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Biomedical subjects

Arno G Motulsky

Publications and source records attributed to Arno G Motulsky.

13 recordsLinked to original sources
PubMed2006

Genetics of complex diseases.

Approaches to the study of the genetic basis of common complex diseases and their clinical applications are considered. Monogenic Mendelian inheritance in such conditions is infrequent but its elucidation may help to detect pathogenic mechanisms in the more common variety of complex diseases. Involvement by multiple genes in complex diseases usually occurs but the isolation and identification of specific genes so far has been exceptional. The role of common polymorphisms as indicators of disease risk in various studies is discussed.

Genetic Diseases, Inborn↗
PubMed2006

Pharmacogenetics, pharmacogenomics and ecogenetics.

Pharmacogenetics and pharmacogenomics deal with the role of genetic factors in drug effectiveness and adverse drug reactions. The promise of a personalized medicine is beginning to be explored but requires much more clinical and translational research. Specific DNA abnormalities in some cancers already have led to effective targeted treatments. Racially determined frequency differences in pharmacogenetic traits may affect choice of treatment requiring specific testing rather than basing treatments according to racial designation. The role of genes in variable responses to foreign chemicals (xenobiotics) has been termed ecogenetics or toxicogenetics raising problems in public health and occupational medicine. Nutrigenetics refers to genetic variation in response to nutrients and may affect nutritional requirements and predisposition to chronic disease.

DNA↗
PubMed2005

Genome scan for quantitative trait loci influencing HDL levels: evidence for multilocus inheritance in familial combined hyperlipidemia.

Several genome scans in search of high-density lipoprotein (HDL) quantitative trait loci (QTLs) have been performed. However, to date the actual identification of genes implicated in the regulation of common forms of HDL abnormalities remains unsuccessful. This may be due, in part, to the oligogenic and multivariate nature of HDL regulation, and potentially, pleiotropy affecting HDL and other lipid-related traits. Using a Bayesian Markov Chain Monte Carlo (MCMC) approach, we recently provided evidence of linkage of HDL level variation to the APOA1-C3-A4-A5 gene complex, in familial combined hyperlipidemia pedigrees, with an estimated number of two to three large QTLs remaining to be identified. We also presented results consistent with pleiotropy affecting HDL and triglycerides at the APOA1-C3-A4-A5 gene complex. Here we use the same MCMC analytic strategy, which allows for oligogenic trait models, as well as simultaneous incorporation of covariates, in the context of multipoint analysis. We now present results from a genome scan in search for the additional HDL QTLs in these pedigrees. We provide evidence of linkage for additional HDL QTLs on chromosomes 3p14 and 13q32, with results on chromosome 3 further supported by maximum parametric and variance component LOD scores of 3.0 and 2.6, respectively. Weaker evidence of linkage was also obtained for 7q32, 12q12, 14q31-32 and 16q23-24.

Adolescent↗
PubMed2005

Priorities and standards in pharmacogenetic research.

The current enthusiasm for pharmacogenetics draws much of its inspiration from the relatively few examples of polymorphisms that have marked and seemingly clinically relevant effects on drug response. In this regard, pharmacogenetic research has paralleled the study of human disease, which has enjoyed success in identifying mutations underlying mendelian conditions. Progress in deciphering the genetics of complex diseases, involving the interaction of multiple genes with each other and with the environment has been considerably less successful. In most instances, drug responses will probably also prove to be complex, influenced by both the environment and multiple genetic factors. For pharmacogenetics to deliver on its potential, this complexity will need to be recognized and accommodated, both in basic research and in clinical application of pharmacogenetics. As the attention of researchers begins to shift toward more systematic pharmacogenetic investigations, we suggest some priorities and standards for pharmacogenetic research.

Drug Design↗
PubMed2004

Low-density lipoprotein particle size loci in familial combined hyperlipidemia: evidence for multiple loci from a genome scan.

OBJECTIVE: Low-density lipoprotein (LDL) size is associated with vascular disease and with familial combined hyperlipidemia (FCHL). METHODS AND RESULTS: We used logarithm of odds (lod) score and Bayesian Markov chain Monte Carlo (MCMC) linkage analysis methods to perform a 10-cM genome scan of LDL size, measured as peak particle diameter (PPD) and adjusted for age, sex, body mass index, and triglycerides in 4 large families with FCHL (n=185). We identified significant evidence of linkage to a chromosome 9p locus (multipoint lod(max)=3.70; MCMC intensity ratio [IR]=21) in a single family, and across all 4 families to chromosomes 16q23 (lod(max)=3.00; IR=43) near cholesteryl ester transfer protein (CETP) and to 11q22 (lod(max)=3.71; IR=120). Chromosome 14q24-31, a region with previous suggestive LDL PPD linkage evidence, yielded an IR of 71 but an lod(max)=1.79 in the combined families. CONCLUSIONS: These results of significant evidence of linkage to 3 regions (9p, 16q, and 11q) and confirmatory support of previous reported linkage to 14q in large FCHL pedigrees demonstrate that LDL size is a trait influenced by multiple loci and illustrate the complementary use of lod score and MCMC methods in analysis of a complex trait.

Adult↗
PubMed2004

X-linked high myopia associated with cone dysfunction.

OBJECTIVE: Bornholm eye disease (BED) consists of X-linked high myopia, high cylinder, optic nerve hypoplasia, reduced electroretinographic flicker with abnormal photopic responses, and deuteranopia. The disease maps to chromosome Xq28 and is the first designated high-grade myopia locus (MYP1). We studied a second family from Minnesota with a similar X-linked phenotype, also of Danish descent. All affected males had protanopia instead of deuteranopia. METHODS: X chromosome genotyping, fine-point mapping, and haplotype analysis of the DNA from 22 Minnesota family individuals (8 affected males and 5 carrier females) and 6 members of the original family with BED were performed. Haplotype comparisons and mutation screening of the red-green cone pigment gene array were performed on DNA from both kindreds. RESULTS: Significant maximum logarithm of odds scores of 3.38 and 3.11 at theta = 0.0 were obtained with polymorphic microsatellite markers DXS8106 and DXYS154, respectively, in the Minnesota family. Haplotype analysis defined an interval of 34.4 cM at chromosome Xq27.3-Xq28. Affected males had a red-green pigment hybrid gene consistent with protanopia. We genotyped Xq27-28 polymorphic markers of the family with BED, and narrowed the critical interval to 6.8 cM. The haplotypes of the affected individuals were different from those of the Minnesota pedigree. Bornholm eye disease-affected individuals showed the presence of a green-red hybrid gene consistent with deuteranopia. CONCLUSIONS: Because of the close geographic origin of the 2 families, we expected affected individuals to have the same haplotype in the vicinity of the same mutation. Mapping studies, however, suggested independent mutations of the same gene. The red-green and green-red hybrid genes are common X-linked color vision defects, and thus are unrelated to the high myopia and other eye abnormalities in these 2 families. CLINICAL RELEVANCE: X-linked high myopia with possible cone dysfunction has been mapped to chromosome Xq28 with intervals of 34.4 and 6.8 centimorgan for 2 families of Danish origin.

Adolescent↗
PubMed2003

Evidence of linkage of HDL level variation to APOC3 in two samples with different ascertainment.

The APOA1-C3-A4-A5 gene complex encodes genes whose products are implicated in the metabolism of HDL and/or triglycerides. Although the relationship between polymorphisms in this gene cluster and dyslipidemias was first reported more than 15 years ago, association and linkage results have remained inconclusive. This is due, in part, to the oligogenic and multivariate nature of dyslipidemic phenotypes. Therefore, we investigate evidence of linkage of APOC3 and HDL using two samples of dyslipidemic pedigrees: familial combined hyperlipidemia (FCHL) and isolated low-HDL (ILHDL). We used a strategy that deals with several difficulties inherent in the study of complex traits: by using a Bayesian Markov Chain Monte Carlo (MCMC) approach we allow for oligogenic trait models, as well as simultaneous incorporation of covariates, in the context of multipoint analysis. By using this approach on extended pedigrees we provide evidence of linkage of APOC3 and HDL level variation in two samples with different ascertainment. In addition to APOC3, we estimate that two to three genes, each with a substantial effect on total variance, are responsible for HDL variation in both data sets. We also provide evidence, using the FCHL data set, for a pleiotropic effect between HDL, HDL3 and triglycerides at the APOC3 locus.

Apolipoproteins C↗
PubMed2003

Genome-wide scan for quantitative trait loci influencing LDL size and plasma triglyceride in familial hypertriglyceridemia.

Small, dense LDLs and hypertriglyceridemia, two highly correlated and genetically influenced risk factors, are known to predict for risk of coronary heart disease. The objective of this study was to perform a whole-genome scan for linkage to LDL size and triglyceride (TG) levels in 26 kindreds with familial hypertriglyceridemia (FHTG). LDL size was estimated using gradient gel electrophoresis, and genotyping was performed for 355 autosomal markers with an average heterozygosity of 76% and an average spacing of 10.2 centimorgans (cMs). Using variance components linkage analysis, one possible linkage was found for LDL size [logarithm of odds (LOD) = 2.1] on chromosome 6, peak at 140 cM distal to marker F13A1 (closest marker D6S2436). With adjustment for TG and/or HDL cholesterol, the LOD scores were reduced, but remained in exactly the same location. For TG, LOD scores of 2.56 and 2.44 were observed at two locations on chromosome 15, with peaks at 29 and 61 cM distal to marker D15S822 (closest markers D15S643 and D15S211, respectively). These peaks were retained with adjustment for LDL size and/or HDL cholesterol. These findings, if confirmed, suggest that LDL particle size and plasma TG levels could be caused by two different genetic loci in FHTG.

Apolipoproteins↗
PubMed2003

Small, dense LDL and elevated apolipoprotein B are the common characteristics for the three major lipid phenotypes of familial combined hyperlipidemia.

OBJECTIVE: Familial combined hyperlipidemia (FCHL) is associated with variable lipid and lipoprotein phenotypes arbitrarily defined as type IIa, IIb, and IV based on plasma total cholesterol and triglyceride levels. This study sought to characterize consistent lipoprotein and lipid abnormalities across the 3 lipoprotein phenotypes in 62 patients with documented FCHL (IIa [n=14], IIb [n=19], and IV [n=29]) and 44 healthy individuals. METHODS AND RESULTS: The lipoprotein cholesterol distribution was determined over 38 fractions obtained by density gradient ultracentrifugation. As expected, FCHL patients with hypertriglyceridemia (IIb and IV) had higher cholesterol levels in VLDL than IIa, whereas IIa showed higher cholesterol in the big, buoyant LDL and in HDL. LDL cholesterol was higher in IIb than IV; most of the increase in LDL cholesterol was associated with big, buoyant LDL rather than small, dense LDL (sdLDL). The differences in lipoproteins between phenotypes were attributable to changes in VLDL and big, buoyant LDL levels. Comparison of the FCHL patients with healthy individuals showed a significant elevation in plasma apolipoprotein B levels and sdLDL in all 3 FCHL phenotypes. CONCLUSIONS: Although triglyceride and cholesterol levels are variable by lipoprotein phenotype, sdLDL and elevated plasma apolipoprotein B levels are consistent characteristics of FCHL shared by the 3 different lipoprotein phenotypes.

Adult↗
PubMed2002

From pharmacogenetics and ecogenetics to pharmacogenomics.

The origin and development of pharmacogenetics are traced with emphasis on early hints by Garrod, Haldane, and later by RJ Williams. The field was delineated by Motulsky in 1957 and described as pharmacogenetics by Vogel in 1959. Kalow's monograph (1962) definitely established the discipline. Resemblance of identical twins in drug metabolism as compared with non identical twins (Vesell, 1970's) established the general importance of polygenic inheritance in disposal of many drugs. Ecogenetics was defined by Brewer in 1971 as dealing with genetic variation affecting the response to any environmental agents with emphasis on xenobiotics. More recent developments have broadened pharmacogenetic approaches to include novel genomic techniques with introduction of the term pharmacogenomics in the 1990's. Genetic and genomic approaches (toxicogenetics and toxicogenomics) are also being applied in the "environmental genome project". The interaction of genetic variation with dietary factors led to the field of Nutritional ecogenetics (Nutrigenomics) which relates the role of genetics to nutritional requirements and nutrition-mediated susceptibility to chronic disease. The total promise of pharmacogenomics is often overstated. The field is likely to have an impact on choice of drug therapy and avoidance of adverse events but is unlikely to lead to a revolution in therapeutics. Aspects of pharmacogenomic approaches and its applications including problems of premature commercialization are discussed.

Genetics↗