Venous Leak Embolization in Patients with Venogenic Erectile Dysfunction via Deep Dorsal Penile Vein Access: Safety and Early Efficacy.

PURPOSE: This all-comers registry aimed to assess safety and early efficacy of venous embolization in patients with venogenic erectile dysfunction due to venous leak in an unselected cohort. METHODS: Between October 2019 and September 2022, patients with venogenic erectile dysfunction resistant to phosphodiesterase-5-inhibitors were treated with venous embolization using ultrasound-guided anterograde access via a deep dorsal penile vein in a single center. A mix of ethiodized oil and modified cyanoacrylate-based glue n-butyl 2 cyanoacrylate (NBCA) monomer plus methacryloxy-sulpholane monomer (Glubran-2, GEM, Italy) was used as liquid embolic agent. Prior to embolization, venous leak had been verified based on penile duplex sonography and computed tomography cavernosography. Procedural success was defined as technically successful and complete target vein embolization. The primary safety outcome measure was any major adverse event 6 weeks after the procedure. The primary feasibility outcome measure was IIEF-15 (International Index of Erectile Function-15) score improvement ≥ 4 points in ≥ 50% of subjects on 6 weeks follow-up post intervention. RESULTS: Fifty consecutive patients (mean age 61.8 ± 10.0 years) with severe erectile dysfunction due to venous leak underwent venous embolization. Procedural success was achieved in 49/50 (98%) of patients with no major adverse events on follow-up. The primary feasibility outcome measure at 6 weeks was reached by 34/50 (68%) of patients. CONCLUSION: Venous leak embolization via deep dorsal penile vein access using a liquid embolic agent was safe for all and efficacious in the majority of patients with severe venogenic erectile dysfunction on 6 weeks follow-up.

A prospective cohort of American Indian and Alaska Native people: study design, methods, and implementation.

In 2001, the National Cancer Institute funded three centers to test the feasibility of establishing a cohort of American Indian and Alaska Native people. Participating tribal organizations named the study EARTH (Education and Research Towards Health). This paper describes the study methods. A computerized data collection and tracking system was developed using audio computer-assisted survey methodology with touch screens. Data were collected on diet, physical activity, lifestyle and cultural practices, medical and reproductive history, and family history of heart disease, diabetes, and cancer. In addition, a small panel of medical measurements was obtained, including height, weight, waist and hip circumferences, blood pressure, and a lipid panel plus glucose. At the completion of the enrollment visit, data were used to provide immediate health feedback to study participants. During the initial funding period, the authors anticipate enrolling 16,000 American Indian and Alaska Native participants. The age distribution of the study population was similar to that reported in the 2000 US Census for the relevant populations. A component critical to the success of the EARTH Study has been the partnerships with tribal members. The study has focused on involvement of American Indian and Alaska Native communities in development and implementation and on provision of feedback to participants and communities.

Genetic basis of familial dyslipidemia and hypertension: 15-year results from Utah.

The genetic and environmental determinants of hypertension, lipid abnormalities, and coronary artery disease (CAD) have been studied for 15 years in Utah in population-based multigenerational pedigrees (2500 subjects among 98 pedigrees), twin pairs (74 monozygous and 78 dizygous), hypertensive siblings (131 sibships), siblings with CAD before age 55 (45 sibships), and anecdotally ascertained pedigrees with type II diabetes (271 subjects among 16 pedigrees), lipoprotein lipase deficiency (106 subjects in a single pedigree), and familial hypercholesterolemia (502 heterozygotes among 50 pedigrees). Estimates of heritability ranged from 20 to 75% for blood pressures and blood lipids. A strong positive family history predicts a future occurrence of hypertension (relative risk [RR] = 3.8) and CAD (RR = 12.7). Segregating single-gene effects were found for several 'intermediate phenotypes' associated with hypertension (erythrocyte sodium-lithium countertransport, intraerythrocytic sodium, a relative fat pattern, total urinary kallikrein excretion, and fasting insulin levels). Strong single-gene effects in segregation analysis were also found for low-density lipoprotein (LDL) cholesterol, lipoprotein (a) (Lp[a]), low high-density lipoprotein (HDL) cholesterol, and high apolipoprotein (apo) B. Deoxyribonucleic acid (DNA) markers of lipid abnormalities or hypertension have included LDL-receptor defects, lipoprotein lipase deficiency, high Lp(a), familial defective apo B, decreased quantitative levels of apo B, apo E phenotype, angiotensinogen, and 'glucocorticoid remediable aldosteronism (GRA) hypertension.' Also tested in Utah studies, but not found to be DNA markers for hypertension, were the genetic loci for the structural genes for renin and angiotensin-converting enzyme, and the sodium antiport system. In addition, important gene-gene interactions (LDL receptor with apo E2) and gene-environment interactions (kallikrein with potassium intake) were found.(ABSTRACT TRUNCATED AT 250 WORDS)

Documented need for more effective diagnosis and treatment of familial hypercholesterolemia according to data from 502 heterozygotes in Utah.

A project to help Utah residents with heterozygous familial hypercholesterolemia (FH) identified affected individuals by collecting detailed questionnaires from: (1) very high-risk persons in computer files of screening data (very high cholesterol levels, very early coronary artery disease, and strong positive family history); (2) confirmed FH index cases from a university lipid clinic; and (3) relatives of any confirmed FH cases. Questionnaires were received from 2,143 persons identifying 101 living index cases and 502 relatives meeting the criteria for the diagnosis of FH. Finding new FH heterozygotes was about one fourth as expensive by tracing relatives of confirmed FH cases by evaluating very high-risk persons. Of those meeting criteria for the diagnosis of heterozygous FH, only 31% reported being told by their physicians that they had FH, only 42% indicated that they were taking a cholesterol-lowering prescription medication, and only 23% had reasonably controlled cholesterol levels (below the 90th percentile). However, the data also suggest that good control is achievable in motivated patients. Among 106 FH heterozygotes who were early responders to a second follow-up questionnaire, 79% were taking prescription medications, of whom 49% had achieved cholesterol levels below the 90th percentile, and 17% even achieved cholesterol levels below the 50th percentile. We conclude that most patients with heterozygous FH are not diagnosed and not adequately treated. We demonstrated how many of these persons needing help could be identified efficiently by tracing relatives of known index cases.

Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics.

Heterozygous familial hypercholesterolemia (FH) is a serious disorder causing twice normal low-density lipoprotein cholesterol levels early in childhood and very early coronary disease in both men and women. Treatment with multiple medications and diet can normalize cholesterol levels in many persons with FH and prevent or delay the development of coronary atherosclerosis. Thus, there is a need for accurate and genetically validated criteria for the early diagnosis of heterozygous FH. Previously published blood cholesterol criteria greatly underdiagnosed new cases of FH among members of known families with FH in Utah and overdiagnosed FH among participants of general population screening, revealing the need for different cholesterol screening criteria in persons from these 2 different settings. The statistical concept of a priori probabilities was applied to derive 2 sets of practical screening criteria: one for persons participating in general population screening studies and another for close relatives of confirmed FH cases, showing dramatic differences. At a cholesterol level of 310 mg/dl, only 4% of persons in the general population would have FH but 95% of persons who were first-degree relatives of known cases would have FH. Detailed tables were derived to provide practical total and low-density lipoprotein blood cholesterol screening criteria for diagnosing FH in different screening settings and specific age groups. In population screening the new FH criteria require a total cholesterol > 360 mg/dl for age 40+ (or 270 mg/dl in youth). Among first-degree relatives of confirmed cases in families with FH, the new total cholesterol criteria are much lower (> 290 mg/dl for age 40+, > 220 mg/dl for youth).(ABSTRACT TRUNCATED AT 250 WORDS)

Methionine for valine substitution in exon 17 of the insulin receptor gene in a pedigree with familial NIDDM.

INSR gene mutations have been described in multiple individuals with extreme insulin resistance, but the INSR gene has not been implicated in familial NIDDM. We previously have screened members of 18 familial NIDDM pedigrees for mutations in exons encoding the tyrosine kinase domain of the INSR gene (exons 13-21) by SSCP. That analysis initially detected only patterns consistent with silent polymorphisms, but on direct sequence analysis of exon 17 we detected a Met-for-Val substitution at position 985 in 1/18 pedigrees. We confirmed the substitution by sequence analysis of subcloned, PCR-amplified DNA from two pedigree members and by hybridization to labeled primers for the normal and mutant sequences. We did not find the mutation in any other individuals. Pedigree members were typed for presence or absence of the Met985 substitution by hybridization of PCR-amplified exon 17 DNA to allele-specific oligonucleotide probes, and typing was confirmed by segregation of INSR haplotypes and by SSCP analysis. The substitution was present in 3 NIDDM individuals in 3 generations, including a lean individual with onset at age 24. The substitution was present in only 50% of NIDDM siblings in generation 2, however. To determine the clinical effect of the Met985 substitution, we compared the 5 nondiabetic pedigree members who carried the mutation with the 9 nondiabetic pedigree members without the mutation and with 266 members of other pedigrees. Fasting and 1-h postglucose insulin levels were not different between carriers and noncarriers (fasting, 71.4 pM vs. 74.5 pM; 1-h, 381 pM vs. 354 pM), even after correction for age, sex, and BMI.(ABSTRACT TRUNCATED AT 250 WORDS)

The associations between family history of coronary heart disease, physical activity, dietary intake and body size.

Physical activity has been associated with coronary heart disease (CHD) as well as several CHD risk factors. In this study, we examine the association of a positive family history of CHD and physical activity on dietary intake and body size indicators among 891 healthy young adults (18 to 39 years of age) and 471 older adults (40 to 83) observed between 1980 and 1986. Participants reported the number of times per week they walked and/or jogged one mile, biked three miles, participated in sports, or performed other intense activities. Older men with a family history of CHD reported more physical activity than men without a family history of CHD (60% compared to 28.6%; p = 0.002). Younger women without a family history of CHD reported more physical activity than women with a family history of CHD (30.2% compared to 15.9%; p = 0.004). Fruit and vegetable intake increased with increasing levels of physical activity in younger adults. The only dietary association with family history was higher levels of fatty foods reported among older women with a family history versus those without a family history (p = 0.03). Young women with a family history of CHD were more likely to have higher BMI levels at all levels of physical activity and a higher percent of their ideal body weight per unit of physical activity (p = 0.01). For instance, young women who were most active with a family history of CHD were at 115% of their ideal body weight, while those without a family history were at 110.2% of their ideal body weight. There were no significant interactions between physical activity and CHD family history in this population. These findings suggest that family history of CHD alone may not be adequate to stimulate one to adopt a more healthy lifestyle.

Familial dyslipidaemic hypertension and other multiple metabolic syndromes.

Data from several different studies are reviewed suggesting that a subset of hypertension is associated with metabolic abnormalities involving lipids, insulin, and often obesity, all aggregating strongly in families. Persons with 'familial dyslipidaemic hypertension (FDH)' have an especially high risk of early coronary disease. The clinical and biochemical features of FDH are compared with Reaven's Syndrome X, familial combined hyperlipidaemia, dense LDL subfractions, diabetes, impaired glucose tolerance, central and general obesity, pre-diabetes, pre-hypertension, and heterozygous lipoprotein lipase deficiency. Some contribution from major gene effects is suggested in specific subsets reported in several different genetic studies reviewed in this report. It seems likely that multiple metabolic abnormalities are genetically heterogeneous. The data also suggest significant contributions from environmental factors such as diet and physical activity.

Dyslipidemias among normoglycemic members of familial NIDDM pedigrees.

OBJECTIVE: To examine the hypothesis that hyperinsulinemia among relatives of NIDDM probands will increase the prevalence of DLPs, we measured insulin levels and examined the frequency of DLPs among NIDDM pedigree members. RESEARCH DESIGN AND METHODS: We performed 2-h 75-g OGTTs and measured lipid and insulin levels of 287 family members and 86 spouses from 16 large Utah pedigrees ascertained for greater than or equal to 2 siblings with NIDDM. RESULTS: One-hour insulin levels were higher among 206 family members with NGT than among 65 NGT spouses (483.3 vs. 361.7 pM, P = 0.05). Among the NGT family members, 32% had cholesterol levels at or above the age- and sex-specific 90th percentile level defined by the LRC studies, 33% had HDL levels less than or equal to 10th percentile, and 20% had triglyceride levels greater than or equal to 90th percentile. DLP (any of the three abnormalities) was found among 58% of NGT family members, which was significantly higher than the expected 27% (P less than 0.00001) and the prevalence among spouses of 45% (P less than 0.05). By NCEP criteria for hyperlipidemia, 40% of family members met criteria for diet and/or pharmacological therapy. CONCLUSIONS: Normoglycemic members of NIDDM pedigrees have a high prevalence of DLPs, which approaches the prevalence in patients with NIDDM. Our data suggest that members of NIDDM pedigrees should be screened carefully for lipid abnormalities.

Risk factors for cardiovascular disease predict the development of diabetes among Utah families.

In 1989, we sent a medical follow-up questionnaire to 2,728 members of 98 Utah families originally screened from 1980 to 1983 in the Cardiovascular Genetics Research Clinic. The response rate was 69.9%. Of 1,134 nondiabetic individuals initially age 18 or older who returned the questionnaire, 10 were found to be newly diagnosed with diabetes. The incidence of diabetes was higher among individuals who were found at baseline to have central obesity, lipid abnormalities, especially increased triglyceride levels, and hypertension. Family histories of coronary heart disease and diabetes were not related to the development of diabetes. Our findings that cardiovascular disease risk factors predict the development of diabetes in this relatively young, Caucasian population are consistent with the results of studies from several different populations.

Prevention of familial cardiovascular disease by screening for family history and lipids in youths.

We analyzed medical family history information from 51,053 families of high school students in Utah and Texas and cholesterol measurements from 853 youths and 1618 adults in Utah families with cardiovascular disease (CVD) to assess the utility of different approaches to risk-factor evaluation for youths. The major question addressed was in which youths should blood cholesterol be tested? Applying National Cholesterol Education Program recommendations suggested that 36% in Utah and 38% in Texas be tested. Heterozygous familial hypercholesterolemia (hFH) is the best documented and most serious cholesterol disorder readily diagnosed in youths. In Utah families ascertained for CVD in adults, blood cholesterol levels among youths were significantly bimodal with hFH present in 84% of youths in the upper cholesterol mode. Blood cholesterol levels in adults from the same families were less bimodal with hFH present in 38% of adults in the upper mode. More overlap existed between high and normal modes in adults than in youths. Data from this study suggest that family histories and cholesterol concentrations obtained from high school students may meet the needs of cholesterol screening, education, and follow-up in a controlled and cost-effective setting.

Major gene effect for insulin levels in familial NIDDM pedigrees.

Insulin resistance and hyperinsulinemia are familial traits that may precede and predict the onset of non-insulin-dependent diabetes mellitus (NIDDM). In some populations, the distribution of fasting insulin levels and measures of in vivo insulin action suggest the effects of a single major gene. We previously noted hyperinsulinemia among unaffected members of 16 large white pedigrees ascertained through two or more NIDDM siblings. To examine the hypothesis that insulin levels are determined by a single major genetic locus, we used segregation analysis to examine fasting insulin levels in 206 family members and 65 spouses who had normal glucose tolerance tests by World Health Organization criteria. Segregation analysis supported a major locus determining fasting insulin levels and segregating as an autosomal recessive allele with a frequency of 0.25. Thus, homozygotes represented 6.25% of the population, and homozygosity for the hyperinsulinemia allele elevated the mean fasting insulin level from 70.3 to 211.1 pM (11.7-35.2 microU/ml). The analysis apportioned the variance in fasting insulin as 33.1% due to the major autosomal locus, 11.4% due to polygenic inheritance, and 55.5% due to unmeasured effects. Homozygotes for the recessive allele had higher 1-h insulin levels than all others (911.7 vs. 427.2 pM [152.0 vs. 71.2 microU/ml]). We also found evidence for a major locus determining 1-h-stimulated insulin levels, with codominant inheritance as the most likely pattern in inheritance. The causal relationship between these findings and NIDDM has not been determined, and segregation of direct measures of insulin action remains to be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary risk factors and the severity of angiographic coronary artery disease in members of high-risk pedigrees.

Affected members of early coronary pedigrees in Utah are at markedly increased risk for the development of clinical coronary heart disease (CHD). The relationship between the presence of coronary risk factors and the severity of angiographic coronary artery disease (CAD) in 53 members of high-risk Utah pedigrees was examined. Mean angiographic severity scores were higher in familial hypercholesterolemia or familial low high-density lipoprotein cholesterol (HDL-C) pedigrees than in type III hyperlipidemia or familial combined hyperlipidemia pedigrees. One sibling pair with hyperhomocyst(e)inemia had the highest mean angiographic severity scores. Clinical CHD (p less than 0.0001), increasing low-density lipoprotein cholesterol (LDL-C) (p = 0.0107), and decreasing HDL-C (p = 0.0068) were significant predictors of angiographic CAD severity. There appeared to be an interaction between gender and body mass index but not between gender and serum lipids in the prediction of angiographic CAD severity. Results of the present study in members of high-risk Utah pedigrees are consistent with results from other angiographic studies in non-high-risk persons. Of particular interest is the suggested independent predictive value of low HDL-C for angiographic CAD severity in members of high-risk pedigrees.

Evidence for gene-environmental interactions in Utah families with hypertension, dyslipidaemia and early coronary heart disease.

1. Among 45,258 Utah families surveyed, about 4% have a strong aggregation of early coronary disease. In detailed clinical evaluation, about 21% of such high risk coronary families were found to have familial dyslipidaemic hypertension (FDH) and about 3% were found to have heterozygous familial hypercholesterolaemia (hFH). 2. Common and potentially modifiable environmental factors seem to play an important role in these high risk families. Non-genetic obesity promotes the expression of FDH. A high fat diet promotes the expression of FH. Cigarette smoking promotes earlier death in all coronary prone families. 3. Practical approaches are suggested for helping coronary prone pedigrees by applying our understanding of genetic and environmental factors that promote earlier coronary disease onset.

Type III dyslipoproteinemia in patients heterozygous for familial hypercholesterolemia and apolipoprotein E2. Evidence for a gene-gene interaction.

In four large pedigrees with heterozygous familial hypercholesterolemia (FH) genetically linked to the low density lipoprotein receptor locus, we have observed a strong interaction between the presence of FH and a single apolipoprotein (apo) E2 allele, resulting in a markedly increased prevalence of type III dyslipoproteinemia (DLPIII). DLPIII was defined by chemical criteria. None of the patients with DLPIII had tuberous or palmar xanthomas characteristic of classically defined type III hyperlipoproteinemia. After exclusion of four persons with apo E 2-2 phenotype, there were 89 FH patients and 110 non-FH subjects. Definite DLPIII (defined as a very low density lipoprotein [VLDL] cholesterol to plasma triglyceride ratio greater than 0.30 with plasma triglycerides greater than or equal to 150 mg/dl) was present in 26% of 43 FH patients with a single E2 allele compared with only 3.4% of 29 non-FH subjects with an E2 allele (p = 0.003). To further characterize this interaction we performed a two-way analysis of covariance, after adjustment for age, sex, and body mass index, to test for any interaction between FH and the apo E loci. There was a statistically significant interaction between FH and the presence of a single E2 allele for the ratio of VLDL cholesterol to plasma triglycerides and for a newly derived estimate of beta-VLDL cholesterol concentration. Estimated beta-VLDL cholesterol level was strongly correlated with age in the subgroup with FH and an E2 allele but not in other subgroups. There was no difference in estimated beta-VLDL cholesterol between sexes. Correlation between estimated beta-VLDL cholesterol level and body mass index in persons older than 18 years was of only marginal significance and of similar magnitude in persons with or without an apo E2 allele. Present knowledge suggests that beta-VLDLs are highly atherogenic; if so, then a sizable subset of FH patients having at least one apo E2 allele and DLPIII may be at increased risk for premature coronary heart disease.

Are there interactions and relations between genetic and environmental factors predisposing to high blood pressure?

An overview of published observations suggests that both genetic predisposition and environment work together to produce hypertension in most persons. High blood pressure before age 55 occurs 3.8 times more often among persons with a strong positive family history of high blood pressure. Much of the total variability in blood pressure in modern populations seems attributable to genetic factors. Estimates of the proportion of the variance attributable to all genetic factors (heritability [H2]) vary from 25% in pedigree studies to 65% in twin studies for sitting diastolic blood pressure. Several biochemical traits associated with high blood pressure are highly genetic (H2, 78-84%) and may help elucidate the pathophysiology of high blood pressure. While pertinent environmental factors such as salt intake, alcohol use, and amount of exercise also correlate significantly among relatives, only 7% of the total variance of diastolic blood pressure seems attributable to all shared environmental factors in family households. Thus most familial aggregation of high blood pressure appears to be due to genes rather than shared family environment. Practical benefit may result from identifying familial predisposition in multiple siblings with high blood pressure before age 55 and lipid abnormalities (labeled "familial dyslipidemic hypertension"). About 12% of high blood pressure patients have familial dyslipidemic hypertension and also have high risk of early coronary heart disease. Hyperinsulinemia and central obesity as well as high triglycerides and low high density lipoprotein cholesterol are prominent features of familial dyslipidemic hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin and glucose levels and prevalence of glucose intolerance in pedigrees with multiple diabetic siblings.

Hyperinsulinemia may be an early inherited marker for a defect in insulin action that subsequently results in glucose intolerance and non-insulin-dependent diabetes mellitus (NIDDM). To examine the role of hyperinsulinemia in individuals at high genetic risk for NIDDM and determine the prevalence of impaired glucose tolerance (IGT) and newly diagnosed diabetes in members of NIDDM pedigrees, we studied 310 members of 16 pedigrees ascertained for greater than or equal to 2 NIDDM siblings. Nondiabetic members of all pedigrees were examined by 75-g oral glucose tolerance test with fasting and 1-h insulin levels. Participants had height and weight recorded. Spouses of pedigree members (n = 88) served as control subjects. The spouse control subjects were older and slightly more obese than the undiagnosed pedigree members. The prevalence of IGT was 14.8% in spouses and 7.7% in pedigree members, and NIDDM was present in 11.3% of spouses and 2.3% of previously undiagnosed pedigree members. However, neither spouses nor pedigree members differed significantly from published age-specific prevalence rates for IGT or newly diagnosed NIDDM. Insulin and glucose levels were examined in pedigree members with normal glucose tolerance (NGT). Fasting insulin levels were not significantly different between spouses and NGT pedigree members. However, after adjustment for age, weight (body mass index), and sex, NGT pedigree members had higher 1-h insulin levels and higher fasting and 1-h glucose levels than spouses. These differences were also evident when pedigree members with at least 1 affected (NIDDM or IGT) parent were compared with spouses with no family history of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

An observational study of isotretinoin recipients treated for acne in a health maintenance organization.

From September 1982 to June 1987, all members (N = 513) of the Group Health Cooperative of Puget Sound, Seattle, Wash, who were prescribed isotretinoin for acne were observed throughout the first 4- to 5-month course of therapy for effectiveness and adverse effects. The highest rates of use were among male subjects aged 15 to 24 years. Excluding 47 subjects whose prescriptions were stopped because of noncompliance or who left the care of Group Health Cooperative physicians, 39 (8.4%) of the remaining 466 discontinued taking the drug because of the following adverse effects: mucous/skin/musculoskeletal effects (17); elevated triglyceride levels (eight); headaches (five); increased liver enzyme levels (three); amenorrhea (two); and other (four). One subject, excluded from the 466 because of noncompliance, became pregnant while using medication from a previous prescription and had a therapeutic abortion; she was not under the care of a physician at the time of pregnancy. Most subjects (97%) developed a mucocutaneous symptom, and 42% developed musculoskeletal symptoms. Moderate elevations in liver enzyme levels developed in six (1.8%) of 341 subjects with normal baseline values. Of 389 subjects with normal baseline triglyceride values (less than 2.25 mmol/L), nine (2.3%) developed moderate elevations (4.5 to 9.0 mmol/L), and one (0.3%) developed a severe elevation (greater than or equal to 9.0 mmol/L). Of 24 subjects with elevated baseline triglyceride levels, three (12.5%) developed moderate elevations. Of an additional 53 subjects whose baseline serum triglyceride levels were not determined, two developed elevations during therapy, one up to 13.4 mmol/L. Subjects who were overweight or had elevated baseline serum triglyceride values had an increased risk of developing elevations in triglyceride levels during therapy (odds ratio, 6.0; 95% confidence interval, 1.6 to 22.0; and odds ratio, 4.35; 95% confidence interval, 0.9 to 20.2, respectively). Acne was improved for at least 94.0% of subjects.

Multigenic human hypertension: evidence for subtypes and hope for haplotypes.

Hypertension that occurs before the age of 60 years is strongly aggregated in families, mostly due to genetic factors with weaker contributions from a shared family environment. Hypertension is probably a heterogeneous collection of overlapping subsets of pathophysiological mechanisms, such as dyslipidemia, obesity, hyperinsulinemia and cation metabolism. Highly heritable traits such as sodium-lithium countertransport, urinary kallikrein excretion and a body fat pattern index show evidence of major gene segregation in families with hypertension. They are thought to be intermediate phenotypes in the chain of pathophysiological events leading from specific genes to the distant phenotype of hypertension. They provide evidence of measurable contributions from single gene traits to the susceptibility to hypertension. Genetic linkage studies have suggested that other specific loci (e.g. histocompatibility leukocyte antigen, blood group MN and the haptoglobin protein) contribute to the susceptibility to hypertension. DNA sequencing has shown a point mutation for lipoprotein lipase that conveys susceptibility to lipid abnormalities, and possibly also hypertension, as seen in families with dyslipidemic hypertension. Further application of these approaches, especially in families that include multiple siblings with hypertension, shows promise of a true understanding of how the combined effects of a few specific genes, the polygenic background and selected environmental factors can lead to essential hypertension. This understanding should foster better tailored and more effective approaches to the prevention, diagnosis and treatment of hypertension.