WW-domain-containing oxidoreductase is associated with low plasma HDL-C levels.

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.

USF1 contributes to high serum lipid levels in Dutch FCHL families and U.S. whites with coronary artery disease.

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 (n=532) and in a cohort of US subjects who underwent diagnostic coronary angiography (n=1533). 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 (P=0.02 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 (P=0.04 to 0.02) and rare allele in females (P=0.05 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 (P=0.0005 to 0.00004). CONCLUSIONS: These data show that USF1 influences several cardiovascular risk factors in a sex-dependent manner in Dutch FCHL families and U.S. Whites with CAD. A significant interaction between sex and genotype was shown to affect TGs and BMI.

Multitargeted Feeding Strategies Improve Nutrition Outcome and Are Associated With Reduced Pneumonia in a Level 1 Trauma Intensive Care Unit.

BACKGROUND: Factors impeding delivery of adequate enteral nutrition (EN) to trauma patients include delayed EN initiation, frequent surgeries and procedures, and postoperative ileus. We employed 3 feeding strategies to optimize EN delivery: (1) early EN initiation, (2) preoperative no nil per os feeding protocol, and (3) a catch-up feeding protocol. This study compared nutrition adequacy and clinical outcomes before and after implementation of these feeding strategies. METHODS: All trauma patients aged ≥18 years requiring mechanical ventilation for ≥7 days and receiving EN were included. Patients who sustained nonsurvivable injuries, received parenteral nutrition, or were readmitted to the intensive care unit (ICU) were excluded. EN data were collected until patients received an oral diet or were discharged from the ICU. The improvement was quantified by comparing nutrition adequacy and outcomes between April 2014-May 2015 (intervention) and May 2012-June 2013 (baseline). RESULTS: The intervention group (n = 118) received significantly more calories (94% vs 75%, P < .001) and protein (104% vs 74%, P < .001) than the baseline group (n = 121). The percentage of patients receiving EN within 24 and 48 hours of ICU admission increased from 41% to 70% and from 79% to 96% respectively after intervention (P < .001). Although there were fewer 28-ay ventilator-free days in the intervention group than in the baseline group (12 vs 16 days, P = .03), receipt of the intervention was associated with a significant reduction in pneumonia (odds ratio, 0.53; 95% confidence interval, 0.31-0.89; P = .017) after adjusting sex and Injury Severity Score. CONCLUSIONS: Implementation of multitargeted feeding strategies resulted in a significant increase in nutrition adequacy and a significant reduction in pneumonia.

Familial combined hyperlipidemia in Mexicans: association with upstream transcription factor 1 and linkage on chromosome 16q24.1.

OBJECTIVE: To investigate the largely unknown genetic component of the common lipid disorder, familial combined hyperlipidemia (FCHL) in Mexicans, we analyzed the upstream transcription factor 1 (USF1) gene that was recently associated with FCHL and high triglycerides (TG) in Finns. We also analyzed the Mexican FCHL families for 26 microsatellite markers residing in the seven chromosomal regions on 2p25.1, 9p23, 10q11.23, 11q13, 16q24.1, 19q13, and 21q21, previously linked to FCHL in whites. METHODS AND RESULTS: We genotyped 314 individuals in 24 Mexican families for 13 SNPs spanning an 88-kb region, including USF1. The FCHL and TG traits showed significant evidence for association with 3 SNPs, hCV1459766, rs3737787, and rs2073658, and haplotype analyses further supported these findings (probability values of 0.05 to 0.0009 for SNPs and their haplotypes). Of these SNPs, hCV1459766 is located in the F11 receptor (F11R) gene, located next to USF1, making it difficult to exclude. Importantly, the association was restricted to a considerably smaller region than in the Finns (14 kb versus 46 kb), possibly because of a different underlying linkage disequilibrium structure. In addition, 1 of the 7 regions, 16q24.1, showed suggestive evidence for linkage (a lod score of 2.6) for total cholesterol in Mexicans. CONCLUSIONS: This study, the first to extensively investigate the genetic component of the common FCHL disorder in Mexicans, provides independent evidence for the role of USF1 in FCHL in an outbred population and links the 16q24.1 region to an FCHL-component trait in Mexicans.

Fine mapping and association studies of a high-density lipoprotein cholesterol linkage region on chromosome 16 in French-Canadian subjects.

Low levels of high-density lipoprotein cholesterol (HDL-C) are an independent risk factor for cardiovascular disease. To identify novel genetic variants that contribute to HDL-C, we performed genome-wide scans and quantitative association studies in two study samples: a Quebec-wide study consisting of 11 multigenerational families and a study of 61 families from the Saguenay-Lac St-Jean (SLSJ) region of Quebec. The heritability of HDL-C in these study samples was 0.73 and 0.49, respectively. Variance components linkage methods identified a LOD score of 2.61 at 98 cM near the marker D16S515 in Quebec-wide families and an LOD score of 2.96 at 86 cM near the marker D16S2624 in SLSJ families. In the Quebec-wide sample, four families showed segregation over a 25.5-cM (18 Mb) region, which was further reduced to 6.6 Mb with additional markers. The coding regions of all genes within this region were sequenced. A missense variant in CHST6 segregated in four families and, with additional families, we observed a P value of 0.015 for this variant. However, an association study of this single-nucleotide polymorphism (SNP) in unrelated Quebec-wide samples was not significant. We also identified an SNP (rs11646677) in the same region, which was significantly associated with a low HDL-C (P=0.016) in the SLSJ study sample. In addition, RT-PCR results from cultured cells showed a significant difference in the expression of CHST6 and KIAA1576, another gene in the region. Our data constitute additional evidence for a locus on chromosome 16q23-24 that affects HDL-C levels in two independent French-Canadian studies.

Genetic variation at the proprotein convertase subtilisin/kexin type 5 gene modulates high-density lipoprotein cholesterol levels.

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 <10th percentile. Segregation with low HDL-C in 1 family was found. Sequencing of the PCSK5 gene in 12 probands with HDL-C <5th 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 (n=182 total) in 457 individuals with documented coronary artery disease. We identified 9 SNPs associated with HDL-C (P<0.05), with the strongest results for rs11144782 and rs11144766 (P=0.002 and P=0.005, respectively). The SNP rs11144782 was also associated with very low-density lipoprotein (P=0.039), triglycerides (P=0.049), and total apolipoprotein levels (P=0.022). In stage 2, we replicated the association of rs11144766 with HDL-C (P=0.014) in an independent sample of Finnish low HDL-C families. In a combined analysis of both stages (n=883), region-wide significance of rs11144766 and low HDL-C was observed (unadjusted P=1.86x10(-4) and Bonferroni-adjusted P=0.031). 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.

Familial combined hyperlipidemia: upstream transcription factor 1 and beyond.

PURPOSE OF REVIEW: Familial combined hyperlipidemia is a common complex disease that accounts for up to 20% of premature coronary heart disease. The upstream transcription factor 1, located on 1q21, was recently shown to be linked and associated with familial combined hyperlipidemia in Finnish families. Upstream transcription factor 1 is the first gene identified by positional cloning for familial combined hyperlipidemia. Replication studies are critical to investigation of complex diseases because only they can verify the importance of the original findings. We review recent studies that examine the genetic contribution and functional consequence of upstream transcription factor 1 variants to familial combined hyperlipidemia and type 2 diabetes mellitus. Aiming beyond upstream transcription factor 1, we also evaluate novel strategies that have made it possible to globally examine the genome and the transcriptome. RECENT FINDINGS: Three independent studies support the role of upstream transcription factor 1 in familial combined hyperlipidemia. The results for type 2 diabetes mellitus and the metabolic syndrome have been less conclusive highlight novel strategies for gene identification in familial combined hyperlipidemia. SUMMARY: 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.