The Institute for Genetics and Nutrition
Funded by the National Dairy Council since 1989, the overall objective of our Institute is to delineate genetic and metabolic factors responsible for individual variation in susceptibility to the effects of dairy fat on cardiovascular disease risk. To this end the Institute benefits from internationally recognized expertise in nutrition and genetics, and also from unique technical capabilities for performing detailed measurements of lipoproteins and lipoprotein subclasses that have provided insights into major genetic effects on lipoproteins and dietary response.
Our previous studies in humans have focused on defining specific genetic traits that affect plasma lipoprotein responses to dairy fat intake. We have shown that low-fat, high-carbohydrate diets produce no overall improvement in the plasma lipoprotein profile in the majority of healthy subjects, and that in many individuals such diets can actually induce a higher risk lipoprotein profile. Those individuals who exhibit the most beneficial lipoprotein responses are the minority with a genetically influenced trait designated atherogenic lipoprotein phenotype (ALP) that is characterized by a predominance of small dense LDL particles (LDL subclass pattern B). More recently we have extended these observations with gene association and linkage studies that have demonstrated a genetic basis for the effects of diet on the expression of this trait, and have narrowed the search for the causative gene to a locus on chromosome 19p. These results have proven that genetic mechanisms lead to variation in LDL subclass responses to dietary fat and carbohydrate intake.
- Specific genotypes in 3 candidate genes are significantly associated with changes in individual LDL subclasses in response to variation in dietary carbohydrate intake (Krauss, 2005).
- Reduced dietary carbohydrate and weight loss each result in improvement in atherogenic dyslipidemia, and these effects are non-additive – namely, the benefit of lowering carbohydrate intake from 54% to 26% is similar to that achieved by a 7% weight reduction, and weight reduction does not further improve the lipoprotein profile on the lower carbohydrate diet. It is also of interest that the lipoprotein changes achieved by both carbohydrate limitation and weight loss are independent of saturated fat intake. (Krauss et al., in press).
Collectively these findings have indicated that an understanding of specific interactions of genes with dietary carbohydrate intake may lead to more targeted interventions in susceptible individuals. They also suggest that both reduced carbohydrate intake and weight loss operate to improve dyslipidemia through common pathways.
Pharmacogenomics and Risk of Cardiovascular Disease (PARC)
The main objective of PARC is to both define and confirm the genetic contribution to the larger inter-individual variability in the effects of statin drugs on cardiovascular disease. To address this objective, we have assembled a multidisciplinary team with expertise in genomics, statistical genetics and information, clinical pharmacology and cardiology, laboratory measurements of cardiovascular risk factors, and epidemiology.
To date PARC has focused on identifying associations of statin responsiveness with single nucleotide polymorphisms (SNPs) in candidate genes involved in pathways mediating effects of statin treatment on cardiovascular risk, as well as systems modulating statin pharmacokinetics. The analyses have been based on measurements of lipoproteins and other cardiovascular risk markers in a cohort of 944 Caucasians and African-Americans who were treated with simvastatin 40 mg/day in a carefully supervised six-week trial. Linkage disequilibrium analysis of SNPs identified in a total of 78 genes was used to determine 891 tag sites that were genotyped in the first half of the cohort. Confirmation of the positive associations as well as testing of additional candidate genes is now being carried out in the second half of the cohort (>700 sites in 60 genes). In addition, we have completed pilot studies of pharmacogenetics of blood pressure response to ACE inhibitors in two study cohorts. In total, these studies will result in deposits in the PharmGKB database of nearly 800,000 individual genotypes as well as the measured phenotypes from both the statin and ACE inhibitor trials.
Link: PARC Profile
NIH Center of Excellence in Nutritional Genomics (NIH National Center for Minority Health and Health Disparities). The objective of our research in this program is to probe gene pathway responses to diet and statin therapy by analysis of global gene expression in human adipose tissue and blood cells.
Link: UC Davis