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The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort.

Astermark, Jan LU ; Donfield, Sharyne M; Gomperts, Edward D; Schwarz, John; Menius, Erika D; Pavlova, Anna; Oldenburg, Johannes; Kessing, Bailey; Dimichele, Donna M and Shapiro, Amy D, et al. (2013) In Blood 121(8). p.1446-1454
Abstract
Studies of determinants of development of inhibitory antibodies to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study Combined Cohort was formed to extend understanding of the genetic background of risk. The study group contains 833 subjects from three 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 SNPs from 1,081 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... (More)
Studies of determinants of development of inhibitory antibodies to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study Combined Cohort was formed to extend understanding of the genetic background of risk. The study group contains 833 subjects from three 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 SNPs from 1,081 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 SNPs were significant predictors of inhibitor status using the criteria of odds ratios (OR) in the same direction in all cohorts, or allowing for a 20% interval around an OR of 1 in one of the three, and significant in at least two. Of the 53, 13 markers had meta p-values of <0.001. 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. (Less)
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Contribution to journal
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published
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Blood
volume
121
issue
8
pages
1446 - 1454
publisher
American Society of Hematology
external identifiers
  • wos:000321750000030
  • pmid:23223434
  • scopus:84874393543
ISSN
1528-0020
DOI
10.1182/blood-2012-06-434803
language
English
LU publication?
yes
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15e389eb-67cd-423a-bbaa-f509d6b1e165 (old id 3347437)
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http://www.ncbi.nlm.nih.gov/pubmed/23223434?dopt=Abstract
date added to LUP
2013-01-02 15:06:29
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2019-05-19 03:21:02
@article{15e389eb-67cd-423a-bbaa-f509d6b1e165,
  abstract     = {Studies of determinants of development of inhibitory antibodies to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study Combined Cohort was formed to extend understanding of the genetic background of risk. The study group contains 833 subjects from three 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 SNPs from 1,081 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 SNPs were significant predictors of inhibitor status using the criteria of odds ratios (OR) in the same direction in all cohorts, or allowing for a 20% interval around an OR of 1 in one of the three, and significant in at least two. Of the 53, 13 markers had meta p-values of &lt;0.001. 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.},
  author       = {Astermark, Jan and Donfield, Sharyne M and Gomperts, Edward D and Schwarz, John and Menius, Erika D and Pavlova, Anna and Oldenburg, Johannes and Kessing, Bailey and Dimichele, Donna M and Shapiro, Amy D and Winkler, Cheryl A and Berntorp, Erik},
  issn         = {1528-0020},
  language     = {eng},
  number       = {8},
  pages        = {1446--1454},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort.},
  url          = {http://dx.doi.org/10.1182/blood-2012-06-434803},
  volume       = {121},
  year         = {2013},
}