Search

Background: Studies of adiposity and brain pathology in African Americans (AA) are sparse despite higher rates of obesity, dementia, and dementia-associated brain pathology in AA. This study examined relations of adiposity to white matter hyperintensities (WMH) and total brain volume (TBV) in AA and non-Hispanic whites (NHW)., Methods: Waist circumference (WC) and body mass index (BMI) were measured in the Genetic Epidemiology Network of Arteriopathy study at Visits 1 (mean age 57 [±11]) and 2 (mean age 61 [±10], mean 5.2 years later). Brain MRIs were obtained shortly after Visit 2 in 1,702 participants (64% women, 48% AA). Multilevel linear regression using generalized estimating equation estimated associations of adiposity (cross-sectional) or adiposity changes with WMH (accounting for intracranial size) or TBV adjusting for demographics, cardiovascular risk factors, and incorporating adiposity-by-race interactions. Adiposity-by-age interactions were examined., Results: Concurrent TBV was inversely associated with BMI (β = -2.76 [95% confidence interval (CI): -4.99, -0.53]) and WC (β = -2.19 [CI: -4.04, -0.34]). Concurrent WMH were negatively associated with BMI (β = -0.04 [CI: -0.06, -0.01]) and, among NHW, with WC (β = -0.04 [CI: -0.06, -0.02]) but not with changes in BMI or WC. BMI increases were associated with lower TBV (β = -16.20, [CI: -30.34, -2.06]) in AA but not in NHW (β = -2.76 [CI: -14.02, 8.51]), although race-by-adiposity interactions were not supported. WC increases were not associated with MRI outcomes., Conclusion: Greater measures of obesity and increases in measures of obesity, which are common in mid-life, could be detrimental to brain health, particularly in AA., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To evaluate cardiac troponin T (cTnT) as a predictor of end-stage renal disease (ESRD) and death in a cohort of African American and white community-dwelling adults with hypertensive families., Patients and Methods: A total of 3050 participants (whites from Rochester, Minnesota; African Americans from Jackson, Mississippi) of the Genetic Epidemiology Network of Arteriopathy study were followed from baseline examination (June 1, 1996, through August 31, 2000) through January 22, 2010. Cox proportional hazards regression models were used to examine the association of cTnT with ESRD and death after adjusting for traditional risk factors., Results: Cohort demographic characteristics and measurements included 1395 whites (45.7%), 2174 hypertensive (71.3%), 992 estimated glomerular filtration rate of less than 60 mL/min per 1.73 m(2) (32.5%), 1574 high-sensitivity C-reactive protein level of greater than 3 mg/L (51.6%), and 66 abnormal cTnT level of 0.01 ng/mL or higher (2.2%). The estimated cumulative incidence of ESRD at 10 years was 27.4% among those with abnormal cTnT levels compared with 1.3% for those with normal levels. Similarly, the estimated cumulative incidence of death at 10 years was 47% among those with abnormal cTnT compared with 7.3% among those with normal cTnT. Abnormal cTnT levels were strongly associated with ESRD and death. This effect was attenuated but was still highly significant after adjustment for demographic characteristics, estimated glomerular filtration rate, and traditional risk factors for ESRD (unadjusted hazard ratio [HR], 23.91; 95% CI, 12.9-44.2; adjusted HR, 2.81; 95% CI, 1.3-5.9) and death (unadjusted HR, 8.43; 95% CI, 6.0-11.9; adjusted HR, 3.46; 95% CI, 2.3-5.1)., Conclusion: Cardiac troponin T makes an independent contribution to the prediction of ESRD and all-cause death in community-dwelling individuals beyond traditional risk markers. Further studies may be needed to determine whether cTnT screening in individuals with hypertension or in a subset of hypertensive individuals would help identify those at risk of ESRD and all-cause death., (Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the effect of demographics including age and sex on excretion of 4 key urinary factors (calcium [Ca], magnesium [Mg], oxalate and uric acid [UA]) related to kidney stone risk., Methods: Twenty-four-hour urine samples were collected from non-Hispanic white sibships in Rochester, MN. Height, weight, blood pressure, serum creatinine, and cystatin C were measured. Diet was assessed using the Viocare food frequency questionnaire. Effects of demographics and dietary elements on urinary excretions were evaluated in univariate, multivariate, and interaction models that included age, sex, and body mass index (BMI)., Results: Samples were available from 709 individuals. In multivariate models, sex was a significant predictor of all 4 urinary factors, age was significant for all but UA excretion, and serum creatinine was significant only for Ca and Mg excretion (P <.05). BMI or weight positively correlated with Mg, oxalate, and UA excretion (P <.05). Use of a thiazide diuretic (lower) and dietary protein (higher) were associated with Ca excretion, whereas dietary Ca was associated with higher Mg excretion. Urinary UA excretion increased with animal protein intake and cystatin C estimated glomerular filtration rate (eGFR) and was lower with concurrent loop diuretic use. Significant interaction effects on urinary UA excretion were observed for loop diuretic use and sex, eGFR and sex, age and animal protein intake, and BMI and eGFR (P <.05)., Conclusion: Age and sex influence excretion of key urinary factors related to kidney stone risk and should be taken into account when evaluating kidney stone patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Chronic kidney disease risk factors may associate with the estimated glomerular filtration rate (eGFR) differently than with the measured GFR. To examine this, we evaluated 1150 patients (mean age 65 years) in two community cohorts for risk factors, measured GFR by iothalamate clearance, and eGFR based on creatinine (Cr), cystatin C (CysC), or both. The interaction between each risk factor and eGFR (relative to measured GFR) identified risk factor associations with eGFR along non-GFR pathways. In a subset of 40 patients with two visits, the mean coefficient of variation was 8.2% for measured GFR, 6.4% for eGFRCr, 8.2% for eGFRCr-CysC, and 10.7% for eGFRCysC. The measured GFR was better correlated with eGFRCr-CysC (r, 0.74) than eGFRCr (r, 0.70) or eGFRCysC (r, 0.68). Lower measured GFR associated with lower 24-hour urine creatinine, albuminuria, hypertension, diabetes, higher triglycerides, and higher uric acid. Lower eGFRCr had these same associations except for an association with higher 24-hour urine creatinine along a non-GFR pathway. Lower eGFRCysC and eGFRCr-CysC also had these same associations but also associated with obesity, albuminuria, hypertension, diabetes, higher triglycerides, higher C-reactive protein, and higher uric acid along non-GFR pathways. Thus, cystatin C improves estimation of GFR over creatinine alone; however, the association between most of the risk factors and GFR was more accurate by eGFR based on creatinine alone. This is explained by the association of these risk factors with the non-GFR determinants of cystatin C.

Objectives: Our goal was to evaluate the associations of central arterial stiffness, measured by aortic pulse wave velocity (aPWV), with subclinical target organ damage in the coronary, peripheral arterial, cerebral, and renal arterial beds., Background: Arterial stiffness is associated with adverse cardiovascular outcomes. We hypothesized that aPWV is associated with subclinical measures of atherosclerosis-coronary artery calcification (CAC) and ankle-brachial index (ABI) and arteriolosclerosis-brain white matter hyperintensity (WMH) and urine albumin-creatinine ratio (UACR)., Methods: Participants (n = 812; mean age 58 years; 58% women, 71% hypertensive) belonged to hypertensive sibships and had no history of myocardial infarction or stroke. aPWV was measured by applanation tonometry, CAC by electron beam computed tomography, ABI using a standard protocol, WMH volume by brain magnetic resonance, and UACR by standard methods. WMH was log-transformed, whereas CAC and UACR were log-transformed after adding 1 to reduce skewness. The associations of aPWV with CAC, ABI, WMH, and UACR were assessed by multivariable linear regression using generalized estimating equations to account for the presence of sibships. Covariates included in the models were age, sex, body mass index, history of smoking, hypertension and diabetes, total and high-density lipoprotein cholesterol, estimated glomerular filtration rate, use of aspirin and statins, and pulse pressure., Results: The mean ± SD aPWV was 9.8 ± 2.8 m/s. After adjustment for age, sex, conventional cardiovascular risk factors, and pulse pressure, higher aPWV (1 m/s increase) was significantly associated with higher log (CAC + 1) (β ± SE = 0.14 ± 0.04; p = 0.0003), lower ABI (β ± SE = -0.005 ± 0.002; p = 0.02), and greater log (WMH) (β ± SE = 0.03 ± 0.009; p = 0.002), but not with log (UACR + 1) (p = 0.66)., Conclusions: Higher aPWV was independently associated with greater burden of subclinical disease in coronary, lower extremity, and cerebral arterial beds, highlighting target organ damage as a potential mechanism underlying the association of arterial stiffness with adverse cardiovascular outcomes., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Sodium lithium countertransport (SLC) is an intermediate phenotype of essential hypertension. The aim of this study was to identify candidate genes for SLC by a strategy of combining gene expression profiling and linkage analysis, and to examine the association between the candidate gene and SLC as well as hypertension., Methods: In order to identify SLC-related genes, the top 1% of the genes that were differentially expressed between high- and low-SLC groups in a gene expression microarray were compared with published SLC/hypertension gene linkage maps so as to identify regions of overlap. The association between the genetic variation in the candidate gene and the SLC and blood pressure phenotypes were further assessed in the Rochester Family Heart Study (RFHS) involving 1,815 individuals of European ancestry, belonging to 252 pedigrees., Results: Based on gene expression profiling and evidence from genome-wide linkage analysis, and in the light of its potential biochemical function, E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) was identified as being both a positional and a functional candidate gene for SLC. The difference in expressions of NEDD4L between the high- and low-SLC groups was confirmed by reverse transcription-PCR (RT-PCR) analysis. After adjusting for age, sex, and body mass index (BMI), four single-nucleotide polymorphisms (SNPs) in NEDD4L were found to be associated with SLC (P ≤ 0.05). Further, haplotype analysis revealed that, after correction for multiple testing, one of the haplotypes (H2) was still significantly (P = 0.006) associated with SLC., Conclusions: The strategy of combining gene expression profiling and linkage analysis successfully guided us in identifying NEDD4L as a candidate gene involved in regulating SLC activity. Variations in the NEDD4L gene are associated with SLC activity.

Background: Midregional pro-atrial natriuretic peptide (MR-proANP) is a newly described stable fragment of the N-terminal part of pro-atrial natriuretic peptide. We tested the hypothesis that in adults with essential hypertension, plasma levels of MR-proANP would be associated with systolic blood pressure (SBP), pulse pressure, and hypertension severity., Methods: Participants included 1,034 African Americans (65 +/- 9 years, 72% women) and 880 non-Hispanic whites (61 +/- 9 years, 55% women) belonging to sibships ascertained on the basis of hypertension. MR-proANP was measured by an immunoluminometric assay. Hypertension severity was based on number of hypertension medication classes used and multiples of SBP and diastolic blood pressure (DBP) deviations from 120/70 mm Hg. Generalized estimating equations were used to assess whether plasma levels of MR-proANP were associated with SBP, pulse pressure, and hypertension severity independent of potential confounding variables., Results: In African Americans, after adjustment for age, sex, body mass index, estimated glomerular filtration rate (eGFR), smoking history, diabetes, total cholesterol, high-density lipoprotein cholesterol, medication (beta-blocker, statin, and aspirin) use, and previous history of myocardial infarction or stroke, higher MR-proANP levels were significantly associated with greater SBP (P < 0.0001), pulse pressure (P < 0.0001), and hypertension severity (P = 0.0013). The associations were replicated in non-Hispanic whites; after adjustment for the above variables, higher MR-proANP levels were significantly associated with greater SBP (P = 0.013), pulse pressure (P = 0.0006), and hypertension severity (P = 0.028)., Conclusion: Plasma MR-proANP may be a marker of arterial stiffness and severity of hypertension in adults with hypertension.

Background: Comparison of atherosclerosis and its risk factors among diverse populations may provide insights into the pathogenesis of the disease. We investigated differences in traditional coronary artery disease (CAD) risk factors and presence and quantity of coronary artery calcification (CAC), a marker of subclinical coronary atherosclerosis, between two diverse non-Hispanic white populations living in the US., Methods and Results: Members of the Old Order Amish (OOA), a unique culture with a physically active rural lifestyle who rarely use prescription medications, were compared to another non-Hispanic white population with a more typical US lifestyle, Epidemiology of Coronary Artery Calcification (ECAC), Study participants from Rochester, Minnesota. Although age- and sex-adjusted presence and quantity of CAC in those with detectable CAC were similar between study groups, there were significant differences in the distribution of many traditional CAD risk factors. OOA had significantly less abdominal adiposity and history of cigarette smoking but a less advantageous lipid profile than ECAC participants. Importantly, after adjusting for CAD risk factors, presence of CAC and quantity of CAC among those with detectable CAC were significantly higher among OOA than ECAC participants., Conclusions: Identification of factors contributing to differences in subclinical disease across groups could increase our understanding of mechanisms for coronary atherosclerosis.

Background: Increased erythrocyte sodium-lithium countertransport (SLC) has been observed in patients with essential hypertension. Consistent evidence of genetic linkage was shown for SLC on chromosome 10, and a region of interest was localized between 26 and 56 Mb., Methods: This study surveyed single nucleotide polymorphisms (SNPs) in 54 genes that reside in the region of interest, and investigated their association with SLC and blood pressure. These SNPs were genotyped in 1,133 non-Hispanic white individuals from 255 pedigrees comprising the second phase of the Rochester Family Heart Study. The variance-components-based genetics software package SOLAR was used for evaluating whether an SNP contributed to a significant fraction of the trait heritability., Results: Of the 77 SNPs surveyed in this study across the region of interest, four SNPs were associated with SLC (P < 0.04), five SNPs were associated with blood pressure (P < 0.04), and two SNPs in mannose-binding lectin 2 (MBL2) were associated with both phenotypes. In general, the pairwise linkage disequilibrium among the genotyped SNPs was low., Conclusions: This fine-mapping survey of genetic variation in a linkage region of interest provides overall support for association-mapping for SLC on chromosome 10. Genes significantly associated with systolic blood pressure and/or SLC in these families will be prioritized for future studies.

Purpose: To assess if the treatment and control of hypertension aggregates in families., Methods: The Genetic Epidemiology Network of Arteriopathy (GENOA) study enrolled sibships between 1997 and 1999, including 1329 hypertensive non-Hispanic blacks (1057 sibling pairs) from Jackson, Mississippi, 1133 hypertensive non-Hispanic whites (859 sibling pairs) from Rochester, Minnesota, and 752 hypertensive Hispanic whites (627 sibling pairs) from Starr County, Texas. Hypertension awareness and drug treatment were ascertained at examination; control was defined by blood pressure levels <140/90 mm Hg. As a measure of familial aggregation, odds ratios were calculated to assess concordance between sibling pairs in the treatment and control of hypertension., Results: Overall, 90.5% of subjects were aware of their hypertension; 90.6% of those who were aware were treated with antihypertensive drugs and 56.0% of those treated had their hypertension controlled. There was statistically significant sib-sib concordance in the treatment of hypertension (odds ratio [OR] = 1.61; 95% confidence interval [CI]: 1.25 to 2.47; P = 0.003) and in the control of drug-treated hypertension (OR = 1.51; 95% CI: 1.25 to 1.81; P <0.0001)., Conclusion: These findings suggest that the treatment and control of hypertension aggregates in families.

Background and Purpose: Hypertension is an important risk factor for stroke, and the 2 diseases may share susceptibility genes in common. We sought to identify genomic regions influencing susceptibility to both hypertension and stroke., Subjects and Methods: Genome-wide linkage scans were performed in samples of 338 white and 265 black hypertensive sibships recruited by the Genetic Epidemiology Network of Arteriopathy Study of the NHLBI Family Blood Pressure Program (FBPP). The hypertensive sibships were stratified by positive (+FH) or negative (-FH) family history of stroke. Genome-wide scans were repeated in each stratum, and the results were compared within each ethnic group by a regression-based analysis of heterogeneity., Results: In whites, the best evidence for linkage was found on chromosome 16 in the unstratified sample of hypertensive sibpairs (logarithm of odds [LOD]=1.85 at 71 cM). In blacks, the best evidence for linkage was found on chromosome 2 in the unstratified sample of hypertensive sibpairs (LOD=1.95 at 230 cM). Additional evidence for linkage (LOD >or=1.5) was observed among white hypertensive sibpairs with a -FH on chromosome 13 and among black hypertensive sibpairs with a +FH of stroke on chromosome 19., Conclusions: Significant evidence for linkage heterogeneity among hypertensive sibpairs stratified by family history of stroke suggests the presence of genes influencing susceptibility to both hypertension and stroke on chromosomes 13 (whites) and 19 (blacks). Although no significant evidence of heterogeneity was observed on chromosome 16 in whites and chromosome 2 in blacks, these chromosomes do provide evidence of linkage to hypertension.

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.

Background: The renin-angiotensin system regulates blood pressure through its effects on vascular tone, renal hemodynamics, and renal sodium and fluid balance., Methods and Results: Using data from a large population-based sample of 1488 siblings having a mean age of 14.8 years and belonging to the youngest generation of 583 randomly ascertained three-generation pedigrees from Rochester, Minn, we carried out variance components-based linkage analyses to evaluate the contribution of variation in four renin-angiotensin system gene regions (angiotensinogen, renin, angiotensin I-converting enzyme, and angiotensin II receptor type 1) to interindividual variation in systolic, diastolic, and mean arterial pressure. We rejected the null hypothesis that allelic variation in the region of the angiotensin-converting enzyme (ACE) gene does not contribute to interindividual blood pressure variability. After conditioning on measured covariates, variation in this region accounted for 0%, 13% (P=0.04), and 16% (P=0.04) of the interindividual variance in systolic, diastolic, and mean arterial pressures, respectively. These estimates were even greater in a subset of subjects with a positive family history of hypertension (0%, 29% [P=0.005], and 32% [P<0.005], respectively). In sex-specific analyses, genetic variation in the region of the ACE gene significantly influenced interindividual blood pressure variation in males (37% for SBP [P=0.03], 38% for DBP [P=0.04], and 53% for MAP [P<0.005]) but not in females., Conclusions: Although it is possible that variation in a gene near the ACE gene may explain the observed results, knowledge about the physiological involvement of ACE in blood pressure regulation supports the proposition that the ACE gene itself influences blood pressure variability in a sex-specific manner.

Objective: To determine whether genetic and non-genetic components of interindividual variation in systolic and diastolic blood pressure are constant throughout the day or are time or activity dependent., Methods: We obtained 24 h ambulatory blood pressure recordings in 263 members of 68 unrelated nuclear families (i.e. parents and their offspring) representative of the Caucasian population of Rochester, MN, USA. Using the time each patient got into bed as a reference point, we identified 198 records in which this reference point was preceded by eight consecutive active hours (out of bed) and followed by four consecutive inactive hours (in bed) in which four or more blood pressure readings taken each hour were judged to be technically satisfactory. For each hourly mean for systolic and diastolic blood pressure, we estimated total interindividual variance, variance associated with concomitant variables (generation; sex within generation strata; and age, height, weight, body mass index, and abdomen-to-hip ratio within generation and sex strata), and variance associated with additive genetic effects (i.e. the chief cause of resemblance between relatives). To assess trends in each component of interindividual blood pressure variance over the 12 h period, we estimated the slope of the linear regression line fit to the hourly estimates., Results: For systolic blood pressure, total interindividual variance did not change significantly (slope of regression line = -0.23, P = 0.717). In contrast, total interindividual variance for diastolic blood pressure was greater during active hours than inactive hours (slope of regression line = -5.53, P < 0.001). For both systolic and diastolic blood pressure, variance associated with the concomitant variables was greater during active hours than during inactive hours (for systolic blood pressure slope of regression line = -2.98, P = 0.001; for diastolic blood pressure slope of regression line = -6.14, P < 0.001). Likewise, for both systolic and diastolic blood pressure, variance associated with additive genetic effects was also greater during active hours than during inactive hours (for systolic blood pressure slope of regression line = -1.65, P = 0.090; for diastolic blood pressure slope of regression line = -1.47, P = 0.018)., Conclusions: This study demonstrates that components of interindividual variation in blood pressure are not constant, but are time or activity dependent.

Objective: To assess the relationship of plasma atrial natriuretic peptide (ANP) levels with blood pressure levels and the occurrence of hypertension in a large population-based sample., Design: We performed a cross-sectional study of the relationship between ANP levels and blood pressure levels, diagnosis of hypertension, and family history of hypertension in Caucasians from Rochester, Minnesota., Material and Methods: Plasma ANP and blood pressure levels were measured in 1,338 Caucasian subjects who were members of 301 three-generation families from the population of Rochester. Hypertension was defined as systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm Hg or more. Each subject in the parental generation was categorized as having zero, one, or two parents with hypertension. Analyses were done separately for each generation and gender stratum., Results: Within gender and generation strata, we noted no consistent pattern of positive or negative correlation of plasma ANP levels with systolic blood pressure, diastolic blood pressure, or heart rate. Within the grandparental generation, mean plasma ANP levels did not differ between those with normal blood pressure and those with hypertension. In the parental generation, mean plasma ANP levels did not differ between subjects with zero, one, or two parents with hypertension., Conclusion: In Caucasians, interindividual differences in plasma ANP levels are not associated with interindividual differences in blood pressure levels, the diagnosis of hypertension, or family history of hypertension.

A variant of the angiotensinogen gene, M235T, has been associated with essential hypertension in selected subjects from Paris, France and Salt Lake City, Utah. In the present report, we studied a population-based sample consisting of 104 subjects diagnosed with hypertension before age 60 and 195 matched normotensive individuals from Rochester, Minnesota. We determined whether there was a relationship between the M235T polymorphism of the angiotensinogen gene and the occurrence of essential hypertension using two methods. First, a contingency chi-square analysis was carried out to test for an association between the M235T polymorphism and hypertension status. Second, multivariable conditional logistic regression was used to determine whether variation at the M235T polymorphism was a significant predictor of the probability of having essential hypertension. We detected no statistically significant association between the M235T polymorphism and the occurrence of essential hypertension. In particular, the association was not significant in either gender or in a subset of severely hypertensive subjects requiring two or more anti-hypertensive medications. Furthermore, variation in the number of M235T alleles did not make a significant contribution to predicting the probability of having essential hypertension, either alone or in conjunction with other predictor variables. These results suggest that the contribution of variation in the angiotensinogen gene to the occurrence of essential hypertension is less than initially suspected, or may not be constant across populations.

The objectives of the present study were to determine whether increased sodium-lithium countertransport is associated with essential hypertension in the general Caucasian population and to determine whether this association is independent of the effects of gender, age, body size, and plasma lipids. We studied 543 men and 589 women from the population of Rochester, Minnesota. Mean sodium-lithium countertransport was higher in hypertensive than in normotensive subjects in men (370 +/- 147 [mean +/- SD] versus 315 +/- 110 mumol/l red blood cells [RBC]/hr, p less than 0.001) and in women (339 +/- 114 versus 269 +/- 92 mumol/l RBC/hr, p less than 0.001). Interindividual differences in plasma triglycerides, body mass index (wt/[ht]2), and plasma total cholesterol explained 13.0% of sodium-lithium countertransport variation in men (p less than 0.001) and 20.2% in women (p less than 0.001). Age did not predict additional sodium-lithium countertransport variation in either gender. Slopes of the regressions of sodium-lithium countertransport on plasma triglycerides, body mass index, and plasma total cholesterol did not differ between diagnostic groups in men (p = 0.31) or in women (p = 0.29). After adjustment to remove sodium-lithium countertransport variation attributable to these covariates, mean sodium-lithium countertransport remained significantly higher in hypertensive than in normotensive subjects in men (354 +/- 139 versus 319 +/- 104 mumol/l RBC/hr, p less than 0.01) and in women (311 +/- 103 versus 278 +/- 83 mumol/l RBC/hr, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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.