Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 x 10(-7)). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 x 10(-4) to 2 x 10(-5). Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function.

Objective-To investigate the largely unknown genetic component of the common lipid disorder, familial combined hyperlipidemia (FCHL)

Objective-Familial combined hyperlipidemia (FCHL) characterized by high serum total cholesterol and/or triglycerides (TGs) is a common dyslipidemia predisposing to coronary artery disease (CAD). Recently, the upstream transcription factor 1 (USF1) was linked and associated with FCHL and TGs in Finnish FCHL families. Here we examined the previously associated rs3737787 SNP in extended Dutch FCHL families (nϭ532) and in a cohort of US subjects who underwent diagnostic coronary angiography (nϭ1533). Methods and Results-In males of the Dutch FCHL families, we observed significant sex-dependent associations between the common allele of rs3737787 and FCHL, TGs, and related metabolic traits (Pϭ0.02 to 0.006). In the U.S. Whites, sex-dependent associations with TGs and related metabolic traits were observed for the common allele of rs3737787 in males (Pϭ0.04 to 0.02) and rare allele in females (Pϭ0.05 to 0.002). This intriguing relationship was further supported by the highly significant genotype x sex interactions observed for TGs in the Dutch and TGs and body mass index (BMI) in U.S. White subjects with CAD (Pϭ0.0005 to 0.00004). Key Words: upstream transcription factor 1 Ⅲ familial combined hyperlipidemia Ⅲ coronary artery disease Ⅲ association Ⅲ lipids F amilial combined hyperlipidemia (FCHL) is a common familial dyslipidemia with a population prevalence of 1% to 2%. 1 Importantly, FCHL is observed in up to 20% of premature coronary artery disease (CAD) patients. 2 In addition to high serum total cholesterol (TC) and triglycerides (TGs), low plasma levels of high-density lipoprotein cholesterol (HDL-C), small dense low-density lipoprotein particles, and elevated apolipoprotein B (apoB) are also often observed in FCHL. 1,2 Association between FCHL and variants of the upstream transcription factor 1 (USF1) located in the FCHL-linked chromosome 1q21 region was originally identified by Pajukanta et al in Finnish FCHL families. 3 Several independent studies have investigated the USF1 variants in samples ascertained for FCHL or risk factors for premature CAD. 2,4 -6 The common allele of rs3737787 or SNPs in linkage disequilibrium (LD) with this SNP were associated with FCHL or one of its component traits in each of these studies. Komulainen et al investigated USF1 variants in a population-based prospective Finnish cohort and observed an association of USF1 with cardiovascular disease and mortality among females, demonstrating a consequence of USF1 at the population level in Finns. 7 In many of these studies, there is evidence of sex specificity, with the common allele of rs3737787 showing strongest evidence for association with high TGs in males. 2,3,7 Interestingly, in females, the minor allele seems to be associated with elevated lipids, as well as cardiovascular disease and mortality. 7 The underlying functional mechanisms explaining this replicated sex specificity are currently unknown. Conclusion-These

Currently, genetic and functional evidence is supportive of a role for upstream transcription factor 1 in the etiology of familial combined hyperlipidemia and its component traits, although the mechanism of causality still remains largely unknown.

Background-A low level of plasma high-density lipoprotein cholesterol (HDL-C) is a risk factor for cardiovascular disease. HDL particles are modulated by a variety of lipases, including endothelial lipase, a phospholipase present on vascular endothelial cells. The proprotein convertase subtilisin/kexin type 5 (PCSK5) gene product is known to directly inactivate endothelial lipase and indirectly cleave and activate angiopoetin-like protein 3, a natural inhibitor of endothelial lipase. We therefore investigated the effect of human PCSK5 genetic variants on plasma HDL-C levels. Methods and Results-Haplotypes at the PCSK5 locus were examined in 9 multigenerational families that included 60 individuals with HDL-C Ͻ10th percentile. Segregation with low HDL-C in 1 family was found. Sequencing of the PCSK5 gene in 12 probands with HDL-C Ͻ5th percentile identified 7 novel variants. Using a 2-stage design, we first genotyped these single-nucleotide polymorphisms (SNPs) along with 163 tagSNPs and 12 additional SNPs (nϭ182 total) in 457 individuals with documented coronary artery disease. We identified 9 SNPs associated with HDL-C (PϽ0.05), with the strongest results for rs11144782 and rs11144766 (Pϭ0.002 and Pϭ0.005, respectively). The SNP rs11144782 was also associated with very low-density lipoprotein (Pϭ0.039), triglycerides (Pϭ0.049), and total apolipoprotein levels (Pϭ0.022). In stage 2, we replicated the association of rs11144766 with HDL-C (Pϭ0.014) in an independent sample of Finnish low HDL-C families. In a combined analysis of both stages (nϭ883), region-wide significance of rs11144766 and low HDL-C was observed (unadjusted Pϭ1.86ϫ10 Ϫ4 and Bonferroni-adjusted Pϭ0.031). Conclusions-We conclude that variability at the PCSK5 locus influences HDL-C levels, possibly through the inactivation of endothelial lipase activity, and, consequently, atherosclerotic cardiovascular disease risk. (Circ Cardiovasc Genet. 2009;2:467-475.)