Interferon Gamma Polymorphisms and Gender Bias in MS

Project: Research project

Project Details


DESCRIPTION (provided by applicant): We propose to pursue observations by the
Principal Investigator and each of the two Co-Investigators that relate
genetic and expression differences in IFNgamma to gender bias in MS. MS is
two to three times as common in women, yet pursues a more benign course in women. Two of the investigators have found that the 12 CA-repeat allele of an
intron 1 polymorphism in the IFNgamma gene (IFNG), which is associated with
increased expression of IFNgamma, is underrepresented in men relative to women
with MS and to controls in ethnically different populations. Other
polymorphisms in linkage disequilibrium (LD) reveal similar findings, and a LD
study suggests that this gender bias trait maps to the 100 kb surrounding the
gene. Another of the Co-Investigators has independently found a gender bias
in IFNgamma expression such that peripheral blood mononuclear cells (PBMCs) of
patients with MS, particularly women, over-express IFNgamma in response to
disease-related and unrelated antigenic stimuli. Our hypothesis is that
genetic variants in IFNG explain some or all of this variation. The Specific
Aims of this application are: 1) to extend the genetic observations to all of
our populations and to fine map this trait further to the locus; 2) to analyze
the functional significance of these genetic variants using appropriate
allelic reporter constructs; and 3) to correlate genotype of individuals with
phenotype (TH1/TH2) of cells of patients with MS and with the level
of IFNgamma expression. The long-term goals of this project are to understand
gender bias in susceptibility to MS and to pursue a genetic association in a
complex genetic disease (MS) to yield definitive conclusions regarding
causality. If successful, this paradigm could be applied to a number of
similar genetic association studies.
StatusNot started


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