Biomedical subjects

Laurence D Parnell

Publications and source records attributed to Laurence D Parnell.

4 recordsLinked to original sources

PubMed2006

Candidate genes affecting Drosophila life span identified by integrating microarray gene expression analysis and QTL mapping.

The current increase in life expectancy observed in industrialized societies underscores the need to achieve a better understanding of the aging process that could help the development of effective strategies to achieve healthy aging. This will require not only identifying genes involved in the aging process, but also understanding how their effects are modulated by environmental factors, such as dietary intake and life style. Although the human genome has been sequenced, it may be impractical to study humans or other long-lived organisms to gain a mechanistic understanding about the aging process. Thus, short-lived animal models are essential to identifying the mechanisms and genes that affect the rate and quality of aging as a first step towards identifying genetic variants in humans. In this study, we investigated gene expression changes between two strains of Drosophila (Oregon and 2b) for which quantitative trait loci (QTLs) affecting life span were identified previously. We collected males and females from both strains at young and old ages, and assessed whole genome variation in transcript abundance using Affymetrix GeneChips. We observed 8217 probe sets with detectable transcripts. A total of 2371 probe sets, representing 2220 genes, exhibited significant changes in transcript abundance with age; and 839 probe sets were differentially expressed between Oregon and 2b. We focused on the 359 probe sets (representing 354 genes) that exhibited significant changes in gene expression both with age and between strains. We used these genes to integrate the analysis of microarray gene expression data, bioinformatics, and the results of genetic mapping studies reported previously, to identify 49 candidate genes and four pathways that could potentially be responsible for regulating life span and involved in the process of aging in Drosophila and humans.

Aging↗

PubMed2006

Dietary intake of n-6 fatty acids modulates effect of apolipoprotein A5 gene on plasma fasting triglycerides, remnant lipoprotein concentrations, and lipoprotein particle size: the Framingham Heart Study.

BACKGROUND: Apolipoprotein A5 gene (APOA5) variation is associated with plasma triglycerides (TGs). However, little is known about whether dietary fat modulates this association. METHODS AND RESULTS: We investigated the interaction between APOA5 gene variation and dietary fat in determining plasma fasting TGs, remnant-like particle (RLP) concentrations, and lipoprotein particle size in 1001 men and 1147 women who were Framingham Heart Study participants. Polymorphisms -1131T>C and 56C>G, representing 2 independent haplotypes, were analyzed. Significant gene-diet interactions between the -1131T>C polymorphism and polyunsaturated fatty acid (PUFA) intake were found (P<0.001) in determining fasting TGs, RLP concentrations, and particle size, but these interactions were not found for the 56C>G polymorphism. The -1131C allele was associated with higher fasting TGs and RLP concentrations (P<0.01) in only the subjects consuming a high-PUFA diet (>6% of total energy). No heterogeneity by sex was found. These interactions showed a dose-response effect when PUFA intake was considered as a continuous variable (P<0.01). Similar interactions were found for the sizes of VLDL and LDL particles. Only in carriers of the -1131C allele did the size of these particles increase (VLDL) or decrease (LDL) as PUFA intake increased (P<0.01). We further analyzed the effects of n-6 and n-3 fatty acids and found that the PUFA-APOA5 interactions were specific for dietary n-6 fatty acids. CONCLUSIONS: Higher n-6 (but not n-3) PUFA intake increased fasting TGs, RLP concentrations, and VLDL size and decreased LDL size in APOA5 -1131C carriers, suggesting that n-6 PUFA-rich diets are related to a more atherogenic lipid profile in these subjects.

Adult↗

PubMed2005

The APOA1/C3/A4/A5 gene cluster, lipid metabolism and cardiovascular disease risk.

PURPOSE OF REVIEW: APOA1/C3/A4/A5 are key components modulating lipoprotein metabolism and cardiovascular disease risk. This review examines the evidence regarding linkage disequilibrium and haplotype structure within the A1/C3/A4/A5 cluster, and assesses its association with plasma lipids and cardiovascular disease risk. In addition, we use genomic information from several species to draw inferences about the location of functional variants within this cluster. RECENT FINDINGS: The close physical distance of these genes and the interrelated functions of these apolipoproteins have encumbered attempts to determine the role of individual variants on lipid metabolism. Therefore, current research aims to define linkage disequilibrium and haplotype structure within this cluster. Functional variants in regulatory regions are most interesting as they are potentially amenable to therapy. Comparative genomics can contribute to the identification of such functional variants. SUMMARY: Genetic variability at the APOA1/C3/A4/A5 cluster has been examined in relation to lipid metabolism and cardiovascular disease risk. However, the findings are inconsistent. This is partly due to the classic approach of studying single and mostly nonfunctional polymorphisms. Moreover, allelic expression may depend on the concurrent presence of environmental factors. Association studies using haplotypes should increase the power to detect true associations and interactions. We hypothesize that phenotypes observed in association with transcriptional regulatory variants can be readily modified by environmental factors. Therefore, studies focusing on regulatory variants may be more fruitful to locate/define future therapeutic targets.

Apolipoprotein A-I↗

PubMed2004

Influence of the APOA5 locus on plasma triglyceride, lipoprotein subclasses, and CVD risk in the Framingham Heart Study.

Several polymorphisms in the APOA5 gene have been associated with increased plasma triglyceride (TG) concentrations. However, associations between APOA5 and lipoprotein subclasses, remnant-like particles (RLPs), and cardiovascular disease (CVD) risk have been less explored. We investigated associations of five APOA5 single-nucleotide polymorphisms (SNPs; -1131T>C, -3A>G, 56C>G IVS3+ 476G>A, and 1259T>C) with lipoprotein subfractions and CVD risk in 1,129 men and 1,262 women participating in the Framingham Heart Study. Except for the 56C>G SNP, the other SNPs were in significant linkage disequilibria, resulting in three haplotypes (11111, 22122, and 11211) representing 98% of the population. SNP analyses revealed that the -1131T>C and 56C>G SNPs were significantly associated with higher plasma TG concentrations in both men and women. For RLP and lipoprotein subclasses, we observed gender-specific association for the -1131T>C and 56C>G SNPs. Female carriers of the -1131C allele had higher RLP concentrations, whereas in males, significant associations for RLPs were observed for the 56G allele. Moreover, haplotype analyses confirmed these findings and revealed that the 22122 and 11211 haplotypes exhibited different associations with HDL cholesterol concentrations. In women, the -1131C allele was associated with a higher hazard ratio for CVD (1.85; 95% confidence interval, 1.03-3.34; P = 0.04), in agreement with the association of this SNP with higher RLPs.

Adult↗