Epistasis Blog

From the Computational Genetics Laboratory at Dartmouth Medical School (www.epistasis.org)

Wednesday, November 19, 2008

MDR Analysis of Vaccine Response

This is a very nice paper that applies MDR to predicting vaccine response.

Kimman TG, Banus S, Reijmerink N, Reimerink J, Stelma FF, Koppelman GH, Thijs C, Postma DS, Kerkhof M. Association of interacting genes in the toll-like receptor signaling pathway and the antibody response to pertussis vaccination. PLoS ONE. 2008;3(11):e3665. [PubMed] [PDF]

BACKGROUND: Activation of the Toll-like receptor (TLR) signaling pathway through TLR4 may be important in the induction of protective immunity against Bordetella pertussis with TLR4-mediated activation of dendritic and B cells, induction of cytokine expression, and reversal of tolerance as crucial steps. We examined whether single nucleotide polymorphisms (SNPs) in genes of the TLR4 pathway and their interaction are associated with the response to whole-cell vaccine (WCV) pertussis vaccination in 490 one-year-old children. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed associations of 75 haplotype-tagging SNPs in genes in the TLR4 signaling pathway with pertussis toxin (PT)-IgG titers. We found significant associations between the PT-IgG titer and SNPs in CD14, TLR4, TOLLIP, TIRAP, IRAK3, IRAK4, TICAM1, and TNFRSF4 in one or more of the analyses. The strongest evidence for association was found for two SNPs (rs5744034 and rs5743894) in TOLLIP that were almost completely in linkage disequilibrium, provided statistically significant associations in all tests with the lowest p-values, and displayed a dominant mode of inheritance. However, none of these single gene associations would withstand correction for multiple testing. In addition, Multifactor Dimensionality Reduction Analysis, an approach that does not need correction for multiple testing, showed significant and strong two and three locus interactions between SNPs in TOLLIP (rs4963060), TLR4 (rs6478317) and IRAK1 (rs1059703). CONCLUSIONS/SIGNIFICANCE: We have identified significant interactions between genes in the TLR pathway in the induction of vaccine-induced immunity. These interactions underline that these genes are functionally related and together form a true biological relationship in a protein-protein interaction network. Practically all our findings may be explained by genetic variation in directly or indirectly interacting proteins at the extra- and intracytoplasmic sites of the cell membrane of antigen-presenting cells, B cells, or both. Fine tuning of interacting proteins in the TLR pathway appears important for the induction of an optimal vaccine response.

Tuesday, November 11, 2008

Biodata Management and Analysis - NIH/CSR

I have been appointed to the Biodata Management and Analysis (BDMA) study section at NIH for a three year term. For more information about this study section see the Center for Scientific Review (CSR) website.

Here is a summary of the areas covered by BDMA:

Methods for data management including: Data representation, standards and ontology development, data capture, data integrity and validation, data archiving, data distribution, data query, hardware and software for computer systems, database robotics, and interoperation and federation of databases.

Methods for data analysis including: Numerical, statistical and mathematical methods; theoretical approaches to design and interpretation of large-scale studies, such as high throughput analyses; computational methods for organizing, maintaining, and integrating datasets, such as in proteomics and genomics.

Visualization techniques: Summary, integration, and representation of data in meaningful ways, for example, graphical, auditory, tactile, and visual; methods for data mining, World Wide Web and other server representations and computer representations and simulations.