Xiaosong Wang

Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility

Ath1 is a quantitative trait locus on mouse chromosome 1 that renders C57BL/6 mice susceptible and C3H/He mice resistant to diet-induced atherosclerosis. The quantitative trait locus region encompasses 11 known genes, including Tnfsf4 (also called Ox40l or Cd134l), which encodes OX40 ligand. Here we report that mice with targeted mutations of Tnfsf4 had significantly (P ≤ 0.05) smaller atherosclerotic lesions than did control mice. In addition, mice overexpressing Tnfsf4 had significantly (P ≤ 0.05) larger atherosclerotic lesions than did control mice. In two independent human populations, the less common allele of SNP rs3850641 in TNFSF4 was significantly more frequent (P ≤ 0.05) in individuals with myocardial infarction than in controls. We therefore conclude that Tnfsf4 underlies Ath1 in mice and that polymorphisms in its human homolog TNFSF4 increase the risk of myocardial infarction in humans.

Use of a dense single nucleotide polymorphism map for in silico mapping in the mouse.

Rapid expansion of available data, both phenotypic and genotypic, for multiple strains of mice has enabled the development of new methods to interrogate the mouse genome for functional genetic perturbations. In silico mapping provides an expedient way to associate the natural diversity of phenotypic traits with ancestrally inherited polymorphisms for the purpose of dissecting genetic traits. In mouse, the current single nucleotide polymorphism (SNP) data have lacked the density across the genome and coverage of enough strains to properly achieve this goal. To remedy this, 470,407 allele calls were produced for 10,990 evenly spaced SNP loci across 48 inbred mouse strains. Use of the SNP set with statistical models that considered unique patterns within blocks of three SNPs as an inferred haplotype could successfully map known single gene traits and a cloned quantitative trait gene. Application of this method to high-density lipoprotein and gallstone phenotypes reproduced previously characterized quantitative trait loci (QTL). The inferred haplotype data also facilitates the refinement of QTL regions such that candidate genes can be more easily identified and characterized as shown for adenylate cyclase 7.

Genetics of Variation in HDL Cholesterol in Humans and Mice

Plasma high-density lipoprotein cholesterol (HDL-C) concentrations are genetically determined to a great extent, and quantitative trait locus (QTL) analysis has been used to identify chromosomal regions containing genes regulating HDL-C levels. We discuss new genes found to participate in HDL metabolism. We also summarize 37 mouse and 30 human QTLs for plasma HDL-C levels, finding that all but three of the mouse QTLs have been confirmed by a second cross or a homologous human QTL, that the mouse QTL map is almost saturated because 92% of recently reported QTLs are repeats of those already found, and that 28 of the 30 human QTLs are located in regions homologous to mouse QTLs. This high degree of concordance between mouse and human QTLs suggests that the underlying genes may be the same. Strategies to more rapidly identify genes underlying mouse and human QTLs for HDL-C include focusing on the mouse and using mouse-human homologies, combining crosses, and haplotyping to narrow the region. Sequence analysis and expression studies can distinguish candidate genes consistent across multiple mouse crosses, and testing the candidate genes in human association studies can provide additional evidence for the candidacy of a gene. Together these strategies can accelerate the pace of finding genes that regulate HDL.

Identifying Novel Genes for Atherosclerosis through Mouse-Human Comparative Genetics

Susceptibility to atherosclerosis is determined by both environmental and genetic factors. Its genetic determinants have been studied by use of quantitative-trait-locus (QTL) analysis. So far, 21 atherosclerosis QTLs have been identified in the mouse: 7 in a high-fat-diet model only, 9 in a sensitized model (apolipoprotein E- or LDL [low-density lipoprotein] receptor-deficient mice) only, and 5 in both models, suggesting that different gene sets operate in each model and that a subset operates in both. Among the 27 human atherosclerosis QTLs reported, 17 (63%) are located in regions homologous (concordant) to mouse QTLs, suggesting that these mouse and human atherosclerosis QTLs have the same underlying genes. Therefore, genes regulating human atherosclerosis will be found most efficiently by first finding their orthologs in concordant mouse QTLs. Novel mouse QTL genes will be found most efficiently by using a combination of the following strategies: identifying QTLs in new crosses performed with previously unused parental strains; inducing mutations in large-scale, high-throughput mutagenesis screens; and using new genomic and bioinformatics tools. Once QTL genes are identified in mice, they can be tested in human association studies for their relevance in human atherosclerotic disease.

Quantitative Trait Loci and Candidate Genes Regulating HDL Cholesterol: A Murine Chromosome Map

Objective—Summarizing the many discovered mouse and human quantitative trait loci (QTL) for high density lipoprotein (HDL) cholesterol (HDL-C) levels is important for guiding future research on the genetic regulation of HDL concentrations and for finding gene targets for upregulating HDL levels in mice and humans. Methods and Results—We summarized the 27 QTL and candidate genes associated with HDL-C concentrations in mice and plotted them on a mouse chromosome map. We also summarized the 22 human QTL for HDL-C levels and compared them with those of the mouse by comparative genomics. At least part of the mouse homologies for 18 of the 22 human HDL-C QTL were within the murine HDL-C QTL. Conclusions—Murine QTL for HDL-C levels may predict their homologous location in humans, and their underlying genes may be appropriate genes to test in humans.

Comparative Genetics of Atherosclerosis and Restenosis: Exploration With Mouse Models

Ischemic heart disease is a consequence of coronary atherosclerosis. In addition to coronary bypass surgery, a common and often successful treatment 0is angioplasty, expanding the internal lumen of the coronary artery with a balloon. However, 30% to 50% of angioplasty patients soon develop significant restenosis, a narrowing of the artery through migration and growth of smooth muscle cells. Stents introduced into the coronary artery to keep it open after angioplasty considerably reduce the incidence of restenosis, but 10% to 50% of patients receiving stents still develop restenosis.1 Recent clinical trials that use local radiation to the treated artery or drugs released by the stent, such as sirolimus and paclitaxel, are reported to improve the clinical outcomes2–5⇓⇓⇓ but may only provide transient protection. Even after these efforts, restenosis remains a major clinical problem in light of the more than 800,000 angioplasty procedures in the United States each year and the generally disappointing results of efforts to prevent restenosis with systemically delivered drugs in humans. See page 955 An understanding of the genetic factors underlying restenosis will help identify those patients resistant to restenosis for whom treatment is most likely to be successful. More importantly, identifying the critical genes involved will clarify the molecular mechanisms controlling restenosis, providing possibilities for substantially more effective therapeutic control of this significant problem. Exploring the genetics of restenosis has now begun in experimental animals with significant implications for the human condition. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Kuhel et al6 have compared the susceptibility of five inbred mouse strains to injury-induced neointimal hyperplasia, which is a model of restenosis, and demonstrated considerable variation among strains. Their results make it clear that susceptibility to restenosis and to atherosclerosis, which …

QTL mapping for genetic determinants of lipoprotein cholesterol levels in combined crosses of inbred mouse strains.

To identify additional loci that influence lipoprotein cholesterol levels, we performed quantitative trait locus (QTL) mapping in offspring of PERA/EiJ×I/LnJ and PERA/EiJ×DBA/2J intercrosses and in a combined data set from both crosses after 8 weeks of consumption of a high fat-diet. Most QTLs identified were concordant with homologous chromosomal regions that were associated with lipoprotein levels in human studies. We detected significant new loci for HDL cholesterol levels on chromosome (Chr) 5 (Hdlq34) and for non-HDL cholesterol levels on Chrs 15 (Nhdlq9) and 16 (Nhdlq10). In addition, the analysis of combined data sets identified a QTL for HDL cholesterol on Chr 17 that was shared between both crosses; lower HDL cholesterol levels were conferred by strain PERA. This QTL colocalized with a shared QTL for cholesterol gallstone formation detected in the same crosses. Haplotype analysis narrowed this QTL, and sequencing of the candidate genes Abcg5 and Abcg8 confirmed shared alleles in strains I/LnJ and DBA/2J that differed from the alleles in strain PERA/EiJ. In conclusion, our analysis furthers the knowledge of genetic determinants of lipoprotein cholesterol levels in inbred mice and substantiates the hypothesis that polymorphisms of Abcg5/Abcg8 contribute to individual variation in both plasma HDL cholesterol levels and susceptibility to cholesterol gallstone formation.

Reply to “Lack of support for association between common variation in TNFSF4 and myocardial infarction in a German population”

Reply to “Lack of support for association between common variation in TNFSF4 and myocardial infarction in a German population”