Fall Meeting Abstracts

Here are the Abstracts for two meetings I will be attending this Fall.

International Genetic Epidemiology Society - Boston

Genomic, transcriptomic, and pathway-based analysis of Carotid Intima-Media Thickness

Detection of subclinical atherosclerosis through measurement of carotid intima-media thickness (IMT) is an important tool for assessment of cardiovascular disease risk. Previous GWAS of IMT have not produced any significant associations. This study used GWAS results to investigate biological pathways influencing IMT phenotypes in 750 Mexican American participants from the San Antonio Family Heart Study. A GWAS (using Illumina’s HumanHap 550K BeadChip) was performed using internal and common carotid IMT near and far wall measurements under an additive measured genotype association model. As with past GWAS, no SNP was significant after correction for multiple testing. Genes within ranges 10kb, 25kb, 50kb, 100kb,150 kb, and 250kb upstream and downstream of marginally significant (p <0.01) SNPs were entered into Ariadne Pathway Studio to identify relevant biological pathways and to investigate how the assignment of intergenic SNPs to genes might impact these results. The WNT-signaling (p=1.04 x 10^-7) pathway remained significant after correction for multiple testing. We then investigated the relationship between lympochyte RNA expression data and IMT. The top gene was glutamate-cysteine ligase, catalytic subunit (GCLC), whose transcript is significantly correlated (p=7.8 x 10^-5) with internal carotid IMT. We conclude that through the use of transcript data and the investigation of biological pathways that we are able to detect genetic signals not identified by GWAS alone.

American Society of Human Genetics - Washington D.C.

Bayesian analysis of hepatic lipase (LIPC) genetic variation suggests different variants influence HDL-C level and HDL particle size

The gene for hepatic lipase (LIPC) is known to have a major role in lipoprotein metabolism and has been implicated as a regulator of HDL-C concentration and HDL particle size reduction through the reverse cholesterol transport pathway. However, the relationship between LIPC and HDL-C levels and HDL particle size phenotypes remains unclear. One LIPC promoter variant, -514C>T (rs1800588), has shown association with HDL-C and related phenotypes in a number of studies and is presumed to be functional. This study investigated the biological relationship between LIPC genetic variation and HDL-C and five HDL size measures, median diameter of particles containing apoA1 (A1), apoA2 (A2), unesterified cholesterol (UC), esterified cholesterol (EC), and ΔHDL, the difference in fractional absorbance patterns between large and small lipoprotein particles. We deep sequenced 28.7 kb coding and conserved non-coding regions of LIPC in 182 founders from 42 extended pedigrees and examined the resulting 625 single nucleotide polymorphism (SNP) genotypes in 1,336 Mexican American participants from the San Antonio Family Heart Study. Genetic association was assessed with measured genotype analysis (MGA) and SNPs with nominal p-values (p <0.1) were used in Bayesian Quantitative Trait Nucleotide (BQTN) analyses. SNPs in high LD (r²>0.9) were grouped, with the single member with the lowest MGA p-value representing the isocorrelated redundant variant (IRV) set. BQTN identified 18 (five novel) potentially functional SNPs with substantial posterior probabilities (pps > 0.50) associated with one or more of the six investigated phenotypes. Seven SNPs demonstrated pps >0.95: two for HDL-C levels (rs1077834, rs16940299), two for A1 (rs375372, rs12914232), one for A2 and UC (rs11071387), and two for ΔHDL (rs485538, rs8023503). The SNP rs11071387 was associated with four size phenotypes (A1, A2, UC, EC). The promoter SNP, rs1077834, is in an IRV set with three other promoter SNPs, rs1800588, -763A>G (rs10077835) and -250G>A (rs2070895). Promoter variants did not demonstrate substantial pps with any of the five HDL-C size measures. Minor allele frequency ranged from 0.0008 for +106481 G>A (HDL-EC, HDL-UC) to 0.4596 for rs375372 (A1). This comprehensive investigation of LIPC genetic variation provides strong evidence that variants in addition to rs1800588 influence HDL-C levels and also suggests that different LIPC variants influence HDL-C levels and HDL particle size differentiation.