👤 Han Hu

In a previous pilot case-control study of individuals diagnosed with esophageal squamous cell carcinoma (ESCC) and matched controls from a high-risk area in China, we identified 38 single nucleotide polymorphisms (SNPs) associated with ESCC located in or near one of 33 genes. In our study, we attempted to replicate the results of these 38 gene-related SNPs in a new sample of 300 ESCC cases and 300 matched controls from the same study conducted in Shanxi Province, China. Among 36 evaluable SNPs, 4 were significant in one or more analyses, including SNPs located in EPHB1, PGLYRP2, PIK3C3 and SLC9A9, although the odds ratios (ORs) for these genotypes were modest. Associations were found with EPHB1/rs1515366 (OR 0.92, 95% CI 0.86-0.99; p = 0.019), PIK3C3/rs52911 (OR 0.93, 95% CI 0.88-0.99; p = 0.02) and PGLYRP2/rs959117 (OR 0.93, 95% CI, 0.86-1.01; p = 0.061) in general linear models (additive mode); and the genotype distribution differed between cases and controls for SLC9A9/rs956062 (p = 0.024). To examine these 4 genes in more detail, 40 HapMap-based tag SNPs from these 4 genes were evaluated in the same subjects and 7 additional SNPs associated with ESCC were identified. Further confirmation of these findings in other populations and other studies are needed to determine if the signals from these SNPs are indirectly associated due to linkage disequilibrium, or are directly related to biologic function and the development of ESCC. Show less

Increased protein level in the cerebrospinal fluid (CSF) is a characteristic of patients with Guillain-Barré syndrome (GBS), an acute inflammatory autoimmune disorder in the peripheral nervous system (PNS). However, the molecular mechanisms underlying the disease remain poorly understood and so far no reliable disease-related markers are available. By comparing the CSF proteome of GBS patients with control subjects suffering from other neurological disorders, it may be possible to identify proteins that involve in the disease process and thus to study the pathogenesis of GBS. We used two-dimensional difference gel electrophoresis (2D DIGE) technique, in combination with matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS), to determine the abnormal CSF proteins in GBS patients. Our data showed that the levels of six proteins and their isoforms in CSF were significantly altered in GBS patients compared with controls. Haptoglobin, apolipoprotein A-IV and PRO2044 (unnamed protein) were considerably increased in the CSF of GBS patients, whereas transthyretin, apolipoprotein E and fibrinogen were considerably decreased. We concluded that these six proteins may be involved in the pathogenesis of GBS and call for further studying the role of these proteins in the pathogenesis of the disease. Show less

The apolipoprotein gene cluster (APOA1/C3/A4/A5) was recently associated with triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) in non-diabetic population. Little is known whether the variations in these genes affect lipid homeostasis in patients with type 2 diabetes. We examined the associations of 10 polymorphisms at APOA1/C3/A4/A5 gene cluster with blood lipids among 902 diabetic women. A linkage disequilibrium (LD) breakdown was observed between APOA5 and other genes. APOA5 S19W was associated with significantly higher fasting TG levels (P=0.001). Two common haplotypes encompassing four APOA5 polymorphisms (SNP1, SNP2, S19W, and SNP3) were associated with 35.6 mg/dL (haplotype 2212, APOA5*2, P=0.016) and 57.8 mg/dL (haplotype 1121, APOA5*3, P=0.0002) higher fasting TG levels compared with the most common (haplotype 1111, APOA5*1), respectively. Adjustment for age, BMI, and other covariates did not appreciably change such associations. In addition, APOC3 promoter polymorphism -455T/C showed significant associations with fasting TG levels (P=0.006), whereas APOA4 +347T/A showed significant associations with lower levels of HDL-C (P=0.017). Our results indicate that the variability in APOA1/C3/A4/A5 gene cluster may affect TG and HDL levels in women with type 2 diabetes. Show less

Apolipoprotein A5 (ApoA5) is present in human serum at a very low concentration. We developed a new method to determine ApoA5 concentration in human serum, and to investigate the correlation between serum ApoA5 and the lipid profiles in healthy subjects, and to analyze whether the correlation was affected by gender. All the subjects (total 92, male 50, female 42) were healthy subjects without any medication. Lipids were measured enzymatically. An ELISA performed by a couple of monoclonal antibodies was used to measure serum ApoA5. The average ApoA5 concentration was 182.7+/-104.7 ng/ml ranging from 5.4 to 455.6 ng/ml. Serum ApoA5 concentration was negatively correlated with TG in female (r=-0.496, P=0.001). In all subjects, ApoA5 concentration was positively correlated to HDL-C (r=0.453, P<0.001). This correlation was more predominant in female (r=0.617, P<0.001) than in male (r=0.289, P=0.042). ApoA5 concentration was negatively correlated to body mass index (BMI) with more significance in female than in male (r=-0.345, P=0.001 for all; r=-0.456, P=0.002 for female; r=-0.198, P=0.167 for male). The serum concentration of ApoA5 was very low. The concentration of ApoA5 was negatively correlated with TG and BMI, but positively correlated with HDL-C. The correlations were affected by gender. Show less

To explore the disease associated gene mutation of multiple exostoses by family analysis. Polymerase chain reaction and DNA sequencing were used to detect the mutation hot spot regions of EXT1 and EXT2 gene, while restriction fragment length polymorphism was performed to screen the mutation. We found a novel heterozygous mutation c.811T ->C in EXT1 gene of patients, which resulted in the substitution of histidine for tyrosine at codon 271 in this hereditary multiple exostoses family. The mutation was not found in the unaffected family members, nor in the 100 unrelated normal individual, which was unreported before. The novel mutation Y271H is the disease-causing mutation in the hereditary multiple exostoses family. Show less

Adequate response to low oxygen levels (hypoxia) by hypoxia inducible factor (HIF) is essential for normal development and physiology, but this pathway may also contribute to pathological processes like tumor angiogenesis. Here we show that hypoxia is an inducer of Notch signaling. Hypoxic conditions lead to induction of the Notch ligand Dll4 and the Notch target genes Hey1 and Hey2 in various cell lines. Promoter analysis revealed that Hey1, Hey2 and Dll4 are induced by HIF-1alpha and Notch activation. Hypoxia-induced Notch signaling may also determine endothelial identity. Endothelial progenitor cells (EPCs) contain high amounts of COUP-TFII, a regulator of vein identity, while levels of the arterial regulators Dll4 and Hey2 are low. Hypoxia-mediated upregulation of Dll4 and Hey2 leads to repression of COUP-TFII in eEPCs. Finally, we show that Hey factors are capable of repressing HIF-1alpha-induced gene expression, suggesting a negative feedback loop to prevent excessive hypoxic gene induction. Thus, reduced oxygen levels lead to activation of the Dll4-Notch-Hey2 signaling cascade and subsequent repression of COUP-TFII in endothelial progenitor cells. We propose that this is an important step in the developmental regulation of arterial cell fate decision. Show less

Demyelinating diseases, such as multiple sclerosis, are characterized by the loss of the myelin sheath around neurons, owing to inflammation and gliosis in the central nervous system (CNS). Current treatments therefore target anti-inflammatory mechanisms to impede or slow disease progression. The identification of a means to enhance axon myelination would present new therapeutic approaches to inhibit and possibly reverse disease progression. Previously, LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) has been identified as an in vitro and in vivo negative regulator of oligodendrocyte differentiation and myelination. Here we show that loss of LINGO-1 function by Lingo1 gene knockout or by treatment with an antibody antagonist of LINGO-1 function leads to functional recovery from experimental autoimmune encephalomyelitis. This is reflected biologically by improved axonal integrity, as confirmed by magnetic resonance diffusion tensor imaging, and by newly formed myelin sheaths, as determined by electron microscopy. Antagonism of LINGO-1 or its pathway is therefore a promising approach for the treatment of demyelinating diseases of the CNS. Show less

MEKK3 is a mitogen-activated protein kinase kinase kinase that participates in various signaling pathways. One of its functions is to activate the ERK5 signal pathway by phosphorylating and activating MEK5. MEKK3 and MEK5 each harbors a PB1 domain in the N-terminus, and they form a heterodimer via PB1-PB1 domain interaction that was reported to be indispensable to the activation of MEK5. Using NMR spectroscopy, we show here that a prolyl isomerization of the Gln38-Pro39 bond is present in MEKK3 PB1, which is the first case of structural heterogeneity within PB1 domains. We have solved the solution structures of both isomers and found a major difference between them in the Pro39 region. Residues Gly37-Leu40 form a type VIb beta-turn in the cis conformation, whereas no obvious character of beta-turn was observed in the trans conformation. Backbone dynamics studies have unraveled internal motions in the beta3/beta4-turn on a microsecond-millisecond time scale. Further investigation of its binding properties with MEK5 PB1 has demonstrated that MEKK3 PB1 binds MEK5 PB1 tightly with a Kd of about 10(-8) M. Mutagenesis analysis revealed that residues in the basic cluster of MEKK3 PB1 contributes differently to the PB1-PB1 interaction. Residues Lys 7 and Arg 5 play important roles in the interaction with MEK5 PB1. Taken together, this study provides new insights into structural details of MEKK3 PB1 and its binding properties with MEK5 PB1. Show less

Recently, a T/C polymorphism of the promoter region of the APOA5 gene at position -1131 and a G/T polymorphism at position 553 were found to be associated with increased levels of plasma triglyceride. Triglyceride plays a role in coronary artery disease (CAD), so this case-control study tested for a possible link between these two APOA5 polymorphisms, their common haplotypes and the risk of CAD. The subjects included 211 CAD patients and 677 unrelated controls. A significantly higher level of triglycerides and a lower level of high-density lipoprotein cholesterol (HDL-C) were noted for carriers with -1131C than for non-carriers (P<0.001 and 0.013, respectively) among controls. Plasma triglyceride levels were significantly higher (P=0.014) in controls with genotypes that contained the c.553T allele than in homozygotes for the G allele. Subjects homozygous for the wild-type haplotype had significantly lower triglyceride levels and higher HDL-C levels than subjects with all other haplotype pairs. The -1131C homozygous carriers and c.553T heterozygous carriers were found more frequently in 211 patients with CAD than in the 317 age/sex-matched controls (P=0.008 and 0.023, respectively) in univariate analysis. The significant association between c.553T allele carriers with CAD remained in multivariate regression analysis (OR, 1.79; CI, 1.07-3.00; P=0.028), after adjustments were made for other risk factors. Notably, haplotype analysis further verified that the APOA5 -1131C and c.553T bi-loci haplotype was significantly overpresented in CAD, as compared to the controls. These results indicate that the variants of APOA5 gene modulate plasma triglyceride and may use them to predict CAD susceptibility in Taiwanese Chinese. Show less

Cardiotoxin III (CTX III) is a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom. This is the first report on the mechanism of the anticancer effect of CTX III in human colorectal cancer Colo205 cells. 2. Cardiotoxin III-induced Colo205 cell apoptosis was confirmed by DNA fragmentation (DNA ladder and sub-G1 formation) with an IC(50) of 4 mg/mL at 48 h. 3. Further mechanistic analysis demonstrate that CTX III induced the loss of mitochondrial membrane potential (Dym), cytochrome c release from mitochondria into the cytosol and activation of capase-9, caspase 3, as well as markedly enhancing the expression of Bax, but not Bcl-2, protein in the cells. Moreover, the CTX III-induced apoptosis was significantly blocked by the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. 4. However, CTX III did not generate the formation of reactive oxygen species and anti-oxidants, including N-acetylcysteine, and catalase could not block CTX III-induced apoptosis in the Colo205 cells. 5. Taken together, these results suggest that CTX III may induce apoptosis through a mitochondrial- and caspase-dependent mechanism and alteration of Bax/Bcl-2 ratio in human colorectal Colo205 cancer cells. Show less

To study the gene mutation in a patient with multiple exostoses, identify the disease-causing gene mutation. Polymerase chain reaction and DNA sequencing were used to screen the EXT1 or EXT2 gene mutation, while mismatch primer amplification and restriction endonuclease digestion were performed to confirm the mutation. By DNA sequencing, a mutation in the seventh intron was detected and located at 26 bp of 3' splice site upstream in EXT1 gene, which was unreported before. Mismatch primer amplification and restriction fragment length polymorphism analysis suggested that this mutation was not detected in the normal control. The mutation 1633-26(C-->A) may be the disease-causing mutation in this patient with multiple exostoses. Show less

Although oligonucleotide chips, cDNA microarrays, differential display reverse transcription-PCR, and other approaches have been used to screen implantation-related molecules, the mechanism by which embryo implantation occurs is still unknown. The aim of this study was to profile the differential gene expression between interimplantation site and implantation site in mouse uterus on day 5 of pregnancy by serial analysis of gene expression (SAGE). In our two SAGE libraries of 11-bp tags, the total numbers of tags sequenced were 48,121 for the interimplantation site and 50,227 for the implantation site. There were 1,039 tags specifically expressed at interimplantation site, and 1,252 tags specifically expressed at the implantation site. Based on the p value, there were 195 tags significantly up-regulated at the interimplantation site and 261 tags significantly up-regulated at the implantation site, of which 100 genes were single matched at the interimplantation site and 127 genes were single matched at the implantation site, respectively. By reverse transcription-PCR, the tag ratio between the implantation site and interimplantation site was verified on 14 significantly changed genes. Using in situ hybridization, 1810014L12Rik, Psmb5, Cd63, Npm1, Fads3, and Tagln2 were shown to be highly expressed at the implantation site compared with the interimplantation site. Compared with the interimplantation site, Ddx39 was strongly expressed in the subluminal stromal cells at the implantation site on day 5 of pregnancy. Ddx39 expression at the implantation site was specifically induced by active blastocysts. Additionally, Ddx39 expression was significantly up-regulated by estrogen in the ovariectomized mice. In our SAGE data, many implantation-related genes were identified in mouse uterus. Our data could be a valuable source for future study on embryo implantation. Show less

To compare the gene mutation between Chinese patients with familial and sporadic hypertrophic cardiomyopathy (HCM). Peripheral blood samples were collected from 36 patients with familial HCM (FHCM) and 50 patients with sporadic HCM (SHCM), all un-related and from different provinces of China. PCR was used to amplify the 26 protein-coding axons of beta-myosin heavy chain (MYH7), 16 exons for cardiac troponin T (TNNT2), and 38 exons for cardiac myosin-binding protein C (MYBPC3). The amplified products were sequenced and compared with the standard sequence in the genBank so as to determine the potential mutation sites. (1) 13 of the 36 FHCM patients (36.1%) harbored 3 different mutations in MYH7 gene: Arg663His in exon18, Glu924Lys in exon 23, and Ile736Thr in exon 20. Of the 50 SHCM patients, only 1 (2%) harbored MYH7 gene missence mutation: Ile736Thr located in exon 20. (2) TNNT2 was not identified in all SHCM patients and FHCM patients. (3) MYBPC3 was not identified in all SHCM patients. Four FHCM patients harbored 2 different mutations: Arg502Trp in exon 18 and Arg346fs in exon 13 respectively. MYH7 and MYBPC3 may be the dominant disease-causing genes in Chinese familial HCM patients; however the mutation rate of MYH7 and MYBPC3 genes is significantly lower in the SHCM patients compared with the FHCM patients. TNNT2 seems not the predominant disease-causing gene in all Chinese patients with HCM. Show less

The aim of this study was to screen the disease-causing gene mutations and investigate the genotype-phenotype correlation in 10 Chinese pedigrees with familial hypertrophic cardiomyopathy (HCM). There are 91 family members from these 10 pedigrees and 5 members were normal mutated carriers, 23 members were HCM patients (14 male) aged from 1.5 to 73 years old. The functional regions of myosin heavy chain gene (MYH7), cardiac myosin-binding protein C (MYBPC3) and cardiac troponin T gene (TNNT2) were screened with PCR and direct sequencing technique. Clinical information from all patients was also evaluated in regard to the genotype. Mutations were found in 5 out of 10 pedigrees. Mutations in MYH7 (Arg663His, Glu924Lys and Ile736Thr) were found in 3 pedigrees and 3 patients from these pedigrees suffered sudden death at age 20-48 years old during sport. Mutations in MYBPC3 were found in 2 pedigrees, 1 with complex mutation (Arg502Trp and splicing mutation IVS27 + 12C > T) and 1 with novel frame shift mutation (Gly347fs) and the latter pedigree has sudden death history. No mutation was identified in TNNT2. Although the Han Chinese is a relatively homogeneous ethnic group, different HCM gene mutations were responsible for familiar HCM suggesting the heterogeneity nature of the disease-causing genes and HCM MYH7 mutations are associated with a higher risk of sudden death in this cohort. Furthermore, identical mutation might result in different phenotypes suggesting that multiple factors might be involved in the pathogenesis of familiar HCM. Show less

To study the genetic control of plant responses to cold stress, Arabidopsis thaliana mutants were isolated by a screen for mutations that impair cold-induced transcription of the CBF3-LUC reporter gene. We report here the characterization and cloning of a mutated gene, atnup160-1, which causes reduced CBF3-LUC induction under cold stress. atnup160-1 mutant plants display altered cold-responsive gene expression and are sensitive to chilling stress and defective in acquired freezing tolerance. AtNUP160 was isolated through positional cloning and shown to encode a putative homolog of the animal nucleoporin Nup160. In addition to the impaired expression of CBF genes, microarray analysis revealed that a number of other genes important for plant cold tolerance were also affected in the mutants. The atnup160 mutants flower early and show retarded seedling growth, especially at low temperatures. AtNUP160 protein is localized at the nuclear rim, and poly(A)-mRNA in situ hybridization shows that mRNA export is defective in the atnup160-1 mutant plants. Our study suggests that Arabidopsis AtNUP160 is critical for the nucleocytoplasmic transport of mRNAs and that it plays important roles in plant growth and flowering time regulation and is required for cold stress tolerance. Show less

To identify the changes in zebrafish embryonic ocular development after early growth response factor 1 (Egr1) gene knockdown by Egr1-specific translation inhibitor, morpholino oligonucleotides (MO). Two kinds of Egr1-MO were microinjected separately with various dosages into one to four celled zebrafish embryos to find an optimal dose generating an acceptable mortality rate and high frequency of specific phenotype. Chordin-MO served as the positive control; a 5 mismatch MO of Egr1-MO1 and a nonspecific MO served as negative controls. We graded the Egr1 morphants according to their gross abnormalities, and measured their ocular dimensions accordingly. Western blot analysis and synthetic Egr1 mRNA rescue experiments confirmed whether the deformities were caused by Egr1 gene knockdown. Histological examination and three kinds of immunohistochemical staining were applied to identify glutamate receptor one expression in retinal ganglion cells and amacrine cells, to recognize acetylated alpha-tubulin expression which indicated axonogenesis, and to label photoreceptor cells with zpr-1 antibody. After microinjection of 8 ng Egr1-MO1 or 2 ng Egr1-MO2, 81.8% and 97.3% of larvae at 72 h postfertilization had specific defects, respectively. The gross phenotype included string-like heart, flat head, and deformed tail. The more severely deformed larvae had smaller eyes and pupils. Co-injection of 8 ng Egr1-MO1 and supplementary 12 pg synthetic Egr1 mRNA reduced the gross abnormality rate from 84.4% to 29.7%, and decreased the severity of deformities. Egr1 protein appeared in the wildtype and rescued morphants, but was lacking in the Egr1 morphants with specific deformities. Lenses of Egr1 morphants were smaller and had some residual nucleated lens fiber cells. Morphants' retinal cells arranged disorderly and compactly with thin plexiform layers. Immunohistochemical studies showed that morphants had a markedly decreased number of mature retinal ganglion cells, amacrine cells, and photoreceptor cells. Retinal axonogenesis was prominently reduced in morphants. The Egr1 gene plays an important role in zebrafish embryonic oculogenesis. Ocular structures including lens and retina were primitive and lacked appropriate differentiation. Such arrested retinal and lenticular development in Egr1 morphants resulted in microphthalmos. Show less

Several independent population studies have reported that the apolipoprotein C3 (APOC3) Sst I polymorphism in apolipoprotein (apo) A1 /C3/A4/A5 gene cluster is associated with Hypertriglyceridaemia (HTG). HTG is a known risk factor for coronary atherosclerotic heart disease(CHD)and type II diabetes mellitus (non-insulin-dependent diabetes, NIDDM). The aim of this study is to investigate the association between the APOC3 gene Sst I polymorphism and the hypertriglyceridaemia in CHD and NIDDM in Chinese population. The genotype and allele frequencies of APOC3 Sst I polymorphism (S1/S2) were analyzed by PCR-restriction fragment length polymorphism in 267 CHD patients, 246 NIDDM patients and 491 unrelated healthy control individuals. The frequencies of minor allele 52 in CHD group, NIDDM group and control group were 0.301, 0.307 and 0.286, respectively. Compared with controls, there was no significant difference in distribution of genotype and allele frequencies of Sst I polymorphic site in CHD patients and NIDDM patients, respectively. However, the frequency of S1 S2 genotype in the HTG subgroup was significantly higher than that of the normal triglyceridaemia subgroup (NTG) in CHD patients (0.542 > 0.357, chi2 = 8.77, P = 0.0124). In NIDDM patients, the frequency of S2 S2 genotype in the HTG subgroup was significantly high, compared with that in the NTG subgroup (0.200 > 0.055, chi2 = 20.21, P = 0.0000), and there was significantly difference in the distribution of allele frequencies in subgroups of NTG and HTG (chi2 = 19.86, P = 0.0000). The level of triglyceride (TG) in S1 S2 genotype patients of CHD group were higher than that of S1 S1 genotype patients (P = 0.036). In NIDDM and controls groups, S2 S2 genotype individuals exhibited a significant increase in plasma TG concentrations, respectively compared with S1 S1 and S1 S2 genotype individuals of each group (P < 0.01). The minor allele S2, which was associated with both CHD with HTG and NIDDM with HTG and may contribute to the susceptibility of hypertriglyceridemia in CHD and NIDDM patients, may be one of the genetic predispositions to both CHD with HTG and NIDDM with HTG in Chinese population. Show less

To explore the disease-causing gene mutation in Chinese with hypertrophic cardiomyopathy (HCM). The peripheral venous blood samples were collected from 5 HCM families without consanguinity, including 5 probands, 2 males and 3 females, 28 sporadic HCM patients, 18 males and 10 females, and 80 healthy controls. The exons in the functional regions of cardiac myosin-binding protein C (MYBPC3) were amplified with PCR and the amplified products were sequenced. A frame shift mutation-Arg346fs mutation in exon 13, the first mutation identified in Chinese-was discovered in one family with HCM. However, the members of the same HCM family with the Arg346fs mutation showed differences in phenotype and prognosis. Cardiac myosin-binding protein C (MYBPC3) may be one of the main disease-causing genes. The heterogeneity of phenotype suggests that multiple factors may be involved in the pathogenesis. Show less

Whole genome association studies of complex human diseases represent a new paradigm in the postgenomic era. In this study, we report application of the Affymetrix, Inc. (Santa Clara, CA) high-density single nucleotide polymorphism (SNP) array containing 11,555 SNPs in a pilot case-control study of esophageal squamous cell carcinoma (ESCC) that included the analysis of germ line samples from 50 ESCC patients and 50 matched controls. The average genotyping call rate for the 100 samples analyzed was 96%. Using the generalized linear model (GLM) with adjustment for potential confounders and multiple comparisons, we identified 37 SNPs associated with disease, assuming a recessive mode of transmission; similarly, 48 SNPs were identified assuming a dominant mode and 53 SNPs in a continuous mode. When the 37 SNPs identified from the GLM recessive mode were used in a principal components analysis, the first principal component correctly predicted 46 of 50 cases and 47 of 50 controls. Among all the SNPs selected from GLMs for the three modes of transmission, 39 could be mapped to 1 of 33 genes. Many of these genes are involved in various cancers, including GASC1, shown previously to be amplified in ESCCs, and EPHB1 and PIK3C3. In conclusion, we have shown the feasibility of the Affymetrix 10K SNP array in genome-wide association studies of common cancers and identified new candidate loci to study in ESCC. Show less

Apolipoproteins AI/CIII/AIV play important roles in the metabolism of triglycerides (TG) and high-density lipoprotein (HDL) cholesterol. However, whether genetic variations in the APOA1/C3/A4 gene cluster are associated with the risk of myocardial infarction (MI) remains uncertain and prospective data are sparse. In a prospective nested case-control study of 385 incident cases of MI and 373 age- and smoking-matched controls from the Physicians' Health Study, we examined the relationship between 2 common single nucleotide polymorphisms (APOA1 XmnI and APOC3 SstI) in the APOA1/C3/A4 gene cluster and haplotypes defined by these SNPs and risk of incident MI. No significant differences in allele or genotype frequency for the APOA1 XmnI and APOC3 SstI polymorphisms were detected between cases and controls. After adjusting for non-lipid coronary risk factors, the relative risks for incident MI were 1.00 (95% CI 0.68-1.47) for men carrying the X2 allele compared with those homozygous for the X1 allele in the APOA1 XmnI site and 1.07 (95% CI 0.69-1.64) for men carrying the S2 versus those homozygous for the S1 allele in the APOC3 SstI site. Moreover, we did not observe any effect modification by HDL or TG levels for the associations of these APOA1 and APOC3 genotypes with MI risk. There were significant differences in TG levels among men carrying different haplotypes (P=0.01) and men carrying the X1-S2 haplotype had higher levels of TG than those carrying the X2-S1 haplotype (202 mg/dl versus 157 mg/dl, P=0.03); however, haplotype frequencies defined by these two polymorphisms did not differ significantly between cases and controls. In this prospective study of apparently healthy middle-aged US men, carriers of the X1-S2 haplotype in the APOA1 XmnI and APOC3 SstI variants across the APOA1/C3/A4 gene cluster had higher TG levels, but there was no evidence for significant associations between these two common variants or haplotypes defined by them and risk of incident MI in this cohort. Show less

As neuronal development enters its final stages, axonal growth is restricted. Recent work indicates that several myelin-derived proteins, Nogo, MAG and OMgp, play a critical role in restricting axonal growth in the mature central nervous system (CNS). These proteins function by binding to an axonal NgR protein that limits axonal growth by activating Rho in neurons. Hypoxic conditions during the later stages of neuronal development have a prominent effect on oligodendrocytes and hence on the expression of these axon growth inhibitors. Reduced expression of these proteins caused by the developmental hypoxia, or direct blockade of the myelin inhibitor pathways in the adult CNS leads to axonal sprouting and the formation of new neuronal connections. The regulation of axonal growth, sprouting and connections in the postnatal brain by myelin proteins is an area of important investigation and potential therapeutic intervention. Show less