Placental blood flow and the risk of preterm delivery.

The goal of this analysis was to estimate the influence of variation in uterine artery and umbilical artery resistance indices (RIs) measured across gestation on variation in the risk of preterm delivery (PTD). Analyses were carried out on data collected in a longitudinal study of 523 gravidas. Uterine and umbilical artery RIs were measured on three occasions during pregnancy (16-20 weeks gestation; 21-29 weeks gestation; and 30-36 weeks gestation). Data were analyzed using the Cox proportional hazards regression model. The primary outcome variable was birth prior to 37 weeks gestation. We found that for mothers who delivered preterm the mean uterine artery RI was consistently larger across all gestational ages, while the mean umbilical artery RI decreased significantly more slowly across gestation than for their term counterparts. In analyses pooled by type of delivery, we found that the hazard ratio (HR) for PTD was statistically significant for either uterine artery RI (HR=2.26, 95% CI: 1.65, 3.11) or umbilical artery RI (HR=3.47, 95% CI: 2.43, 4.95) after adjusting for statistically significant covariates. In stratified analyses, the hazard ratio for PTD was also positively associated with an increased uterine or umbilical artery RI in both spontaneous and indicated deliveries. Our data suggest that pregnancies with either a higher uterine or umbilical artery RI across gestation are more likely to be affected by PTD suggesting that disordered placentation resulting in compromised placental blood flow may be an important pathway to PTD.

Variation in 5' promoter region of the APOE gene contributes to predicting ischemic heart disease (IHD) in the population at large: the Copenhagen City Heart Study.

The objective of this study was to evaluate whether an increased hazard of developing ischemic heart disease (IHD) is associated with any of the three genotypes A560T832/A560T832, A560T832/A560G832 and A560T832/T560T832, defined by variations in two non-coding SNPs in the 5' promoter region of the apolipoprotein E (APOE) gene. These genotypes were selected because they distinguished between high and low levels of HDL-C, TG and/or T-C in our earlier study of multiple samples defined by gender and population. We found a significant increase (p<0.05) in the hazard of IHD in females with the A560T832/T560T832 genotype that remained significant after fitting the effects of dyslipidemia, other established risk factors, and the structural isoform variations of the ApoE molecule. We discuss why this statistically significant genetic predictor may not be an appropriate screening test for IHD in the Danish population at large.

The contribution of individual and pairwise combinations of SNPs in the APOA1 and APOC3 genes to interindividual HDL-C variability.

Apolipoproteins (apo) A-I and C-III are components of high-density lipoprotein-cholesterol (HDL-C), a quantitative trait negatively correlated with risk of cardiovascular disease (CVD). We analyzed the contribution of individual and pairwise combinations of single nucleotide polymorphisms (SNPs) in the APOA1/APOC3 genes to HDL-C variability to evaluate (1) consistency of published single-SNP studies with our single-SNP analyses; (2) consistency of single-SNP and two-SNP phenotype-genotype relationships across race-, gender-, and geographical location-dependent contexts; and (3) the contribution of single SNPs and pairs of SNPs to variability beyond that explained by plasma apo A-I concentration. We analyzed 45 SNPs in 3,831 young African-American (N=1,858) and European-American (N=1,973) females and males ascertained by the Coronary Artery Risk Development in Young Adults (CARDIA) study. We found three SNPs that significantly impact HDL-C variability in both the literature and the CARDIA sample. Single-SNP analyses identified only one of five significant HDL-C SNP genotype relationships in the CARDIA study that was consistent across all race-, gender-, and geographical location-dependent contexts. The other four were consistent across geographical locations for a particular race-gender context. The portion of total phenotypic variance explained by single-SNP genotypes and genotypes defined by pairs of SNPs was less than 3%, an amount that is miniscule compared to the contribution explained by variability in plasma apo A-I concentration. Our findings illustrate the impact of context-dependence on SNP selection for prediction of CVD risk factor variability.

Linkage analysis of plasma ApoE in three ethnic groups: multiple genes with context-dependent effects.

We performed variance component-based linkage analysis in four samples (two of non-Hispanic European-Americans from Rochester, MN; African-Americans from Jackson, MS; and Mexican-Americans from Starr County, TX) to identify chromosomal regions containing genes influencing plasma apolipoprotein E (apoE) levels. The APOE gene region on chromosome (chr) 19 was identified with a LOD > or = 2.00 in both samples from Rochester and the sample from Jackson. Adjustment of apoE levels for differences among means of genotypes defined by the APOE epsilon2/3/4 alleles reduced evidence of linkage, indicating that the APOE gene was responsible for the majority of the linkage signal. In stratified linkage analyses, there was a LOD of 1.70 in the Starr County sibships with average total cholesterol (TC) above the median level for all sibships in that population. Adjustment for APOE genotype did not remove this LOD score, suggesting a second gene in this region may influence apoE variation. Evidence of linkage (LOD= 3.32) on chr 17 was observed in the Starr County sibships with average TC below the median. Inter-individual variation in plasma apoE level may be influenced by variations in the structural gene, and at least one other gene whose effects differ among populations and are dependent on the influence of unmeasured genetic and environmental factors indexed by correlated measures of lipid metabolism.

Evidence for non-additive influence of single nucleotide polymorphisms within the apolipoprotein E gene.

We analyzed 13 single nucleotide polymorphisms (SNPs) within the apolipoprotein E (APOE) gene, to identify pairs of SNPs that interact in a non-additive manner to influence genotypic mean levels of the ApoE protein in blood. An overparameterized general linear model of two-SNP genotype means was applied to data from 456 female and 398 male unrelated European Americans from Rochester, MN, USA. We found statistically significant evidence for non-additivity between SNPs within the male sample, but not within the female sample. We observed nine pairs of SNPs with evidence of non-additivity at the alpha=0.05 level of statistical significance within the male sample, when approximately three were expected by chance. Five of the nine pairs involved three SNPs (560, 624 and 1163) that did not have a statistically significant influence when considered separately in a single-site analysis. Three of the nine pairs involving four SNPs (832, 1998, 3937 and 4951) showed significant evidence for non-additivity in at least one of two other male samples from Jackson, MS, USA and North Karelia, Finland. Although all four of these SNPs had a statistically significant influence in Rochester when considered separately, only SNP 3937 gave a significant result in the other male samples. The four SNPs are located in the promoter, intronic and exonic regions, and 3' to the polyadenylation signal in the APOE gene. Our study suggests that analyses that only consider SNPs located in exons and ignore contexts such as those indexed by gender and population, and disregard non-additivity of SNP effects, may inappropriately model the contribution of a gene to the genetic architecture of a trait that has a complex multifactorial etiology.

Genome-wide linkage analysis reveals evidence of multiple regions that influence variation in plasma lipid and apolipoprotein levels associated with risk of coronary heart disease.

Results of genome-wide linkage analyses to identify chromosomal regions that influence interindividual variation in plasma lipid and apolipoprotein levels in the Rochester, Minn, population are reported. Analyses were conducted for total cholesterol (total-C), triglycerides (TGs), high density lipoprotein cholesterol (HDL-C), apolipoprotein A-I, apolipoprotein A-II, apolipoprotein B, apolipoprotein C-II, apolipoprotein C-III, apolipoprotein E, the total-C/HDL-C ratio, and the TG/HDL-C ratio. Genotypes were measured for 373 genome-wide marker loci on 1484 individuals distributed among 232 multigeneration pedigrees sampled without regard to health status. LOD scores and estimates of additive genetic variance associated with map locations were obtained by using the variance-component method of linkage analysis. No evidence of linkage with genes influencing variation in age served as a negative control. Plasma apolipoprotein E levels and the apolipoprotein E gene served as a positive control (LOD score 4.20). Evidence (LOD score >2.00) was provided that was suggestive of a gene or genes on chromosomes 4 and 5 influencing variation in the apolipoprotein A-II level, on chromosome 12 influencing variation in the apolipoprotein A-I level, and on chromosome 17 influencing variation of total-C/HDL-C. These analyses provide new information about genomic regions in humans that influence interindividual variation in plasma lipid and apolipoprotein levels and serve as a basis for further fine-mapping studies to identify new genes involved in lipid metabolism.

A combinatorial partitioning method to identify multilocus genotypic partitions that predict quantitative trait variation.

Recent advances in genome research have accelerated the process of locating candidate genes and the variable sites within them and have simplified the task of genotype measurement. The development of statistical and computational strategies to utilize information on hundreds -- soon thousands -- of variable loci to investigate the relationships between genome variation and phenotypic variation has not kept pace, particularly for quantitative traits that do not follow simple Mendelian patterns of inheritance. We present here the combinatorial partitioning method (CPM) that examines multiple genes, each containing multiple variable loci, to identify partitions of multilocus genotypes that predict interindividual variation in quantitative trait levels. We illustrate this method with an application to plasma triglyceride levels collected on 188 males, ages 20--60 yr, ascertained without regard to health status, from Rochester, Minnesota. Genotype information included measurements at 18 diallelic loci in six coronary heart disease--candidate susceptibility gene regions: APOA1--C3--A4, APOB, APOE, LDLR, LPL, and PON1. To illustrate the CPM, we evaluated all possible partitions of two-locus genotypes into two to nine partitions (approximately 10(6) evaluations). We found that many combinations of loci are involved in sets of genotypic partitions that predict triglyceride variability and that the most predictive sets show nonadditivity. These results suggest that traditional methods of building multilocus models that rely on statistically significant marginal, single-locus effects, may fail to identify combinations of loci that best predict trait variability. The CPM offers a strategy for exploring the high-dimensional genotype state space so as to predict the quantitative trait variation in the population at large that does not require the conditioning of the analysis on a prespecified genetic model.

Cladistic structure within the human Lipoprotein lipase gene and its implications for phenotypic association studies.

Haplotype variation in 9.7 kb of genomic DNA sequence from the human lipoprotein lipase (LPL) gene was scored in three populations: African-Americans from Jackson, Mississippi (24 individuals), Finns from North Karelia, Finland (24), and non-Hispanic whites from Rochester, Minnesota (23). Earlier analyses had indicated that recombination was common but concentrated into a hotspot and that recurrent mutations at multiple sites may have occurred. We show that much evolutionary structure exists in the haplotype variation on either side of the recombinational hotspot. By peeling off significant recombination events from a tree estimated under the null hypothesis of no recombination, we also reveal some cladistic structure not disrupted by recombination during the time to coalescence of this variation. Additional cladistic structure is estimated to have emerged after recombination. Many apparent multiple mutational events at sites still remain after removing the effects of the detected recombination/gene conversion events. These apparent multiple events are found primarily at sites identified as highly mutable by previous studies, strengthening the conclusion that they are true multiple events. This analysis portrays the complexity of the interplay among many recombinational and mutational events that would be needed to explain the patterns of haplotype diversity in this gene. The cladistic structure in this region is used to identify four to six single-nucleotide polymorphisms (SNPs) that would provide disequilibrium coverage over much of this region. These sites may be useful in identifying phenotypic associations with variable sites in this gene. Evolutionary considerations also imply that the SNPs in the 3' region should have general utility in most human populations, but the 5' SNPs may be more population specific. Choosing SNPs at random would generally not provide adequate disequilibrium coverage of the sequenced region.

Effect of time of day on intraindividual variability in ambulatory blood pressure.

The aim of this study was to determine whether intraindividual blood pressure (BP) variability, measured by noninvasive ambulatory monitoring, differs between the active (daytime) and inactive (nighttime) periods of the day. We obtained ambulatory BP recordings in 143 healthy adults (95 men, 48 women) from Rochester, Minnesota. Readings were obtained every 10 min for a 24-h period. We calculated the standard deviation of each individual's BP readings about the means for the active period and for the inactive period as measures of intraindividual BP variability. In men, mean within-individual standard deviations for both systolic (SBP) and diastolic blood pressure (DBP) were significantly greater during the inactive period than during the active period (for SBP: 10.3 +/- 2.1 v 11.9 +/- 2.7, P < .0001; for DBP: 8.8 +/- 2.0 v 9.7 +/- 2.5, P = .0027). In women, the mean within-individual standard deviation for SBP did not differ significantly between the active and inactive periods (9.7 +/- 2.2 v 10.3 +/- 2.4, P = 0.225) but for DBP was significantly greater during the inactive period than during the active period (8.1 +/- 2.0 v 9.2 +/- 2.3, P = .020). Statistically significant predictors of intraindividual BP variability included measures of age and body size, metabolic traits, neuroendocrine traits, erythrocyte cation traits, and renal function traits. This study demonstrates that intraindividual BP variability, as measured by noninvasive ambulatory monitoring, is as great or greater during the inactive period as during the active period of the day.

Sequence diversity and large-scale typing of SNPs in the human apolipoprotein E gene.

A common strategy for genotyping large samples begins with the characterization of human single nucleotide polymorphisms (SNPs) by sequencing candidate regions in a small sample for SNP discovery. This is usually followed by typing in a large sample those sites observed to vary in a smaller sample. We present results from a systematic investigation of variation at the human apolipoprotein E locus (APOE), as well as the evaluation of the two-tiered sampling strategy based on these data. We sequenced 5.5 kb spanning the entire APOE genomic region in a core sample of 72 individuals, including 24 each of African-Americans from Jackson, Mississippi; European-Americans from Rochester, Minnesota; and Europeans from North Karelia, Finland. This sequence survey detected 21 SNPs and 1 multiallelic indel, 14 of which had not been previously reported. Alleles varied in relative frequency among the populations, and 10 sites were polymorphic in only a single population sample. Oligonucleotide ligation assays (OLA) were developed for 20 of these sites (omitting the indel and a closely-linked SNP). These were then scored in 2179 individuals sampled from the same three populations (n = 843, 884, and 452, respectively). Relative allele frequencies were generally consistent with estimates from the core sample, although variation was found in some populations in the larger sample at SNPs that were monomorphic in the corresponding smaller core sample. Site variation in the larger samples showed no systematic deviation from Hardy-Weinberg expectation. The large OLA sample clearly showed that variation in many, but not all, of OLA-typed SNPs is significantly correlated with the classical protein-coding variants, implying that there may be important substructure within the classical epsilon 2, epsilon 3, and epsilon 4 alleles. Comparison of the levels and patterns of polymorphism in the core samples with those estimated for the OLA-typed samples shows how nucleotide diversity is underestimated when only a subset of sites are typed and underscores the importance of adequate population sampling at the polymorphism discovery stage. [The sequence data described in this paper have been submitted to the GenBank data library under accession no. AF261279.]

Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism.

Three common protein isoforms of apolipoprotein E (apoE), encoded by the epsilon2, epsilon3, and epsilon4 alleles of the APOE gene, differ in their association with cardiovascular and Alzheimer's disease risk. To gain a better understanding of the genetic variation underlying this important polymorphism, we identified sequence haplotype variation in 5.5 kb of genomic DNA encompassing the whole of the APOE locus and adjoining flanking regions in 96 individuals from four populations: blacks from Jackson, MS (n=48 chromosomes), Mayans from Campeche, Mexico (n=48), Finns from North Karelia, Finland (n=48), and non-Hispanic whites from Rochester, MN (n=48). In the region sequenced, 23 sites varied (21 single nucleotide polymorphisms, or SNPs, 1 diallelic indel, and 1 multiallelic indel). The 22 diallelic sites defined 31 distinct haplotypes in the sample. The estimate of nucleotide diversity (site-specific heterozygosity) for the locus was 0.0005+/-0.0003. Sequence analysis of the chimpanzee APOE gene showed that it was most closely related to human epsilon4-type haplotypes, differing from the human consensus sequence at 67 synonymous (54 substitutions and 13 indels) and 9 nonsynonymous fixed positions. The evolutionary history of allelic divergence within humans was inferred from the pattern of haplotype relationships. This analysis suggests that haplotypes defining the epsilon3 and epsilon2 alleles are derived from the ancestral epsilon4s and that the epsilon3 group of haplotypes have increased in frequency, relative to epsilon4s, in the past 200,000 years. Substantial heterogeneity exists within all three classes of sequence haplotypes, and there are important interpopulation differences in the sequence variation underlying the protein isoforms that may be relevant to interpreting conflicting reports of phenotypic associations with variation in the common protein isoforms.

Positional genomic analysis identifies the beta(2)-adrenergic receptor gene as a susceptibility locus for human hypertension.

BACKGROUND: -After genome-wide linkage analyses of blood pressure levels, we resequenced 5 positional candidate genes in a linkage region on chromosome 5 and genotyped selected variants in several family samples from Rochester, Minn. METHODS AND RESULTS: In a sample of 55 pedigrees containing >/=1 sibling-pair(s) discordant for systolic blood pressure, polymorphisms within the beta(2)-adrenergic receptor gene (Arg16Gly, P=0.009) and the glutathione peroxidase 3 gene (-302G-->A, P=0.037; -623A-->C, P=0.013) were significantly related to blood pressure levels. In a second sample of 298 nuclear families (n=1283 individuals), the Arg16Gly polymorphism was significantly associated with diastolic blood pressure in family-based analyses (P=0.016) and with both diastolic (P=0.009) and mean arterial blood pressure (P=0.038) in analyses of the parental generation only. Neither polymorphism in the glutathione peroxidase 3 gene was associated with blood pressure levels in this sample. An additional 291 families (n=1240 individuals) were added to the nuclear family sample, and the Gln27Glu polymorphism in the beta(2)-adrenergic receptor gene was significantly associated with both systolic (P=0.034) and mean arterial blood pressure (P=0.035) in the parental generation of the combined 589 families. The frequencies of both the Gly16 and Glu27 alleles were higher in hypertensives than in normotensives (0.649 versus 0.604 and 0.490 versus 0.429, respectively), and the odds ratio for the occurrence of hypertension was 1.80 (95% confidence interval, 1.08 to 3.00; P=0. 023) for the Glu27 allele. CONCLUSIONS: The results of this study provide support for further detailed investigations of the mechanistic pathways by which variations in the beta(2)-adrenergic receptor gene may influence blood pressure levels.

Predictors of interindividual variation in ambulatory blood pressure and their time or activity dependence.

The objectives of this study were to determine whether total interindividual variation in blood pressure (BP) differs between inactive and active hours of the day, to identify predictors of interindividual variation in BP, and to assess whether variation associated with any of these identified predictors is greater (or less) during inactive hours than during active hours of the day. We obtained ambulatory BP recordings over 20 consecutive hours (12 active, out of bed [daytime]; and 8 inactive, in bed [nighttime]) in a sample of 240 unrelated, non-Hispanic white adults (138 men; 102 women). We estimated total interindividual variation in BP, and the percentage of interindividual variation associated with measures of age and body size, metabolic traits, catecholamines, erythrocyte cation transport, and renal function. We used linear regression to assess changes in the hourly estimates of total interindividual variation and in variation attributable to each set of predictor traits over the 20 h. In both men and women, total interindividual variation in systolic BP was significantly greater (not less) during inactive hours than during active hours. In addition, in women, total interindividual variation in diastolic BP was as great during inactive hours as during active hours. Each set of traits considered predicted a statistically significant percentage of interindividual variation in BP. None of the sets of traits predicted a greater percentage of interindividual variation during the inactive hours than during the active hours. Measures of age and body size, catecholamines, cation transport and renal function traits predicted significantly less interindividual variation during inactive hours than during active hours of the day. That total interindividual variation in BP is as great or greater during inactive hours than during active hours of the day emphasizes the potential for differences in nighttime BP to contribute to the development of cardiovascular disease. In as much as the predictors of interindividual variation in BP differ between the daytime and nighttime, the causes of variation during these two times may also differ.

Impact of age and body size on inter-individual variation in measures of lipid metabolism: influence of gender and apolipoprotein E genotype.

This study was undertaken in 1695 adult subjects (870 women and 825 men) in order to further document the complexity of the influence of the apolipoprotein (apo) E genotypes on the mean levels and intragenotypic variability of seven measures of lipid metabolism. In addition, the statistical relationships between variability in these traits and variation in age, body mass index (BMI) and waist-to-hip ratio (WHR) were assessed. The contribution of variation in age and body size to inter-individual variation was found to be dependent on context, defined by gender and apo E genotype. Our findings are consistent with the reality that it is neither genes nor environments, but their interactions that are responsible for the variation in risk of cardiovascular disease.

Recombinational and mutational hotspots within the human lipoprotein lipase gene.

Here an analysis is presented of the roles of recombination and mutation in shaping previously determined haplotype variation in 9.7 kb of genomic DNA sequence from the human lipoprotein lipase gene (LPL), scored in 71 individuals from three populations: 24 African Americans, 24 Finns, and 23 non-Hispanic whites. Recombination and gene-conversion events inferred from data on 88 haplotypes that were defined by 69 variable sites were tested. The analysis revealed 29 statistically significant recombination events and one gene-conversion event. The recombination events were concentrated in a 1.9-kb region, near the middle of the segment, that contains a microsatellite and a pair of tandem and complementary mononucleotide runs; both the microsatellite and the runs show length variation. An analysis of site variation revealed that 9.6% of the nucleotides at CpG sites were variable, as were 3% of the nucleotides found in mononucleotide runs of >/=5 nucleotides, 3% of the nucleotides found

Complex adaptive systems and human health: the influence of common genotypes of the apolipoprotein E (ApoE) gene polymorphism and age on the relational order within a field of lipid metabolism traits.

We analyzed the influence of age, apolipoprotein E (ApoE) genotype, and their interaction on the variation of each of all possible pairwise correlations among plasma levels of ApoE, ApoB, total cholesterol, triglyceride, and HDL cholesterol. Our cross-sectional study sample included 1,876 individuals (979 females and 897 males) from the Rochester, MN population, unselected for health, with a common ApoE genotype of epsilon32, epsilon33, or epsilon43, and ranging in age from 5 to 90 years. We conducted analyses on data from female and male subjects separately, using a hierarchical set of generalized additive models. The age changes in the correlations were estimated using a 30-year sliding window across the age range. There were qualitative differences between genders in the age at which the peaks in the correlations occurred. For female subjects, peaks in correlations were mostly in the middle and older age windows, whereas in males, peaks were mostly in the younger and middle age windows. We found for both genders that for each of the possible pairwise correlations, the influence of age was significantly dependent on ApoE genotype (all Pr<0.0001). We also found for female and male subjects that the epsilon32- and epsilon43- specific age changes in the correlations were each significantly different from those for the epsilon33 genotype (Pr<0.0001), with two exceptions for males (marginally significant differences, P<0.08). We conclude that the influence of ApoE genotypic variation extends far beyond the levels of the gene product, to the dynamics of the relational order among measures of lipid metabolism with age. Moreover, age and common ApoE genotype are not independent predictors of the gender-specific changes in relational order that we observed among these measures of lipid metabolism. These results have implications for the development and application of therapeutic approaches to treat human disease and our enhanced understanding of the role of genetic variation in the dynamic actions of complex adaptive systems with age that occur in response to environmental change. These dynamic actions emerge as the phenotypes that are measures of human health in the population at large.

Sources of variation in plasma lipid and lipoprotein traits in a sample selected for health.

Substantial variation in plasma lipid, lipoprotein, and apolipoprotein B levels was found in a sample of healthy white collar workers aged 23-59 years (144 women, 371 men) devoid of most clinically identifiable manifestations of cardiovascular disease or major biochemical anomalies and for whom data were gathered in Montreal, Canada, in 1987. The nature of this variability was examined for each gender by means of a stepwise linear regression analysis using indices of biologic variation and behavioral traits. In women, age, height, and weight together accounted for approximately 10% and uric acid for another 7-10% of total cholesterol, low density lipoprotein (LDL) cholesterol, and apolipoprotein B level variation. In men, age alone accounted for 13-16% of the total variation in these traits while uric acid contributed only 3%. The additional contribution of behavioral traits was found to be at least double that associated with the indices of biologic variation for measures of very low density lipoprotein (VLDL) and high density lipoprotein (HDL) cholesterol in women and HDL cholesterol in men. After taking all of the above into account, genetic variation determined by the three common apo E alleles explained an additional 6% of LDL cholesterol variation in women and 3.5% in men. These results emphasize the range of variability in lipid, lipoprotein, and apolipoprotein values in healthy individuals as well as important gender differences in the contribution of biologic, behavioral, and genetic factors in this variability.

Context-dependent associations of the ACE I/D polymorphism with blood pressure.

The objective of the present study was to assess whether the influences of gender, age, or measures of body size on blood pressure are homogeneous among genotypes of the insertion/deletion (I/D) polymorphism of the gene that codes for angiotensin-converting enzyme (ACE). We studied a sample of 1875 non-Hispanic white individuals (988 female and 887 male subjects) between 5 and 90 years of age from the general population of Rochester, Minn. When statistical interactions between effects associated with the I/D polymorphism and age, height, and weight were not considered, there was no evidence of a significant relationship between variation in blood pressure level or diagnostic category (hypertension versus normotension) and variation in ACE genotype in either gender. However, in females 5 to 29.9 years of age, the linear regression relationships of systolic blood pressure level with age and weight and of diastolic blood pressure level with age were significantly heterogeneous among ACE genotypes. For these concomitant traits, the rank order of expected blood pressure levels associated with each genotype reversed from low values of the concomitant, in which blood pressure was lower for I/D heterozygotes than for II or DD homozygous, to high levels of the concomitant, in which blood pressure was higher for I/D heterozygotes than for II or DD homozygotes. In male subjects 50 to 90 years of age, the logistic regression relationship of the probability of having hypertension with height was also heterogeneous among ACE genotypes; it was statistically significant in II homozygotes but not statistically significant in either I/D heterozygotes or DD homozygotes. Findings of this study are consistent with the conclusion that the influence of variation in the ACE gene on interindividual variation in blood pressure is dependent on contexts that are indexed by gender, age, and measures of body size.

Genome-wide linkage analyses of systolic blood pressure using highly discordant siblings.

BACKGROUND: Elevated blood pressure is a risk factor for cardiovascular, cerebrovascular, and renal diseases. Complex mechanisms of blood pressure regulation pose a challenge to identifying genetic factors that influence interindividual blood pressure variation in the population at large. METHODS AND RESULTS: We performed a genome-wide linkage analysis of systolic blood pressure in humans using an efficient, highly discordant, full-sibling design. We identified 4 regions of the human genome that show statistical significant linkage to genes that influence interindividual systolic blood pressure variation (2p22.1 to 2p21, 5q33.3 to 5q34, 6q23.1 to 6q24.1, and 15q25.1 to 15q26.1). These regions contain a number of candidate genes that are involved in physiological mechanisms of blood pressure regulation. CONCLUSIONS: These results provide both novel information about genome regions in humans that influence interindividual blood pressure variation and a basis for identifying the contributing genes. Identification of the functional mutations in these genes may uncover novel mechanisms for blood pressure regulation and suggest new therapies and prevention strategies.

The relationship between risk factor levels and presence of coronary artery calcification is dependent on apolipoprotein E genotype.

An important research question in the study of the genetics of coronary artery disease (CAD) is whether information about genetic variation will improve our ability to predict CAD beyond established risk factors. This question is especially relevant to the goal of identifying young, asymptomatic adults with coronary atherosclerosis who would benefit most from interventions to reduce risk. Coronary artery calcification (CAC) detected by electron-beam computed tomography is a relatively new method for detecting coronary atherosclerosis in asymptomatic individuals that has been shown to be a more accurate indicator of coronary atherosclerosis in asymptomatic individuals than other noninvasive techniques. In a study of asymptomatic women (n=169) and men (n=160) between the ages of 20 and 59 representative of the Rochester, Minnesota population, we used logistic regression to ask whether the most common Apolipoprotein (Apo) E genotypes (epsilon3/2, epsilon3/3, and epsilon4/3) predict the presence of CAC. The addition of information about ApoE genotypes to logistic models containing each separate risk factor did not improve prediction of CAC (P>0.10 in both women and men). However, there was significant evidence (P<0.10) that associations between variation in the probability of having CAC and variation in body mass index, plasma total cholesterol, and plasma ApoB in men and body mass index, plasma triglycerides, plasma ApoA1, and plasma ApoE in women were dependent on ApoE genotype. Thus, variation in the gene coding for ApoE may play a role in determining the contribution of established risk factors to risk of CAC.