Self-reported gastrointestinal disorders among veterans with gulf war illness with and without posttraumatic stress disorder.

BACKGROUND: Gulf War Illness (GWI) is a chronic, multi-symptom disorder affecting 25%-32% of Gulf War veterans. Veterans with GWI disproportionately suffer from gastrointestinal (GI) disorders. Given the increasing evidence supporting a gut-brain axis, we explore the relationship between post-traumatic stress disorder (PTSD), GWI, and self-reported GI disorders among GW veterans. METHODS: Veterans from the Gulf War Era Cohort and Biorepository responded to a mail-based survey (N = 1058). They were stratified by GWI (Centers for Disease Control definition) and PTSD status. This yielded three groups: GWI-, GWI+/PTSD-, and GWI+/PTSD+. Multivariable logistic regression adjusting for demographic and military characteristics examined associations between GWI/PTSD groups and GI disorders. Results were expressed as adjusted odds ratios (aOR) with 95% confidence intervals (95% CI). KEY RESULTS: The most frequently reported GI disorders were irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), and colon polyps (CP). The GWI+/PTSD+ group had a higher odds of these disorders than the GWI+/PTSD- group (aORIBS  = 3.12, 95% CI: 1.93-5.05; aORGERD  = 2.04, 95% CI: 1.44-2.90; aORCP  = 1.85, 95% CI: 1.23-2.80), which had a higher odds of these disorders than the GWI- group (aORIBS  = 4.38, 95% CI: 1.55-12.36; aORGERD  = 2.51 95% CI: 1.63-3.87; aORCP  = 2.57, 95% CI: 1.53-4.32). CONCLUSIONS & INFERENCES: GW veterans with GWI and PTSD have significantly higher odds of specific self-reported GI disorders than the other groups. Given the known bidirectional influences of the gut and brain, these veterans may benefit from a holistic healthcare approach that considers biopsychosocial contributors to the assessment and management of disease.

Maternal and neonatal outcomes for pregnancies before and after gastric bypass surgery.

BACKGROUND: Interaction between maternal obesity, intrauterine environment and adverse clinical outcomes of newborns has been described. METHODS: Using statewide birth certificate data, this retrospective, matched-control cohort study compared paired birth weights and complications of infants born to women before and after Roux-en-Y gastric bypass surgery (RYGB) and to matched obese non-operated women in several different groups. Women who had given birth to a child before and after RYGB (group 1; n=295 matches) and women with pregnancies after RYGB (group 2; n=764 matches) were matched to non-operated women based on age, body mass index (BMI) prior to both pregnancy and RYGB, mother's race, year of mother/s birth, date of infant births and birth order. In addition, birth weights of 13 143 live births before and/or after RYGB of their mothers (n=5819) were compared (group 3). RESULTS: Odds ratios (ORs) for having a large-for-gestational-age (LGA) neonate were significantly less after RYGB than for non-surgical mothers: ORs for groups 1 and 2 were 0.19 (0.08-0.38) and 0.33 (0.21-0.51), respectively. In contrast, ORs in all three groups for risk of having a small for gestational age (SGA) neonate were greater for RYGB mothers compared to non-surgical mothers (ORs were 2.16 (1.00-5.04); 2.16 (1.43-3.32); and 2.25 (1.89-2.69), respectively). Neonatal complications were not different for group 1 RYGB and non-surgical women for the first pregnancy following RYGB. Pregnancy-induced hypertension and gestational diabetes were significantly lower for the first pregnancy of mothers following RYGB compared to matched pregnancies of non-surgical mothers. CONCLUSION: Women who had undergone RYGB not only had lower risk for having an LGA neonate compared to BMI-matched mothers, but also had significantly higher risk for delivering an SGA neonate following RYGB. RYGB women were less likely than non-operated women to have pregnancy-related hypertension and diabetes.

Partial normalization of components of metabolic syndrome does not influence prevalent echocardiographic abnormalities: the HyperGEN study.

BACKGROUND AND AIMS: Metabolic syndrome (MetS) is a complex condition characterized by different phenotypes, according to the combinations of risk factors and is associated with cardiovascular abnormalities. Whether control of MetS components by treatment produces improvement in the associated cardiovascular abnormalities is unknown. We investigated whether partial control of components of MetS was associated with less echocardiographic abnormalities than the complete presentation of MetS based on measured components. METHODS AND RESULTS: We evaluated markers of echocardiographic preclinical cardiovascular disease in MetS (ATP III) defined by measured components or by history of treatment, in 1421 African-American and 1195 Caucasian non-diabetic HyperGEN participants, without prevalent cardiovascular disease or serum creatinine >2 mg/dL. Of 2616 subjects, 512 subjects had MetS by measured components and 328 by history. Hypertension was found in 16% of participants without MetS, 6% of those with MetS by history and 42% of those with MetS by measured components. Obesity and central fat distribution had similar prevalence in both MetS groups (both p < 0.0001 vs. No-MetS). Blood pressure was similar in MetS by history and No-MetS, and lower than in MetS by measured components (p < 0.0001). LV mass and midwall shortening, left atrial (LA) dimension and LA systolic force were similarly abnormal in both MetS groups (all p < 0.0001 vs. No-MetS) without difference between them. CONCLUSIONS: There is a little impact of control by treatment of single components of MetS (namely hypertension) on echocardiographic abnormalities. Lower blood pressure in participants with MetS by history was not associated with substantially reduced alterations in cardiac geometry and function.

Genome-wide meta-analyses of smoking behaviors in African Americans.

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (ß = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

The relationship between body mass index and per cent body fat in the severely obese.

BACKGROUND: International standards define clinical obesity according to body mass index (BMI) without reference to age and gender. Recent studies among adults in the normal to mildly obese BMI ranges have shown that the relationship between BMI and per cent body fat (% fat) differs by age and gender. The extent to which age and gender affect the relationship between BMI and % fat among more severely obese individuals is less known. AIM: The aim was to examine the age-gender association between measured BMI and % fat from a large cohort of adults, including a large number of severely obese subjects (1862 with a BMI > or = 35 kg/m(2)). METHODS: BMI was computed from measured height and weight, and % fat was estimated from bioelectrical impedance in 3068 adults. Two impedance equations, the Sun equation and the Heath equation (specific to severe obesity), were used to calculate % fat. RESULTS: Average age for 991 men and 2077 women was 46 +/- 15 vs. 44 +/- 14 years respectively (p = 0.0003). The average BMI was 36 +/- 9 kg/m(2) for men and 39 +/- 10 kg/m(2) for women (p < 0.0001), with a combined gender BMI range of 19-74 kg/m(2). Using the Sun equation, average % fat was 31 +/- 8 vs. 46 +/- 8% (p < 0.0001) for all men and women respectively. With the Sun equation, age-adjusted Spearman correlations between all BMI and % fat values were r = 0.80 and r = 0.83 for men and women, respectively, but only 0.60 (n = 479) and 0.61 (n = 1383) in severely obese participants (BMI > or = 35 kg/m(2)). Using the Heath equation, only for participants with BMI > or = 35 kg/m(2), the age-adjusted Spearman correlations improved to r = 0.82 (n = 479) and r = 0.70 (n = 1383) for men and women respectively. Finally, by combining the Sun equation for subjects with BMI < 35 kg/m(2) and the Heath equation for those with BMI > or = 35 kg/m(2), correlations improved to 0.89 for men and 0.87 for women. Using these combined equations, the relationship between BMI and % fat was best fit as a linear function for men and curvilinear function (both p < 0.001) for women across the range of BMI. The % fat was approximately 10% higher for any BMI value among women vs. men even among the severely obese (p < 0.0001). CONCLUSIONS: These data that include a large cohort of severely obese individuals demonstrated a linear association between BMI and % fat for men and a curvilinear association between BMI and % fat for women when Sun and Heath equations were combined. Assuming disease risk is driven by adiposity, this study suggests a need to further explore the appropriateness of gender-specific BMI cutpoints for clinical risk assessment due to the marked difference in the BMI-per cent fat relation observed in men and women across the entire range of BMI.

Genotype-by-sex interaction in the aetiology of type 2 diabetes mellitus: support for sex-specific quantitative trait loci in Hypertension Genetic Epidemiology Network participants.

AIMS/HYPOTHESIS: While there are sex-related differences in both the prevalence of type 2 diabetes mellitus and disease risk factors, there is only limited research on sex-specific influences on type 2 diabetes aetiology within the same study population. Thus, we assessed genotype-by-sex interaction using a liability threshold model in an attempt to localise sex-specific type 2 diabetes quantitative trait loci (QTLs). SUBJECTS, MATERIALS AND METHODS: Hypertensive siblings and their offspring and/or parents in the Hypertension Genetic Epidemiology Network of the Family Blood Pressure Program were recruited from five field centres. The diabetic phenotype was adjusted for race, study centre, age and non-linear age effects. In total, 567 diabetic individuals were identified in 385 families. Variance component linkage analyses in the combined sample and stratified by sex and race were performed (SOLAR program) using race-specific marker allele frequencies derived from a random sample of participants at each centre. RESULTS: We observed a QTL-specific genotype-by-sex interaction (p=0.009) on chromosome 17 at 31 cM, with females displaying a robust adjusted logarithm of odds (LOD) of 3.0 compared with 0.2 in males and 1.3 in the combined sample. Three additional regions demonstrating suggestive evidence for linkage were detected: chromosomes 2 and 5 in the female sample and chromosome 22 (adjusted LOD=1.9) in the combined sample. CONCLUSIONS/INTERPRETATION: These findings suggest that multiple genes may regulate susceptibility to type 2 diabetes, demonstrating the importance of considering the interaction of genes and environment in the aetiology of common complex traits.

Adrenergic receptor polymorphisms associated with resting heart rate: the HyperGEN Study.

The association between polymorphisms in the beta1, beta2 and alpha2B adrenergic receptor (ADR) genes (ADRB1, ADRB2 and ADRA2B) and resting heart rate was examined in white and African-American participants of the HyperGEN Study. All analyses were adjusted for age, sex, body mass index, alcohol use, smoking status and daily exercise within strata of race, hypertension status and beta-blocker use. The Ser49Gly polymorphism of the beta1 ADR was associated with resting heart rate in hypertensive African-Americans and hypertensive whites taking beta-blockers, with carriers of the Gly allele having a higher mean resting heart rate by 2.7 and 4.4 beats per minute (bpm), respectively. The Arg389Gly polymorphism of the beta1 ADR was associated with lower heart rate in the normotensive African-American sample. A beta1 haplotype (Ser49Gly-Arg389Gly) was modestly associated with resting heart rate in the hypertensive African-Americans. The alpha2B C/A polymorphism was associated with heart rate in hypertensive whites, and both whites and African-Americans taking beta-blockers, with carriers of the A allele having a higher mean resting heart rate. In summary, each of the ADR gene polymorphisms was associated with heart rate in at least one stratum studied, but there was no consistent association from which one would infer a large genetic contribution to heart rate.

Sex-specific findings from a genome-wide linkage analysis of human fatness in non-Hispanic whites and African Americans: the HyperGEN study.

OBJECTIVE: To conduct a full genome search for genes potentially influencing two related phenotypes: body mass index (BMI, kg/m2) and percent body fat (PBF) from bioelectric impedance in men and women. DESIGN: A total of 3383 participants, 1348 men and 2035 women; recruitment was initiated with hypertensive sibpairs and expanded to first-degree relatives in a multicenter study of hypertension genetics. MEASUREMENTS: Genotypes for 387 highly polymorphic markers spaced to provide a 10 cM map (CHLC-8) were generated by the NHLBI Mammalian Genotyping Service (Marshfield, WI, USA). Quantitative trait loci for obesity phenotypes, BMI and PBF, were examined with a variance components method using SOLAR, adjusting for hypertensive status, ethnicity, center, age, age2, sex, and age2 x sex. As we detected a significant genotype-by-sex interaction in initial models and because of the importance of sex effects in the expression of these phenotypes, models thereafter were stratified by sex. No genotype-by-ethnicity interactions were found. RESULTS: A QTL influencing PBF in women was detected on chromosome12q (12q24.3-12q24.32, maximum empirical LOD score=3.8); a QTL influencing this phenotype in men was found on chromosome 15q (15q25.3, maximum empirical LOD score=3.0). These QTLs were detected in African-American and white women (12q) and men (15q). QTLs influencing both BMI and PBF were found over a broad region on chromosome 3 in men. QTLs on chromosomes 3 and 12 were found in the combined sample of men and women, but with weaker significance. CONCLUSION: The locations with highest LOD scores have been previously reported for obesity phenotypes, indicating that at least two genomic regions influence obesity-related traits. Furthermore, our results indicate the importance of considering context-dependent effects in the search for obesity QTLs.

Blood pressure and pulse responses to three stressors: associations with sociodemographic characteristics and cardiovascular risk factors.

Cardiovascular reactivity is hypothesized to increase the risk of hypertension and other CVD-related conditions. However, studies to date are inconclusive. We compared the association of blood pressure and pulse responses to three stressors (postural challenge, handgrip test, mental arithmetic) with sociodemographic characteristics and CVD risk factors. We included 782 participants from the Hypertension Genetic Epidemiology Study. Blood pressure and pulse responses to stressors were defined as the difference between post- and pre-stress measurements. Stepwise regression analyses examined change in SBP and pulse in response to stressors as a function of sociodemographic and CVD risk factors. Age, race, and gender were forced into models and other variables (education, BMI, waist circumference, resting SBP and DBP, cigarette smoking, LDL and HDL cholesterol, glucose, and antihypertensive medications (beta-blockers, calcium channel blockers, diuretics, ace inhibitors)) were retained if P<0.10. Age was a significant predictor of SBP response to all stressors. The SBP response to a change in posture was not related to other variables. The SBP response to mental arithmetic was significantly higher among men, those with larger waists, higher SBP, beta-blocker users, and lower among smokers. SBP response to the handgrip was significantly higher among those with higher SBP and beta-blocker users. Similarly, the association of the pulse response to the risk factors varied considerably across the stressors. Overall, the socio-demographic and CVD risk factors accounted for between 9 and 14% of the variance in the SBP response to the stressors and from between 4 and 12% of the variance in the pulse response to the three stressors. The associations between sociodemographic and CVD risk factors and the SBP and pulse response to stress were modest and inconsistent across stressors. The findings suggest that cardiovascular reactivity is a concept that needs to be defined in reference to specific stressors so that mechanisms leading to responses can be better understood.

Linkage of body mass index to chromosome 20 in Utah pedigrees.

Several linkage studies have hinted at the existence of an obesity predisposition locus on chromosome 20, but none of these studies has produced conclusive results. Therefore, we analyzed 48 genetic markers on chromosome 20 for linkage to severe obesity (BMI> or =35) in 103 extended Utah pedigrees (1,711 individuals), all of which had strong aggregation of severe obesity. A simple dominant model produced a maximum multipoint heterogeneity LOD score of 3.5 at D20S438 (55.1 cM). Two additional analyses were performed. First, a one-gene, two-mutation model (with one dominant mutation and one recessive mutation) increased the LOD score to 4.2. Second, a two-locus model (with one locus dominant and one recessive) generated a multipoint LOD score of 4.9. We conclude that one or more severe obesity predisposing genes lie within an interval of approx. 10 cM on chromosome 20. This study generated significant LOD scores which confirm suggestive linkage reports from previous studies. In addition, our analyses suggest that the predisposing gene(s) is localized very near the chromosome 20 centromere.

Relationship between left ventricular diastolic relaxation and systolic function in hypertension: The Hypertension Genetic Epidemiology Network (HyperGEN) Study.

The relation of impaired left ventricular relaxation, as measured by prolonged isovolumic relaxation time, to ventricular systolic function in hypertension remains uncertain in population-based samples. In the Hypertension Genetic Epidemiology Network (HyperGEN) Study, echocardiograms were analyzed in 1457 hypertensive participants without diabetes, >/=2+ valvular regurgitation, or coronary disease. Impaired relaxation (isovolumic relaxation time >100 ms) was present in 219 (15%) of the participants; they were older and had higher arterial pressure than did those with normal relaxation. Ventricular chamber size, wall thicknesses, mass, and relative wall thickness were greater, and stress-corrected midwall shortening and end-systolic stress/end-systolic volume index were lower with impaired relaxation than with normal relaxation time. Fractional shortening and ejection fraction did not differ between the groups. In logistic regression, the likelihood of prolonged isovolumic relaxation time decreased with higher stress-corrected midwall shortening (odds ratio, 0.97%; 95% confidence interval, 0.96 to 0.99), independently of age, heart rate, and ventricular mass. Neither ejection fraction nor the end-systolic stress/end-systolic volume index was independently related to isovolumic relaxation time. In hypertension, impaired left ventricular relaxation parallels ventricular midwall dysfunction but not systolic chamber function. Whether combined diastolic and systolic dysfunction identifies hypertensive patients at especially high risk of cardiovascular events requires further study.

Blood pressure response to angiotensin II, low-density lipoprotein cholesterol and polymorphisms of the angiotensin II type 1 receptor gene in hypertensive sibling pairs.

Blood pressure (BP) response to infused angiotensin II (Ang II) has been widely used to characterize hypertensive subjects. High cholesterol levels have recently been found to enhance this response in young men, suggesting an important new link between atherosclerosis and hypertension. The present study assessed the familial resemblance of the BP response following an Ang II infusion and measured the factors affecting the trait in a large set of hypertensive men and women. After a low-salt diet for 7 days a 30-min infusion of Ang II was administered to 218 white hypertensive patients (28 singletons, 80 sibling pairs, 10 trios). Age and gender were significantly correlated to the Ang II systolic but not to the diastolic BP response. Conversely, cholesterol level and especially low-density lipoprotein (LDL) were correlated to both systolic and diastolic changes. Multivariate analysis showed that age, gender, and LDL were the three parameters that explained the systolic BP change whereas plasma LDL remained the only variable significantly correlated to the diastolic BP change. Significant familial resemblances in the Ang II induced systolic and diastolic BP response were observed, especially in female pairs. On this limited number of subjects, suggestive evidence for association and linkage was found between the trait, A1166C, and (CA)n repeat polymorphisms of the Ang II type 1 receptor (AT1R) gene. In conclusion, the Ang II induced BP change is strongly related to plasma LDL in hypertensive men and women, stressing the importance of the lipid profile as a contributor to BP regulation. Familial resemblance of this intermediate phenotype is sex dependent and may be partly explained by polymorphisms of the AT1R gene.

Clinician attributions for symptoms and treatment of Gulf War-related health concerns.

BACKGROUND: Several clinical syndromes are defined solely on the basis of symptoms, absent an identifiable medical etiology. When evaluating and treating individuals with these syndromes, clinicians' beliefs might shape decisions regarding referral, diagnostic testing, and treatment. To assess clinician beliefs about the etiology and treatment of "Gulf War illness," we surveyed a sample of general internal medicine clinicians (GIMCs) and mental health clinicians (MHCs). METHODS: Clinicians (77 GIMCs and 214 MHCs) at the Veterans Affairs Puget Sound Health Care System, Seattle, Wash, and the Veterans Affairs Medical Center in Portland, Ore, responded to a mailed survey of their beliefs about Gulf War illness. RESULTS: Compared with GIMCs, MHCs were more likely to believe that Gulf War illness was the result of a "physical disorder" and that symptoms resulted from viruses or bacteria, immunizations, exposure to toxins, chemical weapons, or a combination of toxins and stress (P <.05). Conversely, GIMCs were more likely than MHCs to believe that Gulf War illness was a "mental disorder" and that symptoms were due to stress or posttraumatic stress disorder (P <.05). In addition, MHCs were more likely to endorse biological interventions to treat Gulf War illness (P <.01), whereas GIMCs were more likely to endorse psychological interventions. CONCLUSIONS: Clinicians' beliefs about the etiology and effective treatment of Gulf War illness vary and thus might contribute to the multiple referrals often reported by Gulf War veterans. Health care models for Gulf War veterans and others with symptom-based disorders necessitate collaborative interdisciplinary approaches.

Evaluation of coronary risk factors in patients with heterozygous familial hypercholesterolemia.

Age at onset of clinically manifested coronary artery disease (CAD) varies widely among patients with familial hypercholesterolemia (FH). A number of factors in addition to high low-density lipoprotein cholesterol (LDL) have been suggested as predictors of risk among patients with FH, but a comprehensive examination of their utility is lacking. We therefore measured plasma lipids, carotid intima-medial thickness, and a variety of coronary risk factors in 262 patients with FH > or = 30 years old (68 of whom had premature CAD). Age (p < 0.0001) and gender were the most important determinants of premature CAD risk, with men having 5.64 times the risk of women (p < 0.0001). In addition, cigarette smoking (odds ratio [OR] 2.71, p = 0.026), smaller LDL as determined by the LDL cholesterol/LDL apolipoprotein B ratio (OR 2.60, p = 0.014), and white blood cell count (p = 0.014) were also statistically significant risk factors. Lipoprotein(a) and the presence of xanthoma were associated with risk only in very early coronary cases. After correction for age, carotid intima-media thickness was not associated with CAD risk. Insulin, fibrinogen, homocysteine, plasma C-reactive protein, and the angiotensin-converting enzyme insertion/deletion polymorphism were unrelated to risk in this cohort. These results provide little justification for extensive investigation of risk factors among patients with FH, at least for the risk factors examined here. Rather, the inherent high LDL cholesterol of these patients should be the focus of preventive efforts. The novel finding of increased risk with smaller LDL may prove useful but needs further confirmation.

Problem drinking and medication adherence among persons with HIV infection.

OBJECTIVE: To examine the relation between problem drinking and medication adherence among persons with HIV infection. DESIGN: Cross-sectional survey. SETTING/PARTICIPANTS: Two hundred twelve persons with HIV infection who visited 2 outpatient clinics between December 1997 and February 1998. MEASUREMENTS AND MAIN RESULTS: Nineteen percent of subjects reported problem drinking during the previous month, 14% missed at least 1 dose of medication within the previous 24 hours, and 30% did not take their medications as scheduled during the previous week. Problem drinkers were slightly more likely to report a missed dose (17% vs 12 %, P =.38) and significantly more likely to report taking medicines off schedule (45% vs 26%, P =.02). Among drinking subtypes, taking medications off schedule was significantly associated with both heavy drinking (high quantity/frequency) (adjusted odds ratio [OR], 4.70; 95% confidence interval [95% CI], 1.49 to 14.84; P <.05) and hazardous drinking (adjusted OR, 2.64; 95% CI, 1.07 to 6.53; P <.05). Problem drinkers were more likely to report missing medications because of forgetting (48% vs 35%, P =.10), running out of medications (15% vs 8%, P =.16), and consuming alcohol or drugs (26 % vs 3 %, P <.001). CONCLUSION: Problem drinking is associated with decreased medication adherence, particularly with taking medications off schedule during the previous week. Clinicians should assess for alcohol problems, link alcohol use severity to potential adherence problems, and monitor outcomes in both alcohol consumption and medication adherence.

Association of plasma bilirubin with coronary heart disease and segregation of bilirubin as a major gene trait: the NHLBI family heart study.

Decreased serum bilirubin levels have been associated with coronary heart disease (CHD). It is believed that bilirubin acts as an antioxidant, preventing formation of oxidized LDL and subsequent atherosclerosis. Serum bilirubin also segregates as a major gene, with the rarer genotype associated with elevated bilirubin levels and occurring in about 12% of the population. Using a large population-based study of random and CHD high risk families, this analysis was designed to replicate the association of lower serum bilirubin levels with early CHD (onset by age 55 for males and 65 for females) using 328 case/control samples and the major gene segregation of bilirubin levels in 555 families. There were significant differences in plasma bilirubin levels between 188 males (12.5 micromol/l) and 140 females (9.3 micromol/l, P<0.0001). Higher serum albumin and lower HDL-C significantly correlated with higher plasma bilirubin levels in females but not males. In sex-specific logistic regression models of early CHD (148 cases and 180 controls), lower plasma bilirubin was associated with increased prevalence of CHD in males with borderline significance (odds ratio=0.93 for a 1 micromol/l increase in bilirubin, P=0.056) but not in females. Bilirubin was found to segregate as a major gene using all 555 families consisting of 1292 individuals, with estimates replicating those in the previously published study. The most parsimonious model was a recessive model for high bilirubin levels that occurred in about 23% of the population. The means were separated by 1.7 standard deviations and there was a significant polygenic effect (h2=0.33, P=0.0009). We conclude that decreased bilirubin is mildly related to CHD in males but not in females. Because of an inverse correlation between HDL-C and bilirubin, the protective high HDL-C levels may have counteracted the CHD risk associated with lower bilirubin levels in females. The inferred major gene for bilirubin may protect against CHD, since elevated levels, rather than lower levels, were associated with this inferred gene.

Identification of a common variant in the lipoprotein lipase gene in a large Utah kindred ascertained for coronary heart disease: the -93G/D9N variant predisposes to low HDL-C/high triglycerides.

Defects in the lipoprotein lipase (LPL) gene are associated with dyslipidemia in the general population. Several rare mutations in the gene, as well as two common coding region polymorphisms, D9N and N291S, exhibit deleterious effects on circulating lipid levels. Using a linkage-based approach, we have identified a large Utah kindred segregating the D9N variant in the LPL gene. The kindred was ascertained for premature coronary heart disease and was expanded based on familial dyslipidemia. A genomic scan identified a region of linkage including LPL, and mutation screening identified the segregating variant. In the kindred, the variant shows high penetrance for a hypoalphalipoproteinemia phenotype, but is also associated with hypertriglyceridemia and elevated insulin levels. The strength of linkage was dependent on the combination of phenotype definition and model parameters, favoring the use of a MOD score approach. Most other studies of LPL have proceeded by mutation screening of randomly chosen individuals or selected affected probands; this is the first example identifying a segregating LPL mutation using direct linkage.

Influence of sodium intake on the reliability of active renin as a measure of the renin-angiotensin system in essential hypertension.

Plasma renin activity (PRA), active renin (AR), prorenin, and angiotensinogen were assessed in 486 hypertensive and 175 normotensive subjects with a sodium intake of 10 or 200 mEq/d during supine and upright posture and after infusion of angiotensin II. PRA and AR levels were compared in hypertensive subjects in each condition. With low sodium intake, particularly while upright, there was a significant correlation between PRA and AR. In upright subjects with low sodium intake who had a PRA of 2.4 ng/mL per hour or less (1.85 nmol.L-1.h-1 or less), the correlation was also strong. With high sodium intake, the correlation was weaker. With intermediate sodium excretion, the correlation was intermediate. Prorenin was less predictive of PRA than was AR, and angiotensinogen had a marginal role. Using PRA during sodium restriction while upright as the standard for determining renin status, the precision of AR for predicting renin status was excellent. AR may be used for surrogate assessment of the renin-angiotensin system activity when the system is activated.

Insulin resistance in hypertensives: effect of salt sensitivity, renin status and sodium intake.

OBJECTIVE: Homeostasis Model Assessment (HOMA index) is predictive of insulin sensitivity in normal and diabetic patients. This study was designed to see if insulin resistance in hypertensives, measured using the HOMA index, differs, based on salt sensitivity, renin status and sodium intake. METHODS: Fasting insulin and glucose were determined in subsets of 426 essential hypertensives, and normotensives. HOMA was calculated as fasting glucose (mmol) x fasting insulin (muU/ml)/22.5. RESULTS: Four hundred and twenty-six essential hypertensives and normotensives from four HERMES centers form the basis of this report. There was no difference in the HOMA index between hypertensives and normotensives (P= 0.291) or between hypertensives grouped according to blood pressure salt sensitivity (P = 0.153). However, when essential hypertensives were subgrouped by renin status, the low-renin group had significantly lower (P< 0.01) HOMA index than the normal/high-renin group. When normal/high-renin group was divided into modulators and non-modulators, the nonmodulators had significantly higher HOMA index (P< 0.001) than other hypertensive subsets. The effect of sodium intake on the HOMA index was significant only for non-modulators (P< 0.002), with salt restriction increasing insulin resistance. CONCLUSION: Insulin sensitivity differs among subsets of essential hypertension, non-modulators being most insulin resistant and the low-renin subset insulin sensitive. Salt restriction might have an adverse effect on insulin sensitivity in non-modulators. The reduction in cardiovascular risk seen in low-renin hypertensives may be related to their increased insulin sensitivity; in contrast, the clustering of cardiovascular risk factors seen in nonmodulators may be due to increased insulin resistance.

Usefulness of cardiovascular family history data for population-based preventive medicine and medical research (the Health Family Tree Study and the NHLBI Family Heart Study).

Detailed medical family history data have been proposed to be effective in identifying high-risk families for targeted intervention. With use of a validated and standardized quantitative family risk score (FRS), the degree of familial aggregation of coronary heart disease (CHD), stroke, hypertension, and diabetes was obtained from 122,155 Utah families and 6,578 Texas families in the large, population-based Health Family Tree Study, and 1,442 families in the NHLBI Family Heart Study in Massachusetts, Minnesota, North Carolina, and Utah. Utah families with a positive family history of CHD (FRS > or =0.5) represented only 14% of the general population but accounted for 72% of persons with early CHD (men before age 55 years, women before age 65 years) and 48% of CHD at all ages. For strokes, 11% of families with FRS > or =0.5 accounted for 86% of early strokes (<75 years) and 68% of all strokes. Analyses of >5,000 families sampled each year in Utah for 14 years demonstrated a gradual decrease in the frequency of a strong positive family history of CHD (-26%/decade) and stroke (-15%/decade) that paralleled a decrease in incidence rates (r = 0.86, p <0.001 for CHD; r = 0.66, p <0.01 for stroke). Because of the collaboration of schools, health departments, and medical schools, the Health Family Tree Study proved to be a highly cost-efficient method for identifying 17,064 CHD-prone families and 13,106 stroke-prone families (at a cost of about $27 per high-risk family) in whom well-established preventive measures can be encouraged. We conclude that most early cardiovascular events in a population occur in families with a positive family history of cardiovascular disease. Family history collection is a validated and relatively inexpensive tool for family-based preventive medicine and medical research.