David Geffen School of Medicine at UCLA
Department of Human Genetics

Speaker Series - Summer Quarter 2006

Every 2nd and 4th Mondays, 11am - 12pm, Gonda Center Conference Room - Room 1357

Mon, Aug 14
11am - 12pm
The Copenhagen City Heart Study - ABC Transporter A1 SNPs and Mutations in the General Population
Ruth Frikke-Schmidt, MD, PhD, Rigshospitalet, University of Copenhagen, Department of Clinical Biochemistry, Section for Molecular Genetics, Copenhagen, Denmark
Contact & Intro: Paivi Pajukanta, ext 72011
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ABSTRACT: The Copenhagen City Heart Study - ABC Transporter A1 SNPs and Mutations in the General Population
Ruth Frikke-Schmidt 1, Anne Tybjærg-Hansen 1,2
1 Rigshospitalet, University of Copenhagen, Department of Clinical Biochemistry, Section for Molecular Genetics, Copenhagen, Denmark
2 The Copenhagen City Heart Study, Copenhagen, Denmark

Background: HDL cholesterol is a major risk factor for ischemic heart disease (IHD). We have recently shown that common single nucleotide polymorphisms (SNPs) and mutations in ABC Transporter A1 (ABCA1) contribute to HDL cholesterol levels in the general population. Whether SNPs and mutations identified in the general population predicts risk of IHD and whether this risk is reflected in HDL cholesterol levels is not known.
Methods: In 9,259 individuals from the general population, we determined the lipid phenotype and the predictive value for IHD during 25 years of follow-up for six nonsynonymous SNPs and seven nonsynonymous and one nonsense mutation previously identified by resequencing 190 individuals with extreme HDL cholesterol levels from the same general population.
Results: Five SNPs predicted increased risk of IHD in genders combined (three SNPs), in women only (one SNP), or in men (one SNP). Hazard ratios varied from 1.2 to 1.7 for a single SNP, but increased up to 3.5 for pairwise combinations of SNPs, and could not be explained by effects on HDL cholesterol. Six mutations had in vivo effects either on HDL cholesterol or on risk of IHD and these same mutations were predicted to be deleterious by in silico prediction tools or resulted in a truncated protein, and were highly conserved across species.
Conclusions: We show that both rare and common genetic variation in ABCA1 predicts risk of IHD beyond HDL cholesterol levels in the general population, and that pairwise combinations of SNPs identify subgroups of individuals at substantially increased risk. Taken together, we suggest that the genetic architecture of common multifactorial disease consists of a mixture of rare alleles with large effects, common variants with subtle effects, and combined genotype subgroups of common variants with high disease susceptibility. Acknowledging this raises future needs for composite genetic risk scores.

Thu, Aug 17
12-1pm
Regulation of Initiation of DNA Replication in Mouse and Human Embryonic Stem Cells
Carl Schildkraut, PhD, Professor, Department of Cell Biology, Albert Einstein College of Medicine
Contact & Intro: Guoping Fan, ext 70439
Thu, Aug 31
12-1pm
Genetic and Environmental Influences on Obesity
David Allison, PhD, Professor, Biostatistics, Head, Section on Statistical Genetics, Director, Clinical Nutrition Research Center, The University of Alabama at Birmingham
Contact & Intro: Janet Sinsheimer, ext 58002
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ABSTRACT: There is now incontrovertible evidence that obesity has a genetic component. Yet identifying the specific genetic influences on obesity in humans has proven quite difficult and it remains less than crystal clear that we have unequivocally identified specific variants that are both associated with and linked to obesity let alone actually cause variations in human adiposity. In contrast, model organisms have yielded fascinating results about some of the genes that can affect adiposity, as opposed to the genes that do affect adiposity. In considering how to best find genetic variants that influence adiposity, it may help to ask why we want to identify such genetic variants. In this talk, I will consider such questions as well as how genetic factors may be influencing our obesity epidemic, and what genetic studies tell us about the environmental influences on obesity.

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