Fred Hutchinson Cancer Research Center

About: Fred Hutchinson Cancer Research Center is a nonprofit organization based out in Cape Town, South Africa. It is known for research contribution in the topics: Population & Transplantation. The organization has 12322 authors who have published 30954 publications receiving 2288772 citations. The organization is also known as: Fred Hutch & The Hutch.

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction

Abstract: Exome sequence analysis of nearly 10,000 people was carried out to identify alleles associated with early-onset myocardial infarction; mutations in low-density lipoprotein receptor (LDLR) or apolipoprotein A-V (APOA5) were associated with disease risk, identifying the key roles of low-density lipoprotein cholesterol and metabolism of triglyceride-rich lipoproteins. Sekar Kathiresan and colleagues use exome sequencing of nearly 10,000 people to probe the contribution of multiple rare mutations within a gene to risk for myocardial infarction at a population level. They find that mutations in low-density lipoprotein receptor (LDLR) or apolipoprotein A-V (APOA5) are associated with disease risk. When compared with non-carriers, LDLR mutation carriers had higher plasma levels of LDL cholesterol, whereas APOA5 mutation carriers had higher plasma levels of triglycerides. As well as confirming that APOA5 is a myocardial infarction gene, this work informs the design and conduct of rare-variant association studies for complex diseases. Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1,2. When MI occurs early in life, genetic inheritance is a major component to risk1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3,4,5,6,7,8, whereas common variants at more than 45 loci have been associated with MI risk in the population9,10,11,12,13,14,15. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol16. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl−1. At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15,17 and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

Nomenclature for factors of the HLA system, 2004

Abstract: Correspondence to: Dr Steven G. E. Marsh Anthony Nolan Research Institute Royal Free Hospital Pond Street Hampstead London NW3 2QG UK Tel.: þ442072848321 Fax: þ442072848331 e-mail: marsh@ebi.ac.uk Following the decision to hold their next full meeting after the 14th International Histocompatibility Workshop in 2005, the WHO Nomenclature Committee for Factors of the HLA System has decided to publish an interim report listing updated tables of alleles including those assigned since the publication of the last full report in 2002 (1). The alleles named during the period follow the principles established in previous reports (1–17).

Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein

Abstract: p21 inhibits cyclin-dependent kinase (CDK) activity and proliferating cell nuclear antigen (PCNA)-dependent DNA replication by binding to CDK/cyclin complexes and to PCNA through distinct domains. The human papillomavirus (HPV)-16 E7 oncoprotein (16E7) abrogated a DNA damage-induced cell cycle arrest in vivo, despite high levels of p21. Using cell lysates and purified proteins we show that 16E7 prevented p21 both from inhibiting CDK2/cyclin E activity and PCNA-dependent DNA replication, whereas the nononcogenic HPV-6 E7 had reduced effects. Inactivation of both inhibitory functions of p21 was attained through binding between 16E7 and sequences in the carboxy-terminal end of p21 that overlap with the PCNA-binding site and the second p21 cyclin-binding motif. These data imply that the carboxyl terminus of p21 simultaneously modulates both CDK activity and PCNA-dependent DNA replication and that a single protein, 16E7, can override this modulation to disrupt normal cell cycle control.

Alternative splicing of HLA-G transcripts yields proteins with primary structures resembling both class I and class II antigens.

Abstract: We have investigated HLA-G mRNA expression in cells and tissues expressing the gene. This analysis has demonstrated that the HLA-G primary transcript is alternatively spliced to yield at least three distinct mature mRNAs. Sequencing of the transcripts has shown that the largest mRNA is essentially that previously characterized, encoding a leader sequence, three external domains, a transmembrane region, and a cytoplasmic sequence. Of the two smaller messages, a 900-base mRNA does not include exon 3, resulting in a predicted protein sequence with the alpha 1 and alpha 3 external domains joined. The smallest mRNA results from splicing out exons 3 and 4, connecting the alpha domain directly to the transmembrane sequence. Alternative splicing of HLA-G mRNA was found in placental tissues and in eye tissue as well as in HLA-G-transfected cell lines. In term placental tissue the smallest mRNA appeared to be more abundant than the full-length form, while in a cell line derived from an earlier developmental stage the larger form predominated. Immunoprecipitation of [35S]methionine-labeled cell lysates showed that three different HLA-G proteins were present in transfected cells, with sizes corresponding to those predicted from the three alternative mRNA sequences. These findings are discussed in terms of potential functions of the alternative HLA-G proteins.