Texas Biomed Staff

Summary

Moses and his group are currently studying a cohort of pre-eclampsia families from Australia and New Zealand. The original genome scan in these families identified a susceptibility locus on chromosome 2 and they have subsequently identified additional susceptibility loci on chromosomes 5q and 13q. In efforts to identify the underlying genetic risk variants at these loci, the team has developed an objective prioritization strategy that combines bioinformatic interrogation, gene-centric SNP genotyping and transcriptional profiling in disease relevant tissues to generate a priority list of positional candidate genes at each of these three loci.

The team also is integrating high-density genotype data, genome-wide transcriptional profiling data in lymphocytes, deep gene re-sequencing and comprehensive phenotypic data to identify novel candidate cardiovascular disease-related genes. A recent example is the VNN1 gene, whose mRNA expression the group has shown is correlated with HDL-C levels. In a new project, Moses plans to use an integrative approach to identify those genes that are most likely to participate with VNN1 in the global regulatory networks that ultimately play a role in cholesterol metabolism.

In the group’s cystinosis research, Moses has initiated an innovative genomic approach to the dissection of a monogenic disease such as cystinosis that avoids the immediate need for large families with individuals affected with the disease. In this strategy, he is employing normal human variation as a model for pathological human variation. In order to determine the larger role of cystinosin, the team has exhaustively enumerated normal human variation in the CTNS gene in a large sample of unaffected families and has tested whether this genetic variation influences the quantitative expression of any other gene (via the measurement of genome-wide gene expression in lymphocytes). Genes that are influenced by causal variation in CTNS become potential targets for pharmacological intervention. Conversely, the group has also used genome-scanning technology to localize novel modifier genes that influence quantitative expression of the CTNS gene. It was argued that for individuals with cystinosis who have incomplete loss of function of cystinosin, ‘upstream’ trans-acting regulatory genes become possible targets for focused therapeutic intervention aimed ultimately at producing more cystinosin.

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