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Biomedical subjects

L Baum

Publications and source records attributed to L Baum.

At least 19 recordsLinked to original sources
PubMed2006

Association of lipoprotein lipase S447X, apolipoprotein E exon 4, and apoC3 -455T>C polymorphisms on the susceptibility to diabetic nephropathy.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. In DN patients, triglyceride (TG) level is elevated and lipoprotein lipase (LPL) activity, which hydrolyzes TG, is decreased. The LPL S447X and apolipoprotein E (APOE) exon 4 polymorphisms affect TG levels, and the APOC3 -455T>C polymorphism affects LPL activity. Our aim was to examine the association of these polymorphisms with nephropathy in type 2 diabetes. We examined these polymorphisms in a case-control study of type 2 diabetic patients including 374 with DN and 392 without DN. LPL 447X-containing genotypes (447X+) were significantly decreased in DN patients [18.6 vs 25.6%, odds ratio (OR) = 0.66, p = 0.02], as were APOE epsilon3/epsilon3 genotypes (64.8 vs 73.1%, OR = 0.68, p = 0.01). In addition, combinations of genotypes [APOE epsilon3/epsilon3 and LPL 447X+ (OR = 0.56), APOC3 CC and LPL 447X+ (OR = 0.31), APOE epsilon3/epsilon3 and APOC3 CC (OR = 0.61] were protective for DN compared with the most common combination of the respective polymorphisms. Our findings suggest the importance of interactions among lipid genes in modulating the risk of DN.

Aged↗
PubMed2006

Apolipoprotein E epsilon4 allele is associated with the volume of white matter changes in patients with lacunar infarcts.

The relationship between the apolipoprotein E (APOE) exon 4 polymorphism and white matter changes (WMC) in elderly subjects or patients with Alzheimer's disease is controversial. To investigate this polymorphism in relation to WMC in patients with lacunar infarcts, we prospectively observed 67 patients with acute lacunar infarct and 134 age- and sex-matched controls. Genotypes were determined using a nested polymerase chain reaction. WMC were measured quantitatively and were divided into two groups, severe and mild, with the mean volume of WMC as the cut point. Twenty-two patients (33%) had severe WMC. There was a significant difference in the distribution of APOE epsilon2, epsilon3, and epsilon4 alleles between severe and mild WMC groups (P = 0.002). The frequency of epsilon4 alleles was higher in patients with severe WMC than in those with mild WMC (25% vs. 7%, P = 0.003). These results suggest that APOE epsilon4 may exacerbate WMC in patients with lacunar infarcts. Further studies are required to confirm this finding.

Aged↗
PubMed2005

Gene mutations in retinitis pigmentosa and their clinical implications.

Retinitis pigmentosa (RP) is a group of inherited progressive retinal diseases affecting about 1 in 3500 people worldwide. So far, there is no prevention or cure, with permanent visual loss or even blindness the ultimate consequence usually after midlife. The genetics of RP are complex. It can be sporadic, autosomal dominant, autosomal recessive, or X-linked. Thirty-two genes are known to be associated with RP, sometimes the same gene gets involved in different inheritance traits. Some RP cases have a digenic cause. About 60% RP cases still have no known genetic cause. A large number of mutations cause RP, and they can be deletions, insertions, or substitutions that cause missense mutations or truncations. The RHO, RP1, and RPGR genes contribute the greatest number of known mutations causative of RP. But there is no single mutation that alone accounts for more than 10% of unrelated patients. Genetic testing for RP therefore requires screening for a group of genes. High-throughput and automated sequence detection technologies are essential. Due to the complexity in phenotype and genetics, and the fact that RP is untreatable, genetic testing for presymptomatic diagnosis of RP is controversial. Meanwhile, new genes are still to be identified, mostly by family linkage and sib-pair analysis. Research on gene therapy for RP requires information on gene mutations causative of RP.

Eye Proteins↗
PubMed2003

APOA5-1131T>C polymorphism is associated with triglyceride levels in Chinese men.

A new apolipoprotein gene, APOA5, was recently discovered near the APOA1/C3/A4 gene cluster. Transgenic mice overexpressing the homologous gene, apoa5, showed reduced plasma triglyceride levels, while knockout mice had greatly increased triglycerides, suggesting that human genetic variants affecting expression of the protein product, APOAV, might affect triglyceride levels. Polymorphisms in the APOA5 gene were indeed found to be associated with triglyceride levels in men, though not in women. We sought to confirm the association of the APOA5-1131T>C polymorphism with triglyceride levels in 167 Chinese men chosen for having either high (>/=1.7 mm, n = 82) or low (</=1.2 mm, n = 85) triglycerides. More subjects with high triglycerides had one or two copies of the minor (C) allele of the polymorphism (67%) than did low triglyceride subjects (48%), and combining all subjects showed that those with one or two C alleles had higher triglyceride levels [1.67 +/- 2.20 (geometric mean +/- SD)] than those without (1.22 +/- 2.08 mm, p = 0.01), confirming the reported effect in a different ethnic group. The C allele is more common in Chinese than in Caucasians (26-40% vs. 8% of alleles), suggesting that the impact of this polymorphism on triglyceride levels in the population and therefore on public health is greater among Chinese.

Adult↗
PubMed2001

RP1 in Chinese: Eight novel variants and evidence that truncation of the extreme C-terminal does not cause retinitis pigmentosa.

Heterozygous truncating mutations in the RP1 gene cause approximately 7% of autosomal dominant retinitis pigmentosa (RP) cases. To examine the role of RP1 mutations in RP, we screened 101 unrelated Chinese RP patients (unselected for mode of inheritance) and 190 elderly normal control subjects for sequence changes in the coding exons for the 2156 amino acid RP1 protein. One patient had a mutation, thus RP1 mutations cause about 0.0% to 5.4% (95% confidence interval) of all RP among Chinese. The mutation was R677X, the most common found in Americans. Five other known sequence changes were found. In addition, nine novel sequence alterations were identified: 746G>A (R249H), 1437G>T (M479I), 2116G>C (G706R), 3024G>A (Q1008Q), 3188G>A (Q1063R), 5797C>T (R1933X), 6423A>G (I2141M), and the variants 6542C>T and 6676T>A, both in the 3' untranslated region. One control subject and three members of a non-RP family were heterozygous for R1933X, which is therefore likely to be a non-disease-causing variant. The most C-terminal truncation previously reported was due to Tyr1053 (1-bp del) and occurred in RP patients. Thus the presence of a normal level of at least part of RP1 between amino acids 1052 and 1933 appears necessary to prevent RP. Hum Mutat 17:436, 2001.

3' Untranslated Regions↗
PubMed2001

Molecular diagnostics for retinitis pigmentosa.

BACKGROUND: At least 1 million people worldwide have retinitis pigmentosa (RP), making it relatively common among the inherited forms of blindness. Mutations in many genes may cause RP. The most common known mutation, Pro347Leu in rhodopsin, is found in no more than about 1% of unrelated patients, implying the impracticality of a diagnostic test which would screen only for a few, common mutation sites. CONCLUSIONS: Ongoing discovery and study of RP genes makes it feasible to consider a molecular diagnostic test which would screen coding regions of all known RP genes by a mutation detection method such as conformation-sensitive gel electrophoresis followed by sequencing. The parallel development of RP genetic knowledge and treatments such as gene therapy will make such tests both possible and necessary.

China↗
PubMed2001

Rhodopsin mutations in Chinese patients with retinitis pigmentosa.

AIM: To determine the pattern of rhodopsin mutations in Chinese retinitis pigmentosa (RP) patients. METHODS: The rhodopsin gene was examined in 101 RP patients and 190 controls from Hong Kong. RESULTS: Three coding changes were identified: Pro347Leu, Ala299Ser, and 5211delC. Each protein sequence alteration was found in one patient. Ala299Ser also existed in two controls. CONCLUSION: The C-terminal nonsense mutation may cause mis-sorting of rhodopsin protein. The finding of controls with Ala299Ser suggests this is only the third missense alteration reported that does not cause RP. The expected frequency of rhodopsin mutations in RP is <7% (2/101=2.0%, 95% confidence interval: 0.2%-7.0%).

Adult↗
PubMed2001

High-throughput conformation-sensitive gel electrophoresis for discovery of SNPs.

High-throughput screening for single nucleotide polymorphisms (SNPs) or mutations can be achieved by inexpensive technologies. We modified the original protocols of conformation-sensitive gel electrophoresis (CSGE) to increase throughput several fold to 1.3 samples/min, which is about five times faster than denaturing high-performance liquid chromatography (DHPLC). The modifications include decreasing the gel thickness, increasing the number of lanes to 96, and increasing the number of samples per lane to seven. This high-throughput CSGE method is fast, robust, and as simple as the original protocols. Together with a two-stage strategy for screening homozygotes and the replacement of ethidium bromide with SYBR Gold DNA dye staining, this protocol is a reliable and cost-effective alternative for laboratories that require high-throughput screening.

Heterozygote↗
PubMed2000

Apolipoprotein E isoforms in Alzheimer's disease pathology and etiology.

The apolipoprotein E (apoE) epsilon4 allele increases risk of Alzheimer's disease (AD), perhaps by accelerating plaque formation, or by impairing neuron repair. Considerable evidence supports both mechanisms. AD patients with epsilon4 have more and earlier amyloid deposits than do patients without epsilon4. The same is true of non-demented control subjects. In vitro, all apoE isoforms inhibit amyloid beta protein (Abeta) aggregation, but apoE4 less effectively than apoE3. Transgenic amyloid-producing mice expressing apoE3 or apoE4 develop less Abeta deposition than apoE knockout mice. These observations are consistent with an effect of apoE isoforms on Abeta aggregation in AD. ApoE is important for neurite maintenance since apoE knockout mice lose neurites and suffer behavioral deficits with aging or treatment with excitotoxins. ApoE4 mice show similar defects, but apoE3 mice are normal. AD patients with epsilon4 show more neuritic deficits than epsilon3 carriers. ApoE epsilon4 also worsens neurological impairment in head injury, stroke, and multiple sclerosis. Thus, apoE4 is less effective at neurite maintenance. Perhaps epsilon4 increases AD risk by both mechanisms: allowing amyloid deposition and failing to repair neurites. In either case, introducing apoE3 or apoE2 into the brain, for example by gene therapy or cell grafts, might delay AD progression.

Alzheimer Disease↗
PubMed2000

Roles for lipoprotein lipase in Alzheimer's disease: an association study.

Lipoprotein lipase (LPL) assists lipid transport by transferring lipids between lipoprotein particles and cells. LPL binds apolipoprotein E (apoE) lipoprotein particles and a major apoE receptor, low density lipoprotein receptor related protein (LRP). Because apoE and LRP polymorphisms alter Alzheimer's disease (AD) risk, and LPL itself is found in AD amyloid plaques, we examined whether LPL variants also affect AD risk. In case-control studies in the United States and Canada, the frequencies of two LPL alleles known to affect LPL enzymatic activity were measured in Caucasian AD or elderly normal (N) subjects. Pathologically confirmed subjects in both studies exhibited similar trends toward fewer 447Ter and more 291Ser alleles in AD. Combining results from both countries gave allele frequencies for 447Ter of 13.7% (26/190) in N and 9.4% (80/852) in AD (P = 0.10), and for 291Ser of 0.0% (0/184) in N and 1. 3% (8/636) in AD (P = 0.21). The trend appeared even greater for homozygous 447Ter subjects: 4.2% (4/95) of N vs. 1.4% (6/426) of AD (P = 0.09). These trends are consistent with a putative protective effect of 447Ter and causative effect of 291Ser on AD. Furthermore, brains of AD patients with 447Ter showed trends toward fewer plaques, tangles, and glia, and more neurons and cortical thickness than AD patients without 447Ter. Hippocampal plaques were significantly reduced. LPL might affect hippocampal function and thus dementia via its role as supplier of membrane components or antioxidants to neurons. Alternatively, LPL may play a part in plaque formation through its interaction with apoE and LRP.

Aged↗
PubMed2000

Absence of trabecular meshwork-inducible stretch response (TISR)/oculomedin gene and proximal promoter mutation in primary open angle glaucoma patients.

We investigated the coding exon and promoter sequence in the trabecular meshwork-inducible stretch response (TISR)/oculomedin gene for mutations in Chinese primary open angle glaucoma (POAG) subjects. The entire TISR/oculomedin coding sequence, together with 138 bp of promoter sequence 5' to the start codon and 170 bp of the 3' untranslated region in 110 Chinese POAG patients and 108 unrelated control subjects without glaucoma, aged 50 years or above, were screened for alterations by DNA sequencing. One heterozygous sequence alteration, K28E, was identified in one control subject, and two homozygous sequence alterations, K28K and 135+36delC, were universally found in every sample. As a result, no common TISR/ oculomedin coding sequence nor any proximal promoter mutation that causes POAG was found. The effect of TISR/ oculomedin in glaucoma has yet to be established.

Adolescent↗
PubMed2000

Compound heterozygosity of Leu252Val and Leu252Arg causing lipoprotein lipase deficiency in a chinese patient with hypertriglyceridemia.

BACKGROUND: We investigated lipoprotein lipase (LPL) gene mutations in a Chinese male with severe hypertriglyceridemia and recurrent pancreatitis. METHODS: We screened for LPL sequence mutation in the LPL gene in this patient, his relatives and 160 unrelated hypertriglyceridaemic subjects. We determined the postheparin plasma LPL activity of subjects carrying a LPL mutation and studied the in vitro expression of mutant LPL in COS-1 cells. RESULTS: The proband was found to be a compound heterozygote for a novel Leu252Val and a reported Leu252Arg mutation in the LPL gene. He had low plasma levels of postheparin LPL activity and mass. The two mutations segregated independently in his family. In vitro expression analysis showed that Leu252Arg abolished both the catalytic function and secretion of LPL, while Leu252Val abolished the catalytic function but only reduced secretion by about half. We have also detected heterozygous Leu252Val and Leu252Arg mutations each in one hypertriglyceridaemic individual. CONCLUSION: These results indicated that the leucine 252 is critical for the catalytic activity and secretion of LPL. Why the substitution by valine instead of arginine resulted only in a partial suppression of LPL secretion, remains to be investigated. Leu252Val and Leu252Arg are the likely cause of hypertriglyceridemia in these subjects because of their deleterious effects on LPL activity or secretion. Leu252Val/Leu252Arg is the first compound heterozygous mutation known to occur in the same codon of the LPL gene. So far they are found only in Chinese.

Adolescent↗
PubMed2000

The apolipoprotein E epsilon4 allele is unlikely to be a major risk factor of age-related macular degeneration in Chinese.

Apolipoprotein E (ApoE) is a major transporter of lipids and cholesterol in the nervous system. Age-related macular degeneration (ARMD), characterized by drusen containing lipids, was reported to show a lower frequency of the ApoE epsilon4 allele than control subjects. We sought to examine the association of this polymorphism with ARMD in Hong Kong Chinese. Among 98 ARMD subjects, the frequency of epsilon4 carriers showed a trend toward a decrease compared to controls, but it was not significant (11.2 vs. 15.0%, p < 0.52). The association of epsilon4 with an apparent reduced risk of ARMD was reported previously in the exudative form of the disease, however among 39 exudative ARMD patients there was also no significant difference in epsilon4 frequency (12.8%, p < 0.93). The lack of a statistically significant effect of epsilon4 may be due to the lower frequency of epsilon4 in Chinese than Europeans. Thus we cannot exclude a possible effect of this allele on ARMD risk, but we can conclude that this allele is likely not a major factor influencing ARMD risk in the Chinese.

Adult↗
PubMed2000

Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway.

Susceptibility to Alzheimer's disease (AD) is governed by multiple genetic factors. Remarkably, the LDL receptor-related protein (LRP) and its ligands, apoE and alpha2M, are all genetically associated with AD. In this study, we provide evidence for the involvement of the LRP pathway in amyloid deposition through sequestration and removal of soluble amyloid beta-protein (Abeta). We demonstrate in vitro that LRP mediates the clearance of both Abeta40 and Abeta42 through a bona fide receptor-mediated uptake mechanism. In vivo, reduced LRP expression is associated with LRP genotypes and is correlated with enhanced soluble Abeta levels and amyloid deposition. Although LRP has been proposed to be a clearance pathway for Abeta, this work provides the first in vivo evidence that the LRP pathway may modulate Abeta deposition and AD susceptibility by regulating the removal of soluble Abeta.

Adult↗
PubMed2000

Hunting for disease genes in multi-functional diseases.

Disease genes may be identified through functional, positional, and candidate gene approaches. Although extensive and often labor-intensive studies such as family linkage analysis, functional investigation of gene products and genome database searches are usually involved, thousands of human disease genes, especially for monogenic diseases with Mendelian transmission, have been identified. However, in diseases caused by more than one gene, or by a combination of genetic and environmental factors, identification of the genes is even more difficult. Common examples include atherosclerosis, cancer, Alzheimer's disease, asthma, diabetes, glaucoma, and age-related macular degeneration. There have been conflicting reports on the roles of associated genes. Even with population-based case-control studies and new statistical methods such as the sib-ship disequilibrium test and the discordant alleles test, there is no agreement on whether alpha2-macroglobulin (A2M) is a gene for Alzheimer's disease. Another example is the inconsistent association between age-related macular degeneration and ATP-binding cassette transporter (ABCR). Ethnic variation causes further complications. In our investigation of LDL-receptor variants in familial hypercholesterolemia, and the trabecular meshwork inducible glucocorticoid response protein, or myocillin (TIGR-MYOC) mutation pattern in primary open angle glaucoma, we did find dissimilar results in Chinese compared to Caucasians. New information from the Human Genome Project and advancements in technologies will aid the search for and confirm identification of disease genes despite such challenges.

ATP-Binding Cassette Transporters↗