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Biomedical subjects

Klaus Lindpaintner

Publications and source records attributed to Klaus Lindpaintner.

14 recordsLinked to original sources
PubMed2003

A genome-wide search for genes affecting circulating fibrinogen levels in the Framingham Heart Study.

INTRODUCTION: Circulating levels of fibrinogen are associated with atherosclerosis and predict future coronary heart disease and stroke. Levels of fibrinogen are correlated among family members, suggesting a heritable component. Variants of the beta-fibrinogen gene subunit on 4q28 are associated with fibrinogen levels but explain only a small proportion of the total genetic variability. It remains unknown what role, if any, is played by other genetic variants in the inter-individual variability in levels of fibrinogen in the general population. MATERIALS AND METHODS: We conducted a 10-cM spaced genome-wide scan using 402 original cohort subjects and 1193 offspring subjects from 330 extended families of the Framingham Heart Study. Heritability and linkage analyses were carried out using variance component methods. Regression analyses were performed to adjust for traditional risk factors and HindIII beta-148 genotypes. RESULTS AND DISCUSSIONS: The total heritability was estimated as 0.24. The highest and second highest LOD scores of linkage were found on chromosomes 2 (LOD=1.5 at 243 cM) and 10 (LOD=2.4 at 87 cM) using only offspring subjects in the analysis, and on chromosomes 2 (LOD=2.1 at 242 cM) and 10(LOD=1.4 at 86 cM), 17 (LOD=1.4 at 96 cM) and 20 (LOD=1.4 at 80 cM) using both original cohort and offspring. These results suggest that there may be influential genetic regions on these chromosomes. While no linkage with genome-wide significance was detected, further research to confirm our findings is warranted.

Adult↗
PubMed2003

Alanine for proline substitution in the peroxisome proliferator-activated receptor gamma-2 (PPARG2) gene and the risk of incident myocardial infarction.

OBJECTIVE: Recent studies have implicated the potential importance of peroxisome proliferator-activated receptors as a molecular mechanism involved in atherothrombosis. A common alanine (A) for proline (P) substitution at codon 12 in the peroxisome proliferator activated receptor gamma-2 gene (PPARG2) has been associated with reduced risk of developing type 2 diabetes mellitus. Because diabetes and atherothrombosis share common antecedents, we sought evidence that this polymorphism might also be associated with reduced risk of myocardial infarction. METHODS AND RESULTS: Using DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we evaluated a P12A polymorphism in the PPARG2 among 523 individuals who subsequently developed myocardial infarction and among 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. As hypothesized, presence of the A12 allele was associated with significantly reduced risk of myocardial infarction (odds ratio in an age- and smoking-adjusted dominant model of inheritance, 0.77; 95% CI, 0.60 to 0.98; P=0.034). This protective effect remained statistically significant in analyses controlling for traditional cardiovascular risk factors, was present among nondiabetic study participants, was observed to be of similar magnitude in analyses assuming codominant or dominant modes of inheritance, and was seen in fully adjusted post hoc analyses in which we limited our control group to those individuals specifically matched to myocardial infarction cases (OR, 0.71; 95% CI, 0.53 to 0.96; P=0.024). CONCLUSIONS: In this cohort, a common A for P substitution at codon 12 in the PPARG2 was associated with reduced incidence of myocardial infarction. If confirmed in other cohorts, these data would have implications for novel treatments of cardiovascular disease, including development of PPARG-targeted therapy.

Adult↗
PubMed2003

Pharmacogenetics and the future of medical practice.

Pharmacogenetics is today widely proclaimed to be about to revolutionize the face of medicine. In a more realistic assessment, the implementation of molecular genetics and biology will continue to provide us, as it has done already, with better ways to diagnose and treat illnesses, but it will do so at a stepwise and evolutionary pace, based on an improved understanding of the nature of disease, allowing more specific treatments, better risk prediction, and the implementation of preventive strategies. As such, future progress in biomedicine will travel the same well-trodden paths of improved differential diagnosis and risk prediction along which it has advanced in the past decades and centuries. Thus, while meaningful biomedical research today by and large depends on the use of the newly developed tools of genetics and genomics and the insights that we gain through them, it is unlikely fundamentally to change the direction of medical progress.

Clinical Medicine↗
PubMed2003

Statistical methods for analyzing microarray feature data with replications.

Expression levels in oligonucleotide microarray experiments depend on a potentially large number of factors, for example, treatment conditions, different probes, different arrays, and so on. To dissect the effects of these factors on expression levels, fixed-effects ANOVA methods have previously been proposed. Because we are not necessarily interested in estimating the specific effects of different probes and arrays, we propose to treat these as random effects. Then we only need to estimate their means and variances but not the effect of each of their levels; that is, we can work with a much reduced number of parameters and, consequently, higher precision for estimating expression levels. Thus, we developed a mixed-effects ANOVA model with some random and some fixed effects. It automatically accounts for local normalization between different arrays and for background correction. The method was applied to each of the 6,584 genes investigated in a microarray experiment on two mouse cell lines, PA6/S and PA6/8, where PA6/S enhances proliferation of Pre B cells in vitro but PA6/8 does not. To detect a set of differentially expressed genes (multiple testing problem), we applied the method of controlling the false discovery rate (FDR), which successfully identified 207 genes with significantly different expression levels.

Algorithms↗
PubMed2003

Pharmacogenetics and pharmacogenomics in drug discovery and development: an overview.

Pharmacogenetics is today widely proclaimed as about to revolutionize the face of medicine. In a more realistic assessment, the implementation of molecular genetics and biology will continue to provide us, as it has done already, with better ways to diagnose and treat diseases, but it will do so at a stepwise and evolutionary pace, based on an improved understanding of the nature of disease, allowing more specific treatments, better risk prediction, and the implementation of preventive strategies. As such, future progress in biomedicine will travel the same well-treaded paths of improved differential diagnosis and risk prediction along which it has advanced for the last decades and centuries. So, while meaningful biomedical research today by and large depends on the use of the newly developed tools of genetics and genomics, and the insights we gain through them, it is unlikely to fundamentally change the direction of medical progress.

Drug Design↗
PubMed2002

Efficacy of SSH PCR in isolating differentially expressed genes.

BACKGROUND: Suppression Subtractive Hybridization PCR (SSH PCR) is a sophisticated cDNA subtraction method to enrich and isolate differentially expressed genes. Despite its popularity, the method has not been thoroughly studied for its practical efficacy and potential limitations. RESULTS: To determine the factors that influence the efficacy of SSH PCR, a theoretical model, under the assumption that cDNA hybridization follows the ideal second kinetic order, is proposed. The theoretical model suggests that the critical factor influencing the efficacy of SSH PCR is the concentration ratio (R) of a target gene between two cDNA preparations. It preferentially enriches "all or nothing" differentially expressed genes, of which R is infinite, and strongly favors the genes with large R. The theoretical predictions were validated by our experiments. In addition, the experiments revealed some practical limitations that are not obvious from the theoretical model. For effective enrichment of differentially expressed genes, it requires fractional concentration of a target gene to be more than 0.01% and concentration ratio to be more than 5 folds between two cDNA preparations. CONCLUSION: Our research demonstrated theoretical and practical limitations of SSH PCR, which could be useful for its experimental design and interpretation.

Journal Article↗
PubMed2002

Localization of a gene for peripheral arterial occlusive disease to chromosome 1p31.

Peripheral arterial occlusive disease (PAOD) results from atherosclerosis of large and medium peripheral arteries, as well as the aorta, and has many risk factors, including smoking, diabetes, hypertension, and hyperlipidemia. PAOD often coexists with coronary artery disease and cerebrovascular disease. Cross-matching a population-based list of Icelandic patients with PAOD who had undergone angiography and/or revascularization procedures with a genealogy database of the entire Icelandic nation defined 116 extended families containing 272 patients. A genomewide scan with microsatellite markers revealed significant linkage to chromosome 1p31 with an allele-sharing LOD score of 3.93 (P=1.04 x 10(-5)). We designate this locus as "PAOD1." Subtracting 35 patients with a history of stroke increased the LOD score to 4.93. This suggests that, although PAOD and other vascular diseases share risk factors, genetic factors specific to subtypes of vascular disease may exist.

Arterial Occlusive Diseases↗
PubMed2002

Localization of a susceptibility gene for common forms of stroke to 5q12.

Stroke is one of the most complex diseases, with several subtypes, as well as secondary risk factors, such as hypertension, hyperlipidemia, and diabetes, which, in turn, have genetic and environmental risk factors of their own. Here, we report the results of a genomewide search for susceptibility genes for the common forms of stroke. We cross-matched a population-based list of patients with stroke in Iceland with an extensive computerized genealogy database clustering 476 patients with stroke within 179 extended pedigrees. Linkage to 5q12 was detected, and the LOD score at this locus meets the criteria for genomewide significance (multipoint allele-sharing LOD score of 4.40, P=3.9 x 10(-6)). A 20-cM region on 5q was physically and genetically mapped to obtain accurate marker order and intermarker distances. This locus on 5q12, which we have designated as "STRK1," does not correspond to known susceptibility loci for stroke or for its risk factors and represents the first mapping of a locus for common stroke.

Alleles↗
PubMed2002

A prospective study of TaqIB polymorphism in the gene coding for cholesteryl ester transfer protein and risk of myocardial infarction in middle-aged men.

BACKGROUND: Molecular variations in the gene coding for the cholesteryl ester transfer protein (CETP) such as the TaqIB polymorphism are associated with higher plasma high-density lipoprotein (HDL) concentration. However, whether this polymorphism is associated with risk of myocardial infarction (MI) is uncertain. METHODS AND RESULTS: In a prospective cohort of 14916 apparently healthy men enrolled in the Physicians' Health Study, allelic status for the TaqIB polymorphism in the CETP gene was determined among 384 participants who subsequently developed a first MI (cases) and among an equal number of age and smoking-matched participants who remained free of cardiovascular disease during follow-up (controls). Overall, the B2B2 genotype was present in 17% of the study participants and was associated with higher HDL cholesterol levels (mean mg/dl [+/- S.D.], 45 +/- 11 for the B1B1 genotype, 48 +/- 13 for the B1B2 genotype and 50 +/- 12 for the B2B2 genotype; P=0.01). However, the risk of developing MI did not differ significantly across these three genotypes. After adjustment for coronary risk factors (but not HDL), the relative risks for future MI were 1.12(95% CI 0.74-1.70) for the B1B2 genotype and 0.95(95% CI 0.54-1.66) for the B2B2 genotype, compared with the B1B1 genotype. In subgroup analysis of individuals with low HDL levels, B2B2 genotype appeared to have a lower risk of MI compared with the B1B1 genotype. However, participants with high HDL were at lower risk of developing MI regardless of their CETP genotype. CONCLUSIONS: In this prospective study of apparently healthy middle-aged US men, carriers of the B2 allele of the TaqIB in the CETP gene had higher HDL concentrations, but did not have lower risk of MI. CONDENSED ABSTRACT: In a cohort of apparently healthy middle-aged US men, the relation between CETP genotype and MI risk was prospectively examined in a nested case-control study. After adjusting for coronary risk factors (but not HDL), the 9-year risk of developing MI did not differ significantly by genotype. Comparing to the B1B1 genotype, the relative risks for future MI were 1.12 (95% CI 0.74-1.70) for the B1B2 genotype and 0.95 (95% CI 0.54-1.66) for the B2B2 genotype.

Carrier Proteins↗
PubMed2002

The impact of pharmacogenetics and pharmacogenomics on drug discovery.

It is widely perceived at present that pharmacogenetics and pharmacogenomics are about to revolutionize the face of medicine. In a more realistic assessment, the implementation of molecular genetics and biology will provide us with better ways to treat illnesses, and has already begun to do so in an incremental and evolutionary fashion. However, it is unlikely to change fundamentally the direction of medical progress. Advances are most likely to be made in the area of pharmacodynamics, as we learn to differentiate broader conventional clinical diagnoses into separate molecular subtypes.

Gene Expression↗
PubMed2002

Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity.

A retrospective pharmacogenetic study was conducted to identify possible genetic susceptibility factors in patients in whom the administration of the anti-Parkinson drug, tolcapone (TASMAR), was associated with hepatic toxicity. We studied 135 cases of patients with elevated liver transaminase levels (ELT) of >/=1.5 times above the upper limit of normal, in comparison with matched controls that had also received the drug but had not experienced ELT. DNA samples were genotyped for 30 previously described or newly characterized bi-allelic single nucleotide polymorphisms (SNPs), representing 12 candidate genes selected based on the known metabolic pathways involved in the tolcapone elimination. SNPs located within the UDP-glucuronosyl transferase 1A gene complex, which codes for the enzymes involved in the main elimination pathway of the drug, were found to be significantly associated with the occurrence of tolcapone-associated ELTs.

Benzophenones↗
PubMed2002

Pharmacogenetics and the future of medical practice.

Pharmacogenetic approaches are widely expected to bring about a "revolution" in medicine. While the application of molecular genetic approaches to disease research will provide us with new opportunities for progressively more targeted and, hopefully, more effective treatments, these developments will be evolutionary in nature and will, for their realization, still require the painstaking process that discovering and developing a new drug entails. It is also quintessential for the realization of these promises that we support a more rational understanding and more realistic expectations in the public at large through dialogue and information.

Drug Design↗
PubMed2002

Pharmacogenetics and the future of medical practice.

Pharmacogenetics, in the different scenarios included in this term, will represent an important new avenue towards understanding disease pathology and drug action, and will offer new opportunities of stratifying patients to achieve optimal treatment success. As such, it represents a logical, consequent step in the history of medicine--evolution, rather than revolution. Its implementation will take time, and will not apply to all diseases and all treatments equally. If society finds ways to sanction the proper use of this information, thus allowing and protecting its unencumbered use for the patient's benefit, important progress in health care will be made.

Delivery of Health Care↗