title: The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort.
abstract: Studies of determinants of development of inhibitory Abs to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort was formed to extend our understanding of the genetic background of risk. The study group contains 833 subjects from 3 independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status. Using an Illumina iSelect platform, 13 331 single-nucleotide polymorphisms from 1081 genes, primarily immune response and immune modifier genes, were typed. Each cohort was analyzed separately with results combined using a meta-analytic technique. After adjustment for potential confounders, 53 single-nucleotide polymorphisms were found to be significant predictors of inhibitor status using the criteria of odds ratios in the same direction in all cohorts or allowing for a 20% interval around an odds ratio = 1 in 1 of the 3 and significant in at least 2. Of the 53 markers, 13 had meta P < .001. Eight of the 53 were significant predictors among the discordant pairs. Results support the complexity of the immune response and encourage further research with the goal of understanding the pathways involved.
authors.affiliation: Centre for Thrombosis and Haemostasis, Lund University, Skåne University Hospital, Malmö, Sweden. jan.astermark@med.lu.se
authors.forename: Jan
authors.initials: J
authors.lastname: Astermark
authors.forename: Sharyne M
authors.initials: SM
authors.lastname: Donfield
authors.forename: Edward D
authors.initials: ED
authors.lastname: Gomperts
authors.forename: John
authors.initials: J
authors.lastname: Schwarz
authors.forename: Erika D
authors.initials: ED
authors.lastname: Menius
authors.forename: Anna
authors.initials: A
authors.lastname: Pavlova
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.forename: Bailey
authors.initials: B
authors.lastname: Kessing
authors.forename: Donna M
authors.initials: DM
authors.lastname: DiMichele
authors.forename: Amy D
authors.initials: AD
authors.lastname: Shapiro
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.forename: Erik
authors.initials: E
authors.lastname: Berntorp
mesh_terms: D000293:Adolescent; D000906:Antibodies / Q000276:immunology; D002648:Child; D015331:Cohort Studies; D004351:Drug Resistance / Q000235:genetics / Q000276:immunology; D005169:Factor VIII / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006467:Hemophilia A / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D035781:Siblings; D059467:Transcriptome
chemical_list: D000906:Antibodies; D005819:Genetic Markers; D005169:Factor VIII