, 3.2-21.5).

The replication cohort, including 40 cases and 148 warfarin-treated controls, was genotyped specifically for rs78132896. That SNP was similarly found in 35.0% of cases (n = 14) and 4.8% of controls (n = 7), with an odds ratio of 8.24 (95% CI, 3.1-25.3).

“Genome-wide significance of this cohort was achieved when the cohorts were combined via meta-analysis,” said the investigators, who reported an odds ratio of 8.27 for that analysis (95% CI, 4.18-16.38).

Compared with wild-type alleles, the rs16871327 and rs78132896 risk alleles increased EPHA7 gene transcription, results of gene assay analyses further showed.

Expression of the EPHA7 gene on vascular endothelial cells and peripheral lymphocytes is increased during inflammation, according to Dr. Perera and her coauthors. Increased EPHA7 expression might lead to bleeding in patients who are taking warfarin.

“This haplotype might also have potential implications for bleeding risk with direct oral anticoagulants,” they said.

Dr. Perera and her coauthors reported no conflicts of interest related to their work on this study, which was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of General Medicine; the National Institutes of Health; and the American Heart Association Midwest Affiliate; as well as a research award from the University of Illinois at Chicago College of Pharmacy.

SOURCE: Perera MA et al. JAMA. 2018 Oct 23. doi: 10.1001/jama.2018.14955.