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Epigenetics in multiple sclerosis susceptibility: difference in transgenerational risk localizes to the major
Michael J Chao1, Sreeram V Ramagopalan, Blanca M Herrera
1Department of Clinical Neurology, Level 3 West Wing, John Radcliffe Hospital, University of Oxford, Oxford OX3 7BN, UK.
Human Molecular Genetics
|December 23, 2008
Summary
Genetic risk for multiple sclerosis (MS) involves HLA-DRB1*1501. Epigenetic factors may explain differing MS risk across generations, particularly in females, suggesting gene-environment interactions influence susceptibility.
Area of Science:
- Genetics
- Immunology
- Epidemiology
Background:
- Multiple sclerosis (MS) susceptibility has a complex inheritance pattern, with HLA-DRB1*1501 haplotypes carrying significant genetic risk.
- Epidemiological data suggest epigenetic factors contribute to MS, evidenced by transmission distortions in extended families.
Purpose of the Study:
- To investigate the role of epigenetic factors in MS susceptibility by comparing HLA-DRB1*1501 allele frequencies and transmission patterns across different family structures.
- To explore the heterogeneity of genetic risk associated with HLA-DRB1*1501 and its potential interaction with environmental factors.
Main Methods:
- Analysis of HLA-DRB1*1501 allele frequencies in affected aunts versus nieces within aunt/uncle-niece/nephew (AUNN) families.
- Family-based transmission disequilibrium test (TDT) comparing HLA-DRB1*1501 transmission in affected sibling pair (ASP) families versus AUNN families.
- Calculation of odds ratios (OR) to assess the risk associated with HLA-DRB1*1501 in different family structures.
Main Results:
- HLA-DRB1*1501 allele frequencies differed significantly between first and second-generation affected individuals in AUNN families, with affected aunts having lower frequencies than affected nieces.
- Transmission patterns of HLA-DRB1*1501 differed between ASP and AUNN families, indicating transmission heterogeneity.
- The risk conferred by HLA-DRB1*1501 was higher in AUNN families (OR = 4.07) compared to ASP families (OR = 2.17), suggesting increased risk with affected second-degree relatives.
Conclusions:
- Observations strongly implicate gene-environment interactions in MS susceptibility, with epigenetic modifications potentially differentiating human leukocyte antigen (HLA) class II risk haplotypes.
- Epigenetic modifications may contribute to the gender bias in MS, with female-specific increasing risk potentially mediated by HLA alleles or adjacent variations.
- Comparing allele transmission in vertically affected pedigrees (AUNN) versus collinear sibling pairs (ASP) may serve as a screening method for epigenetic marks.
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