Comparison of linkage-disequilibrium methods for localization of genes influencing quantitative traits in humans.
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Linkage disequilibrium has been used to help in the identification of genes predisposing to certain qualitative diseases. Although several linkage-disequilibrium tests have been developed for localization of genes influencing quantitative traits, these tests have not been thoroughly compared with one another. In this report we compare, under a variety of conditions, several different linkage-disequilibrium tests for identification of loci affecting quantitative traits. These tests use either single individuals or parent-child trios. When we compared tests with equal samples, we found that the truncated measured allele (TMA) test was the most powerful. The trait allele frequencies, the stringency of sample ascertainment, the number of marker alleles, and the linked genetic variance affected the power, but the presence of polygenes did not. When there were more than two trait alleles at a locus in the population, power to detect disequilibrium was greatly diminished. The presence of unlinked disequilibrium (D'*) increased the false-positive error rates of disequilibrium tests involving single individuals but did not affect the error rates of tests using family trios. The increase in error rates was affected by the stringency of selection, the trait allele frequency, and the linked genetic variance but not by polygenic factors. In an equilibrium population, the TMA test is most powerful, but, when adjusted for the presence of admixture, Allison test 3 becomes the most powerful whenever D'*>.15. (+info)
Synergistic effects of prothrombotic polymorphisms and atherogenic factors on the risk of myocardial infarction in young males.
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Several recent studies evaluated a possible effect of the prothrombotic polymorphisms such as 5,10 methylenetetrahydrofolate reductase (MTHFR) nt 677C --> T, factor V (F V) nt 1691G --> A (F V Leiden), and factor II (F II) nt 20210 G --> A on the risk of myocardial infarction. In the present study, we analyzed the effect of these prothrombotic polymorphisms, as well as apolipoprotein (Apo) E4, smoking, hypertension, diabetes mellitus, and hypercholesterolemia, on the risk of myocardial infarction in young males. We conducted a case-control study of 112 young males with first acute myocardial infarction (AMI) before the age of 52 and 187 healthy controls of similar age. The prevalences of heterozygotes for F V G1691A and F II G20210A were not significantly different between cases and controls (6.3% v 6.4% and 5.9% v 3.4% among cases and controls, respectively). In contrast, the prevalence of MTHFR 677T homozygosity and the allele frequency of Apo E4 were significantly higher among patients (24.1% v 10.7% and 9.4% v 5.3% among cases and controls, respectively). Concomitant presence of hypertension, hypercholesterolemia, or diabetes and one or more of the four examined polymorphisms increased the risk by almost ninefold (odds ratio [OR] = 8.66; 95% confidence interval [CI], 3.49 to 21.5) and concomitant smoking by almost 18-fold (OR = 17.6; 95% CI, 6.30 to 48.9). When all atherogenic risk factors were analyzed simultaneously by a logistic model, the combination of prothrombotic and Apo E4 polymorphisms with current smoking increased the risk 25-fold (OR = 24.7; 95% CI, 7.17 to 84.9). The presented data suggest a synergistic effect between atherogenic and thrombogenic risk factors in the pathogenesis of AMI, as was recently found in a similar cohort of women. (+info)
Thrombophilia as a multigenic disease.
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BACKGROUND AND OBJECTIVE: Venous thrombosis is a common disease annually affecting 1 in 1000 individuals. The multifactorial nature of the disease is illustrated by the frequent identification of one or more predisposing genetic and/or environmental risk factors in thrombosis patients. Most of the genetic defects known today affect the function of the natural anticoagulant pathways and in particular the protein C system. This presentation focuses on the importance of the genetic factors in the pathogenesis of inherited thrombophilia with particular emphasis on those defects which affect the protein C system. INFORMATION SOURCES: Published results in articles covered by the Medline database have been integrated with our original studies in the field of thrombophilia. STATE OF THE ART AND PERSPECTIVES: The risk of venous thrombosis is increased when the hemostatic balance between pro- and anti-coagulant forces is shifted in favor of coagulation. When this is caused by an inherited defect, the resulting hypercoagulable state is a lifelong risk factor for thrombosis. Resistance to activated protein C (APC resistance) is the most common inherited hypercoagulable state found to be associated with venous thrombosis. It is caused by a single point mutation in the factor V (FV) gene, which predicts the substitution of Arg506 with a Gln. Arg506 is one of three APC-cleavage sites and the mutation results in the loss of this APC-cleavage site. The mutation is only found in Caucasians but the prevalence of the mutant FV allele (FV:Q506) varies between countries. It is found to be highly prevalent (up to 15%) in Scandinavian populations, in areas with high incidence of thrombosis. FV:Q506 is associated with a 5-10-fold increased risk of thrombosis and is found in 20-60% of Caucasian patients with thrombosis. The second most common inherited risk factor for thrombosis is a point mutation (G20210A) in the 3' untranslated region of the prothrombin gene. This mutation is present in approximately 2% of healthy individuals and in 6-7% of thrombosis patients, suggesting it to be a mild risk factor of thrombosis. Other less common genetic risk factors for thrombosis are the deficiencies of natural anticoagulant proteins such as antithrombin, protein C or protein S. Such defects are present in less than 1% of healthy individuals and together they account for 5-10% of genetic defects found in patients with venous thrombosis. Owing to the high prevalence of inherited APC resistance (FV:Q506) and of the G20210A mutation in the prothrombin gene, combinations of genetic defects are relatively common in the general population. As each genetic defect is an independent risk factor for thrombosis, individuals with multiple defects have a highly increased risk of thrombosis. As a consequence, multiple defects are often found in patients with thrombosis. (+info)
High polymorphism at the human melanocortin 1 receptor locus.
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Variation in human skin/hair pigmentation is due to varied amounts of eumelanin (brown/black melanins) and phaeomelanin (red/yellow melanins) produced by the melanocytes. The melanocortin 1 receptor (MC1R) is a regulator of eu- and phaeomelanin production in the melanocytes, and MC1R mutations causing coat color changes are known in many mammals. We have sequenced the MC1R gene in 121 individuals sampled from world populations with an emphasis on Asian populations. We found variation at five nonsynonymous sites (resulting in the variants Arg67Gln, Asp84Glu, Val92Met, Arg151Cys, and Arg163Gln), but at only one synonymous site (A942G). Interestingly, the human consensus protein sequence is observed in all 25 African individuals studied, but at lower frequencies in the other populations examined, especially in East and Southeast Asians. The Arg163Gln variant is absent in the Africans studied, almost absent in Europeans, and at a low frequency (7%) in Indians, but is at an exceptionally high frequency (70%) in East and Southeast Asians. The MC1R gene in common and pygmy chimpanzees, gorilla, orangutan, and baboon was sequenced to study the evolution of MC1R. The ancestral human MC1R sequence is identical to the human consensus protein sequence, while MC1R varies considerably among higher primates. A comparison of the rates of substitution in genes in the melanocortin receptor family indicates that MC1R has evolved the fastest. In addition, the nucleotide diversity at the MC1R locus is shown to be several times higher than the average nucleotide diversity in human populations, possibly due to diversifying selection. (+info)
Genetic polymorphism in the 5'-flanking region of human CYP1A2 gene: effect on the CYP1A2 inducibility in humans.
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A genetic polymorphism was identified in the 5'-flanking region of human CYP1A2 gene, and its effect on the transcriptional activation of the CYP1A2 gene was investigated. Nucleotide sequence analysis revealed the existence of a point mutation from guanine (wild type) to adenine (mutated type) at position -2964 in the gene. This point mutation was detected by a polymerase chain reaction-restriction fragment length polymorphism method using DdeI or BslI restriction enzyme, and was proven to be genetically inherited. Allele frequency in 116 Japanese subjects showed 0.77 and 0.23 for the wild and mutated types of allele, respectively. The point mutation caused a significant decrease of CYP1A2 activity measured by the rate of caffeine 3-demethylation in Japanese smokers (p<0.05). Gel retardation analysis showed the existence of protein bound to the polymorphic locus. These results suggest that this polymorphism is a causal factor of decreased CYP1A2 inducibility. (+info)
The frequency and allelism of lethal chromosomes in isolated desert populations of Drosophila pseudoobscura.
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Second-chromosome lethals were extracted from four populations of Drosophila pseudoobscura in Southern California. Two of the populations were from desert oases and two from the classic habitat on Mt. San Jacinto, previously studied by Dobzhansky. Allelism tests were made on the lethals within and between all locations. The frequency of lethal second-chromosomes in each location was 0.18, and this was not different from the results of other workers for samples throughout the species range. Interpopulational allelism rates were about 0.005, and not different from earlier results of Dobzhansky. Intrapopulational rates in this study were, with one exception, the same as the interpopulational rates, and significantly lower than Dobzhansky found using the third chromosome. This may be due to lethals being linked with heterotic third-chromosome inversions. The allelism rate of the exceptional population (about 0.03 and equal to Dobzhansky's intrapopulational results) may be due to heterotic lethals, or a founder effect. Two lethals were found in three populations each, possibly due to migration among these populations, which are up to 334 km apart. (+info)
Gene differences between third-chromosome inversions of Drosophila pseudobscura.
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Associations of alleles of the acid phosphatase-3 locus with the different third-chromosome inversions from different populations of D. pseudoobscura are described. We observe only the allele AP-3(1.0) in the Standard and Arrowhead inversions and the allele AP-3.98 in the Santa Cruz, Treeline, Cuernavaca and the Pikes Peak arrangements. The Chiricahua gene arrangement is polymorphic. (+info)
Iron overload in porphyria cutanea tarda.
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BACKGROUND AND OBJECTIVE: Porphyria cutanea tarda (PCT) is a disorder of porphyrin metabolism associated with decreased activity of uroporphyrinogen decarboxylase (URO-D) in the liver. The relevance of iron in the pathogenesis of PCT is well established: iron overload is one of the factors that trigger the clinical manifestations of the disease and iron depletion remains the cornerstone of therapy for PCT. A role for genetic hemochromatosis in the pathogenesis of iron overload in PCT has been hypothesized in the past but only after the recent identification of the genetic defect causing hemochromatosis has the nature of this association been partially elucidated. This review will outline current concepts of the pathophysiology of iron overload in PCT as well as recent contributions to the molecular epidemiology of hemochromatosis defects in PCT. EVIDENCE AND INFORMATION SOURCES: The authors of the present review have a long-standing interest in the pathogenesis, etiology and epidemiology of iron overload syndromes. Evidence from journal articles covered by the Science Citation Index(R) and Medline(R) has been reviewed and collated with personal data and experience. STATE OF THE ART AND PERPECTIVES: Mild to moderate iron overload plays a key role in the pathogenesis of PCT. The recent identification of genetic mutations of the hemochromatosis gene (HFE) in the majority of patients with PCT confirms previous hypotheses on the association between PCT and hemochromatosis, allows a step forward in the understanding of the pathophysiology of the disturbance of iron metabolism in the liver of PCT patients, and provides an easily detectable genetic marker which could have a useful clinical application. Besides the epidemiological relevance of the association between PCT and hemochromatosis, however, it remains to be fully understood how iron overload, and in particular the cellular modifications of the iron status secondary to hemochromatosis mutations, affect the activity of URO-D, and how the altered iron metabolism interacts with the other two common triggers for PCT and etiological agents for the associated liver disease: alcohol and hepatitis viruses. The availability of a genetic marker for hemochromatosis will allow some of these issues to be addressed by studying aspects of porphyrins and iron metabolism in liver samples obtained from patients with PCT, liver disease of different etiology and different HFE genotypes, and by in vitro studies on genotyped cells and tissues. (+info)