Members of the apolipoprotein gene cluster (APOA1/C3/A4/A5) on human chromosome 11q23 play an important role in lipid metabolism. Polymorphisms in both APOA5 and APOC3 are strongly associated with plasma triglyceride concentrations. The close genomic locations of these two genes as well as their functional similarity have hindered efforts to define whether each gene independently influences human triglyceride concentrations. In this study, we examined the linkage disequilibrium and haplotype structure of 49 SNPs in a 150-kb region spanning the gene cluster. We identified a total of five common APOA5 haplotypes with a frequency of greater than 8% in samples of northern European origin. The APOA5 haplotype block did not extend past the 7 SNPs in the gene and was separated from the other apolipoprotein gene in the cluster by a region of significantly increased recombination. Furthermore, one previously identified triglyceride risk haplotype of APOA5 (APOA5*3) showed no association with three APOC3 SNPs previously associated with triglyceride concentrations, in contrast to the other risk haplotype (APOA5*2), which was associated with all three minor APOC3 SNP alleles. These results highlight the complex genetic relationship between APOA5 and APOC3 and support the notion that APOA5 represents an independent risk gene affecting plasma triglyceride concentrations in humans. KeywordsSingle nucleotide polymorphism; Apolipoprotein A5; Haplotype; Linkage disequilibrium; Recombination; Four-gamete testThe apolipoprotein gene cluster on human chromosome 11q23 contains four apolipoprotein genes (APOA1/C3/A4/A5) in a genomic interval of approximately 60 kb [1]. Three of these genes (APOA1/C3/A4) have been well described, and each plays an important role in lipid metabolism in humans and mice. For example, mice lacking apoA1 have significantly reduced plasma high-density lipoprotein (HDL) cholesterol levels [2]. In contrast, mice lacking apoC3 show lower concentration of plasma triglycerides compared to control littermates [3].In humans, analyses of genetic sequence variants around these three genes have revealed polymorphisms associated with plasma lipid levels (for a review, see [4] in APOA1 primarily affect HDL-cholesterol cocentrations, while variation in APOC3 is primarily associated with altered plasma triglyceride concentrations. In APOC3, two rare alleles in the promoter region (−482C →T and −455T →C) and a minor allele in the 3′UTR (SstI polymorphism, 3238G →C) have repeatedly been associated with elevated plasma triglyceride concentrations in several human populations [5][6][7][8][9][10][11][12][13][14][15]. However, the lack of strong functional data at least for the SstI polymorphism raises questions whether the association seen in humans is due to these sequence variants in APOC3 directly or due to other functional variants in APOC3 or possibly in one of the neighboring apolipoprotein genes.Recently, we identified a fourth member (APOA5) of the chromosome 11 apolipoprotein gene cluster, located approximatel...

Increased plasma triglyceride (TG) levels are an important cardiovascular risk factor and are strongly associated with atherosclerotic heart disease ( 1, 2 ). Plasma TG levels vary widely between individuals, and both genetic and environmental factors have been shown to contribute to elevated plasma TG concentrations ( 3-7 ). Elevated plasma TG levels are often observed in obese and diabetic individuals and in individuals affected by the metabolic syndrome, a common chronic disorder associated with obesity, insulin resistance, hypertension, and alterations in plasma lipid profi le such as elevated serum TG and low HDL levels. This characteristic pattern is similar to lipid abnormalities reported in familial combined hyperlipidemia ( 8 ).The Metabolic Risk Complications of Obesity Genes (MRC-OB) project was established in 1994 to identify the genetic determinants of the metabolic syndrome and its metabolic abnormalities ( 9 ). As part of the project, basic anthropomorphic phenotypes, plasma lipid measures, and fasting glucose and insulin levels were ascertained for 2,209 individuals from 507 families. A genome-wide linkage scan of these families identifi ed a quantitative trait locus (QTL) on human chromosome 7q36 linked to plasma TG levels (LOD = 3.7) ( 10 ). This region has also been implicated in numerous other studies (11)(12)(13)(14)(15) ؊ 4 in 920 unrelated individuals of the replication cohort, combined P = 9.9 × 10 ؊ 6 ). Individuals homozygous for the T allele had 9% higher TG levels and 2-fold lower expression of INSIG1 in surgical liver biopsy samples when compared with individuals homozygous for the G allele. Also, the T allele showed additional binding of nuclear proteins from HepG2 liver cells in gel shift assays. Finally, the variant rs7566605 in INSIG2 , the only homolog of INSIG1 , enhances the effect of rs2721 ( P = 0.00117). The variant rs2721 alone explains 5.4% of the observed linkage in our cohort, suggesting that additional, yet-undiscovered genes and sequence variants in the QTL interval also contribute to alterations in TG levels in humans. -Smith,

This study reveals the canonical pathways and gene networks associated with NAFLD in morbidly obese Caucasians. The application of gene network analysis highlights the transcriptional relationships among NAFLD-associated genes and allows identification of hub genes that may represent high-priority candidates for NAFLD.

ROTEM analysis during neonatal cardiac surgery is sensitive and specific for thrombocytopenia and hypofibrinogenemia, identifying deficits within 10 minutes. Platelet and cryoprecipitate transfusion during neonatal CPB normalizes platelet count, fibrinogen level, and ROTEM amplitudes.

IMPORTANCE Sensorineural hearing loss (SNHL) is commonly caused by conditions that affect cochlear structures or the auditory nerve, and the genes identified as causing SNHL to date only explain a fraction of the overall genetic risk for this debilitating disorder. It is likely that other genes and mutations also cause SNHL. OBJECTIVE To identify a candidate gene that causes bilateral, symmetric, progressive SNHL in a large multigeneration family of Northern European descent. DESIGN, SETTING, AND PARTICIPANTS In this prospective genotype and phenotype study performed from January 1, 2006, through April 1, 2016, a 6-generation family of Northern European descent with 19 individuals having reported early-onset hearing loss suggestive of an autosomal dominant inheritance were studied at a tertiary academic medical center. In addition, 179 unrelated adult individuals with SNHL and 186 adult individuals reporting nondeafness were examined. MAIN OUTCOMES AND MEASURES Sensorineural hearing loss. RESULTS Nine family members (5 women [55.6%]) provided clinical audiometric and medical records that documented hearing loss. The hearing loss is characterized as bilateral, symmetric, progressive SNHL that reached severe to profound loss in childhood. Audiometric configurations demonstrated a characteristic dip at 1000 to 2000 Hz. All affected family members wear hearing aids or have undergone cochlear implantation. Exome sequencing and linkage and association analyses identified a fully penetrant sequence variant (rs35725509) on chromosome 12q21 (logarithm of odds, 3.3) in the TMTC2 gene region that segregates with SNHL in this family. This gene explains the SNHL occurrence in this family. The variant is also associated with SNHL in a cohort of 363 unrelated individuals (179 patients with confirmed SNHL and 184 controls, P = 7 × 10−4). CONCLUSIONS AND RELEVANCE A previously uncharacterized gene, TMTC2, has been identified as a candidate for causing progressive SNHL in humans. This finding identifies a novel locus that causes autosomal dominant SNHL and therefore a more detailed understanding of the genetic basis of SNHL. Because TMTC2 has not been previously reported to regulate auditory function, the discovery reveals a potentially new, uncharacterized mechanism of hearing loss.