Determinants of variation in serum paraoxonase enzyme activity in baboons

Paraoxonase (PON), an HDL-associated enzyme, is one of many circulating antioxidants thought to play a vital protective role. To better understand the determinants of quantitative variation in serum PON activity, we assayed PON in samples from 611 pedigreed baboons fed three diets. PON was measured enzymatically; the main determinant of variation was genetic and consisted of at least three components: two loci detected by linkage analyses and a residual polygenic component. Multipoint linkage analyses gave peak log of the odds (LOD) scores on the baboon homolog of human chromosome 7q21-22 (near PON1, the structural gene) of 9.1 on the low-cholesterol, high-fat diet and 4.1 on the high-cholesterol, high-fat diet (genome-wide P values were 1 x 10(-8) and 0.0018, respectively). Surprisingly, a second locus on the baboon homolog of human chromosome 12q13 gave a LOD score of 2.9 on the high-cholesterol, high-fat diet (genome-wide P value was 0.032). We identified several significant covariates, including age, sex, diet, and apolipoprotein A-I concentrations. We estimate that 53% of total trait variation in baboons is explained by genes and 17% by covariates, thus accounting for approximately 70% of total variation in baboon PON. Although the generation of free radicals is influenced primarily by environmental factors, our findings suggest strong genetic regulation of one component in the antioxidant defense system that plays a major role in susceptibility to atherosclerosis.     

Genetic determination of acute phase reactant levels: the strong heart study

OBJECTIVE: C-reactive protein (CRP), fibrinogen and plasminogen activating inhibitor-1 (PAI-1) are acute phase reactants (APRs); and high levels are indicative of physiologic inflammatory responses. Basal (non-stimulated) APR levels have also been shown to predict atherosclerotic complications in a number of populations. We sought to determine the relative contributions of genetic and environmental factors influencing basal serum levels of APRs. METHODS: This study used univariate quantitative genetic analyses to partition the phenotypic variance of these APRs into their additive genetic and environmental components using maximum likelihood variance decomposition methods. Bivariate analyses were done to detect genetic correlation between APRs. The computer program SOLAR was used to perform these analyses. RESULTS: The Strong Heart Study (SHS) includes information on approximately 1,294 American Indian relative pairs. The proportion of variance due to environmental and acquired covariates affecting these APRs was modest, ranging from 16-20%. The proportion of variance due to genetic factors (heritability) ranged from 24-46%. In addition, there were significant genetic correlations between CRP/fibrinogen (rho=0.41 +/- 0.12) and CRP/PAI-1 (rho=0.46 +/- 0.19); but not between fibrinogen/PAI-1. CONCLUSION: In the SHS cohort, the levels of APRs are determined to a substantial degree by genetic influences, and CRP shares common genetic determinants with fibrinogen and PAI-1.     

Genetic and environmental influences on expression of recurrent headache as a function of the reporting age in twins.

To explore age-related mechanisms in the expression of recurrent headache, we evaluated whether genetic and environmental influences are a function of the reporting age using questionnaire information that was gathered in 1973 for 15- to 47-year-old Swedish twins (n = 12,606 twin pairs). Liability to mixed headache (mild migraine and tension-type headache) was explained by non-additive genetic influences (49%) in men aged from 15 to 30 years and additive genetic plus shared environmental influences (28%) in men aged from 31 to 47 years. In women, the explained proportion of variance, which was mainly due to additive genetic effects, ranged from 61% in adolescent twins to 12% in twins aged from 41 to 47 years, whereas individual specific environmental variance was significantly lower in twins aged from 15 to 20 years than in twins aged from 21 to 30 years. Liability to migrainous headache (more severe migraine) was explained by non-additive genetic influences in men, 32% in young men and 45% in old men, while total phenotypic variance was significantly lower in young men than in old men. In women, the explained proportion of variance ranged from 91% in the youngest age group to 37% in the oldest age group, with major contributions from non-additive effects in young and old women (15-20 years and 41-47 years, respectively) and additive genetic effects in intermediate age groups (21-40 years). While total variance showed a positive age trend, genetic variance tended to be stable across age groups, whereas individual specific environmental variance was significantly lower in adolescent women as compared to older women.     

Paraoxonase 1 and atherosclerosis: is the gene or the protein more important?

The oxidation of low-density lipoprotein (LDL) is centrally involved in the initiation and progression of atherosclerosis. High-density lipoprotein (HDL) paraoxonase 1 (PON1) retards the oxidation of LDL and is a major antiatherosclerotic component of HDL. The PON1 gene contains a number of functional polymorphisms in both the coding and the promoter regions, which affect either the level or the substrate specificity of PON1. Genetic case-control and prospective studies conducted to date have produced confusing results. Meta-analysis of these studies indicates no simple relationship between the PON1 polymorphisms and the presence of coronary heart disease (CHD). However, at the present moment in time, it seems that PON1 status, i.e., activity and/or concentration, is more closely related to CHD, and indeed, PON1 has shown to be an independent risk factor for CHD in a prospective study, compared to the genetic polymorphisms. PON1 levels can also be modulated by environmental\lifestyle and possibly pharmaceutical factors. Larger, better designed, preferably prospective studies are needed to determine further the association of PON1 genetic polymorphisms and status with CHD.     

Does the PI polymorphism alone control alpha-1-antitrypsin expression?

Whether genetic factors other than the protease-inhibitor (PI) polymorphism itself contribute to variation in alpha-1-antitrypsin is of both theoretical and practical interest. We have measured the quantity of alpha-1-antitrypsin (by an immunoturbidometric assay) and its activity (by assaying elastase inhibitory capacity [EIC]) in 583 individuals from 114 twin kinships who were also typed for PI by isoelectric focusing. Models of variation were fitted directly to the raw observations by a maximum-likelihood method. Specification of phenotypic means led to highly significant improvements in fit over models including only individual environment variance and additive genetic variance. The 29 phenotype means could also be described as the appropriate additive combinations of the 12 allelic effects. Only small improvements in fit could then be obtained by addition of polygenic components of variance. We conclude that nearly all genetic variation in alpha-1-antitrypsin quantity and activity can be explained by detectable variation at the PI locus and that this variance is largely additive. Bivariate analysis of alpha-1-antitrypsin and EIC revealed marginal evidence for differences in specific activities of molecules coded by different PI alleles. The correlation between environmental deviations for the two measures was only .63, which may reflect, in part, the rather low reliability of the assays and account for the modest heritabilities (less than .5) of the two measures. An intriguing finding was the presence of significant differences in E1 variance for different PI types, suggesting that different phenotypes have differing capacities to react to environmental challenges.     

Mouse serum paraoxonase-1 lactonase activity is specific for medium-chain length fatty acid lactones

Recent studies suggest that paraoxonase-1 (PON1), complexed with high-density lipoproteins, is the major lactonase in the circulation. Using 5-hydroxy eicosatetraenoate δ-lactone (5-HETEL) as the substrate, we observed lactonase activity in serum from Pon1-/- mice. However, 6-12 carbon fatty acid γ- and δ-lactones were not hydrolyzed in serum from Pon1-/- mice. Serum from both wild-type and Pon1-/- mice contained a lactonase activity towards 5-HETEL and 3-oxo-dodecanoyl-homoserine lactone that was resistant to inactivation by EDTA. This lactonase activity was sensitive to the serine esterase inhibitor phenyl methyl sulfonyl fluoride and co-eluted with carboxylesterase activity by size-exclusion chromatography. Analysis of serum from the Es1e mouse strain, which has a deficiency in the carboxylesterase, ES-1, proved that this activity was due to ES-1. PON1 activity predominated at early time points (30 s), whereas both PON1 and ES-1 contributed equally at later time points (15 min). When both PON1 and ES-1 were inhibited, 5-HETEL was stable in mouse serum. Thus, while long-chain fatty acid lactones are substrates for PON1, they can be hydrolyzed by ES-1 at neutral pH. In contrast, medium-chain length fatty acid lactones are stable in mouse serum in the absence of PON1, suggesting that PON1 plays a specific role in the metabolism of these compounds.     

Lipoprotein-associated PAF-acetylhydrolase activity in subjects with the metabolic syndrome

Plasma- and lipoprotein-associated activity of the platelet activating factor acetylhydrolase (PAF-acetylhydrolase, PAF-AH) plays an important role in inflammation and in atherosclerotic process, which are present in the metabolic syndrome (MS). Paraoxonase 1 (PON1) is an esterase associated with high-density lipoprotein (HDL) which contributes to the anti-atherogenic effects of this lipoprotein. We investigated the activities of both enzymes in 60 patients with MS and 110 age- and sex-matched subjects without it (non-MS group). Plasma PAF-AH activity was higher in the MS compared to the non-MS group, while HDL-PAF-AH and serum PON1 activities were lower in the MS compared to the non-MS group. Univariate regression analysis in the MS group showed that plasma PAF-AH activity was positively associated with systolic blood pressure, whereas HDL-PAF-AH activity was inversely associated with the homeostasis model assessments (HOMA) index. Both associations remained significant in the multivariate regression analysis, suggesting that insulin resistance and systolic hypertension are major determinants for the alterations in plasma and HDL-associated PAF-AH activity among those observed in MS patients.     

Determinants of homocysteine-thiolactonase activity of the paraoxonase-1 (PON1) protein in humans.

Homocysteine (Hcy)-thiolactonase (HTase) activity of the paraoxonase-1 (PON1) protein detoxifies Hcy-thiolactone in human blood and could thus delay the development of atherosclerosis. To gain insight into physiological role(s) of the PON1 protein, we studied HTase activities and PON1 genotypes in a group of 184 subjects, 32.6% of whom were healthy, 27.7% had angiographically proven coronary artery disease but did not have myocardial infarction (CAD), and 39.7% had myocardial infarction (MI). We found that the hydrolytic activities of the serum PON1 protein towards Hcy-thiolactone and the organophosphate paraoxon substrates were strongly correlated. PON1-192-RR and PON1-55-LL genotypes were associated with high HTase activity. HTase activity was negatively correlated with age (beta = -0.135, p =0.002), plasma total Hcy (in 192-QR subjects only; r = -0.46, p = 0.001), and positively correlated with total cholesterol (beta = 0.169, p<0.001), but not with HDL cholesterol. Mean HTase activities were similar in CAD subjects, MI subjects, and in healthy controls. However, the frequency of the PON1-192-RR genotype tended to be lower in CAD subjects than in controls (2% vs 10.0%, p = 0.057) and higher in MI subjects that in CAD subjects (10.9% vs 2.0%, p = 0.001). The R-allele was marginally associated with CAD (26.7% in controls vs 17.6% in CAD, p = 0.146) and significantly associated with MI (17.6% in CAD vs 31.5% in MI, p = 0.018). Multiple regression analysis suggests that PON1 genotype, total Hcy, total cholesterol, and age are major determinants of HTase activity in humans.     

Multiple QTLs influence variation in paraoxonase 1 activity in Mexican Americans

Paraoxonase 1 (PON1), a high-density-lipoprotein-associated enzyme known to protect against cellular damage from toxic agents, may also have antioxidant properties. Although the importance of the influence of the PON1 structural locus on chromosome 7q21-22 for variation in the concentration and activity of the enzyme is well-documented, the contribution of other loci is poorly understood. Based on the recent observations of at least one additional quantitative trait locus (QTL) for PON1 activity in pedigreed baboons, we conducted a whole-genome linkage screen for QTLs other than the PON1 structural locus that may influence PON1 activity in humans. We measured PON1 activity in frozen serum for 1,406 individuals in more than 40 extended pedigrees from the San Antonio Family Heart Study (SAFHS). We used a maximum-likelihood-based variance decomposition approach implemented in SOLAR to test for QTLs that may influence PON1 activity. In addition to a QTL for which we detected the strongest, significant evidence (LOD = 31.41) at or near the PON1 structural locus on chromosome 7q21-22, we also localized at least one additional significant QTL on chromosome 12 (LOD = 3.56). Furthermore, we detected suggestive evidence for two more PON-related QTLs on chromosomes 17 and 19. We have provided evidence that other genes, in addition to the well-known ones on chromosome 7, play a role in influencing normal variation in PON1 activity.     

A DNA probe for the LDL receptor gene is tightly linked to hypercholesterolemia in a pedigree with early coronary disease.

A large, multigenerational family with dominantly inherited hypercholesterolemia was analyzed for genetic linkage between blood levels of low-density lipoprotein (LDL) cholesterol and the locus for the LDL receptor. A genetic marker was identified by restriction fragment length polymorphism (RFLP) in a cloned segment of the LDL receptor gene. We found no exceptions to segregation of the high-LDL cholesterol phenotype with a unique allele at the LDL receptor locus in this pedigree; tight linkage was indicated by a maximum lod score of 7.52 at theta = 0. Knowledge of the LDL receptor genotype will enable investigators to study variability of phenotypic expression in response to environmental influences or to different genetic determinants.     

The genera of bacteriophages and their receptors are the major determinants of host range

The host range of phages is a key to understand their impact on bacterial ecology and evolution. Because of the complexity of phage–host interactions, the variables that determine the breadth of a phage host range remain poorly understood. Here, we propose a novel holistic approach to identify the host range determinants of a new collection of phages infecting Salmonella, isolated from animal, environmental and wastewater samples that were able to infect 58 of the 71 Salmonella strains in our collection. By using a set of statistic approaches (non-metric dimensional scaling, Bray–Curtis distance, PERMANOVA), we analysed phenotypic (host range on wild-type and receptor mutants) and genetic data (taxonomic assignment and receptor binding proteins) to evaluate the impact of isolation strain and niche, phage receptor and genus on the host range. Statistical analysis revealed that two phage characteristics influence the host range by explaining the most variance: the receptor by 45% and the genus by 51%. Interestingly, phage genus and receptor in combination explained 79% of the variance, establishing these characteristics as the major determinants of the host range. This study demonstrates the power and the novelty of applying statistical approaches to phenotypic and genetic data to investigate the ecology of phage–host interactions.     

HDL subfraction distribution of paraoxonase-1 and its relevance to enzyme activity and resistance to oxidative stress

The subfraction distribution of HDL-associated peptides has implications for their functions and the impact of pathological modifications to lipoprotein metabolism on these functions. We have analyzed the subfraction distribution of paraoxonase-1 (PON1) and the consequences for enzyme activity and stability. HDL subfractions were defined by the presence (LpA-I,A-II) or absence (LpA-I) of apolipoprotein A-II (apoA-II). PON1 was present in both subfractions, although increased concentrations of HDL were associated with significantly increased PON1 in LpA-I. ApoA-II did not modify the capacity of native human HDL or reconstituted HDL to promote PON1 secretion from cells or to stabilize enzyme activity, nor did apoA-II decrease PON1 activity when added to rabbit serum normally devoid of the apolipoprotein. LpA-I,A-II particles isolated from human serum or reconstituted HDL (LpA-I,A-II) showed a significantly greater capacity than HDL(LpA-I) to stabilize secreted PON1 and purified recombinant PON1 added to such particles. PON1 associated with apoA-II-containing particles showed greater resistance to inactivation arising from oxidation. ApoA-I, apoA-II, and LpA-I,A-II, but not LpA-I, were independent determinants of serum PON1 concentration and activity in multivariate analyses. PON1 is at least equally distributed between LpA-I and LpA-II,A-II HDL particles. This dichotomous distribution has implications for PON1 activity and stability that may impact on the physiological role of the enzyme.     

TagSNP analyses of the PON gene cluster: effects on PON1 activity, LDL oxidative susceptibility, and vascular disease

Paraoxonase 1 (PON1) activity is consistently predictive of vascular disease, although the genotype at four functional PON1 polymorphisms is not. To address this inconsistency, we investigated the role of all common PON1 genetic variability, as measured by tagging single-nucleotide polymorphisms (tagSNPs), in predicting PON1 activity for phenylacetate hydrolysis, LDL susceptibility to oxidation ex vivo, plasma homocysteine (Hcy) levels, and carotid artery disease (CAAD) status. The biological goal was to establish whether additional common genetic variation beyond consideration of the four known functional SNPs improves prediction of these phenotypes. PON2 and PON3 tagSNPs were secondarily evaluated. Expanded analysis of an additional 26 tagSNPs found evidence of previously undescribed common PON1 polymorphisms that affect PON1 activity independently of the four known functional SNPs. PON1 activity was not significantly correlated with LDL oxidative susceptibility, but genotypes at the PON1(-108) promoter polymorphism and several other PON1 SNPs were. Neither PON1 activity nor PON1 genotype was significantly correlated with plasma Hcy levels. This study revealed previously undetected common functional PON1 polymorphisms that explain 4% of PON1 activity and a high rate of recombination in PON1, but the sum of the common PON1 locus variation does not explain the relationship between PON1 activity and CAAD.     

Paraoxonase-2 deficiency aggravates atherosclerosis in mice despite lower apolipoprotein-B-containing lipoproteins: anti-atherogenic role for paraoxonase-2

Paraoxonases (PONs) are a family of proteins that may play a significant role in providing relief from both toxic environmental chemicals as well as physiological oxidative stress. Although the physiological roles of the PON family of proteins, PON1, PON2, and PON3, remain unknown, epidemiological, biochemical, and mouse genetic studies of PON1 suggest an anti-atherogenic function for paraoxonases. To determine whether PON2 plays a role in the development of atherosclerosis in vivo, we generated PON2-deficient mice. When challenged with a high fat, high cholesterol diet for 15 weeks, serum levels of high density lipoprotein cholesterol, triglycerides, and glucose were not significantly different between wild-type and PON2-deficient mice. In contrast, serum levels of very low density lipoprotein (VLDL)/low density lipoprotein (LDL) cholesterol were significantly lower (-32%) in PON2-deficient mice compared with wild-type mice. However, despite lower levels of VLDL/LDL cholesterol, mice deficient in PON2 developed significantly larger (2.7-fold) atherosclerotic lesions compared with their wild-type counterparts. Enhanced inflammatory properties of LDL, attenuated anti-atherogenic capacity of high density lipoprotein, and a heightened state of oxidative stress coupled with an exacerbated inflammatory response from PON2-deficient macrophages appear to be the main mechanisms behind the larger atherosclerotic lesions in PON2-deficient mice. These results demonstrate that PON2 plays a protective role in atherosclerosis.     

Cysteine substitutions in apolipoprotein A-I primary structure modulate paraoxonase activity

Paraoxonase (PON) is transported primarily on apolipoprotein A-I (apoA-I) -containing high-density lipoprotein (HDL) and is thought to protect against early atherogenic events including low-density lipoprotein (LDL) oxidation and monocyte migration. It has been proposed that apoA-I may be necessary for PON's association with plasma HDL. On the basis of this, we examined the effect of apoA-I on PON's enzymatic activity and its ability to associate with HDL. Additionally, we examined whether changes in apoA-I primary structure (cysteine substitution mutations) could modulate these effects. Chinese hamster ovary cells stably transfected with human PON1A cDNA were incubated in the presence and absence of recombinant wild-type apoA-I (apoA-I(WT)) and specific Cys substitution mutations. Extracellular accumulation of PON activity in the presence of apoA-I(WT) was 0.095 +/- 0.013 unit/mg of cell protein (n = 7) compared to 0.034 +/- 0.010 unit/mg of cell protein in the absence of apoA-I (n = 7), a 2.79-fold increase in activity when apoA-I was incubated with the cells. Lipid-free apoA-I did not increase PON activity, while preformed nascent HDL increased PON activity only 30%, suggesting that maximal PON activity is lipid-dependent and requires coassembly of PON and apoA-I on nascent HDL. The cysteine mutations R10C, R27C, and R61C significantly increased (p < 0.01) PON activity 32.6% +/- 14.7%, 31.6% +/- 18.9%, and 27.4% +/- 20%, respectively, over that of wild type (WT). No changes in PON activity were observed with apoA-I cysteine substitution mutations in the C-terminal portion of the protein. The data suggest that, for optimal PON activity, coassembly of the enzyme onto nascent HDL is required and that the N-terminal region of apoA-I may be important in the assembly process.     

Association of the novel cardiovascular risk factors paraoxonase 1 and cystatin C in type 2 diabetes

Paraoxonase 1 (PON1) has been reported to be associated with proteinuria in subjects with type 2 diabetes mellitus (T2DM). Plasma cystatin C is more accurate than creatinine for identifying stage 3 kidney disease in T2DM. We tested the hypothesis that PON1 and cystatin C would be associated in T2DM subjects from an Aboriginal Canadian community, who are at high risk for the development of nephropathy. PON1 A(-162)G and PON2 Ala148Gly genotypes, cystatin C, HbA1c, high density lipoprotein cholesterol (HDLC), waist circumference (waist), and duration of diabetes were included in the regression analysis with log_e (ln) of PON1 mass as the dependent variable. A regression model including PON2 Ala148Gly genotype, HDLC, and ln cystatin C explained 25.8% of the variance in PON1 mass. Conversely, waist, age, ln HbA1c, ln duration of diabetes, and ln PON1 mass, but not PON2 genotype, explained 38% of the variance in cystatin C. Subjects with cystatin C estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m² (stage 3 kidney disease) had significantly lower PON1 mass compared with subjects with cystatin C-eGFR >60 ml/min per 1.73 m². The lower mass of PON1, an anti-inflammatory HDL-associated enzyme, in T2DM with cystatin C-eGFR <60 ml/min per 1.73 m² may contribute to their increased risk for cardiovascular disease.     

Gene-environment interactions in atherosclerosis

The importance of environment and genetics working together to shape an individual's risk for atherosclerosis seems intuitively obvious. However, it is only recently that research strategies have begun to evolve that attempt to answer questions related to apportionment of risk that is due to specific environmental and genetic factors. These factors may impact upon risk either singly or, more likely, through a complex interaction that affects the metabolic history of the whole organism. Because the genetic bases of lipid and lipoprotein metabolism have been well-studied, and because of the epidemiologic and pathobiochemical associations between genetic disorders of lipid metabolism and atherosclerosis, researchers have searched for gene-environment interactions within animal and human systems in which the phenotype is defined by some index of lipoprotein metabolism. From work done in the lipoprotein area to this point a clear case can be made for: 1) the genetic influence over the phenotypic response to an environmental stimulus; 2) the environmental modulation of the phenotypic expression of severe genetic defects. In the realm of gene-environment interactions that affect lipoprotein phenotype, diet is the best-studied environmental factor.     

Paraoxonase-1 does not reduce or modify oxidation of phospholipids by peroxynitrite

Serum paraoxonase (PON1) is a high-density lipoprotein (HDL)-associated esterase/lactonase implicated to play a role in protection against atherosclerosis. However, the exact mechanism(s) and substrates for PON1 are still uncertain. In this article, we review some of the evidence for PON1's antioxidant activity, as well as our efforts to identify the actual substrates and products for this activity. We originally reported that PON1 had phospholipase activity toward oxidized phosphatidylcholine (J. Biol. Chem. 276:24473-24481; 2001). Subsequently, Marathe et al. (J. Biol. Chem. 278:3937-3947; 2003) reported that this activity was due to a contaminating lipase. However, that article did not replicate the conditions used in our previous study. To address this controversy, we purified serum PON1 by a modified method that separates the paraoxonase activity from an activity detectable as platelet-activating factor acetyl hydrolase (PAF-AH) (Teiber et al., J. Lipid. Res. 2004; Epub ahead of print, PMID 15342686) and reexamined the oxidation of phosphatidylcholine by peroxynitrite using 3-morpholinosydnonimine as a peroxynitrite generator and apolipoprotein AI-phosphatidylcholine- PON1 complexes. The phosphatidylcholines were studied by electrospray ionization tandem mass spectrometry. PON1 preparations free of PAF-AH activity showed no phospholipase activity when reconstituted into apolipoprotein AI-phosphatidylcholine complexes. We conclude that PON1 does not affect the accumulation of phosphatidylcholine oxidation products. Further, we have no evidence that PON1 has an intrinsic phospholipase A2 activity toward oxidized phospholipids.     

Quantitative genetic study of maximal electroshock seizure threshold in mice: evidence for a major seizure susceptibility locus on distal chromosome 1

We conducted a quantitative trait locus (QTL) mapping study to dissect the multifactorial nature of maximal electroshock seizure threshold (MEST) in C57BL/6 (B6) and DBA/2 (D2) mice. MEST determination involved a standard paradigm in which 8- to 12-week-old mice received one shock per day with a daily incremental increase in electrical current until a maximal seizure (tonic hindlimb extension) was induced. Mean MEST values in parental strains were separated by over five standard deviation units, with D2 mice showing lower values than B6 mice. The distribution of MEST values in B6xD2 F2 intercrossed mice spanned the entire phenotypic range defined by parental strains. Statistical mapping yielded significant evidence for QTLs on chromosomes 1, 2, 5, and 15, which together explained over 60% of the phenotypic variance in the model. The chromosome 1 QTL represents a locus of major effect, accounting for about one-third of the genetic variance. Experiments involving a congenic strain (B6.D2-Mtv7(a)/Ty) enabled more precise mapping of the chromosome 1 QTL and indicate that it lies in the genetic interval between markers D1Mit145 and D1Mit17. These results support the hypothesis that the distal portion of chromosome 1 harbors a gene(s) that has a fundamental role in regulating seizure susceptibility.     

Genetic and environmental explanations for the distribution of sodium-lithium countertransport in pedigrees from Rochester, MN.

An elevated level of erythrocyte sodium-lithium (Na-Li) countertransport has been suggested as a predictor of predisposition to essential hypertension. In order to evaluate whether a single genetic or environmental factor with large effects explains the mixture of distributions in Na-Li countertransport in the general population, complex segregation analyses were conducted by using 1,273 individuals more than age 20 years from 276 pedigrees selected without respect to disease risk factors or health status. Either a single genetic locus or a single environmental factor with large gender-specific effects explained the mixture of distributions for Na-Li countertransport in this sample equally well. In the subsample of pedigrees supporting a single-locus etiology, the single genetic locus explained 29.0% of the variability in adjusted Na-Li countertransport in males and 16.6% of that in females. In a subsample of pedigrees supporting an environmental factor etiology, the environmental factor explained 35.2% of the adjusted Na-Li countertransport in males and 20.5% of that in females. These results suggest that there are at least two different explanations for the mixture of distributions in Na-Li countertransport in the general population. Attempts to relate genetic variation in Na-Li countertransport to risk of essential hypertension must consider that the factor with large phenotypic effects on this trait is gender specific and may not be a single major locus in all pedigrees.