Biomedical subjects

Stephen T Turner

Publications and source records attributed to Stephen T Turner.

At least 19 recordsLinked to original sources

PubMed2007

Associations of serum uric acid with markers of inflammation, metabolic syndrome, and subclinical coronary atherosclerosis.

BACKGROUND: We examined the associations of serum uric acid (UA) with indices of coronary heart disease (CHD) risk, including the 10-year probability of CHD (10y-CHDr), metabolic syndrome (MS), inflammation (C-reactive protein [CRP] and fibrinogen), and the presence and quantity of coronary artery calcium (CAC). METHODS: Subjects (n = 1107, mean age 58 years, 59% women) belonged to sibships with > or =2 individuals with hypertension diagnosed before age 60 years. UA was measured by a colorimetric method, CAC by electron beam computed tomography, and CAC score calculated using the method of Agatston. The correlation of UA with 10y-CHDr, MS components, log CRP, and fibrinogen was assessed after adjustment for age and gender. Multivariable regression was used to assess whether UA was associated with CAC presence and quantity after (1) adjustment for age and gender, and (2) additional adjustment for CHD risk factors. RESULTS: Most subjects (71%) had hypertension and 14% had diabetes. Mean (+/- SD) UA level was 5.97 +/- 1.6 mg/dL, and CAC was detectable in 63% of patients. After adjustment for age and gender, UA was significantly correlated with 10y-CHDr, number of MS components, log CRP, and fibrinogen. UA was associated with CAC presence and quantity after adjustment for age and gender but not after further adjustment for systolic blood pressure (BP), diabetes, total and HDL-cholesterol, smoking, and body mass index (BMI). CONCLUSIONS: Serum UA was significantly correlated with several indices of CHD risk. UA was associated with presence and quantity of CAC, but not independently of conventional risk factors.

Aged↗

PubMed2007

Brachial artery diameter and vasodilator response to nitroglycerine, but not flow-mediated dilatation, are associated with the presence and quantity of coronary artery calcium in asymptomatic adults.

In the present study, we investigated whether measures of brachial artery reactivity were associated with the presence and extent of subclinical coronary atherosclerosis in asymptomatic adults. Electron beam computed tomography was employed to assess the presence and quantity of CAC (coronary artery calcium) in 441 participants (mean age, 61 years; 49% men) without prior history of CHD (coronary heart disease) or stroke, and CAC score was calculated using the method described by Agatston and co-workers [(1990) J. Am. Coll. Cardiol. 15, 827-832] High-resolution ultrasound was employed to measure BAD (brachial artery diameter), FMD (flow-mediated dilatation) and NMD (nitroglycerine-mediated dilatation). CAC score and FMD were log-transformed after adding 1 to reduce skewness. Multivariable logistic and linear regression models based on generalized estimating equations were used to assess whether BAD, FMD and NMD were each independently associated with the presence and quantity of CAC after adjustment for CHD risk factors and use of statin and hypertension medication. CAC was detectable in 64% of participants. After adjustment for age and sex, FMD was not correlated (r=-0.06; P=0.27), BAD was positively correlated (r=0.16; P=0.004) and NMD was inversely correlated in a borderline significant manner (r=-0.10; P=0.084) with log(CAC+1). In multivariable logistic regression analyses, FMD was not associated, whereas higher BAD (P=0.021) and lower NMD (P=0.030) were independently associated with the presence of CAC. In multivariable linear regression analyses, higher BAD (P=0.004) and lower NMD (P=0.016), but not FMD, were independently associated with log(CAC+1). We conclude that greater diameter of the brachial artery and lower vasodilator response to nitroglycerine, but not FMD, are associated with subclinical coronary atherosclerosis.

Adult↗

PubMed2006

Aortic valve calcification: determinants and progression in the population.

BACKGROUND: Aortic valve calcification (AVC) is considered degenerative. Recent data suggested links to atherosclerosis or coronary disease (CAD). METHODS AND RESULTS: AVC and coronary artery calcifications (CAC) were prospectively assessed by Electron-Beam-Computed-Tomography in 262 population-based research participants > or = 60 years. AVC was frequent (27%) with aging (P<0.01) and in men (P<0.05). AVC was associated with diabetes, hypertension, higher body-mass-index, and serum glucose (all P<0.05). AVC was a marker of higher prevalence (P<0.01) and severity of CAD (CAC score: 441+/-802 versus 265+/-566, P<0.05) independently of age. After follow-up of 3.8+/-0.9 years, AVC score increased (94+/-271 versus 54+/-173, P<0.01, +11+/-32 U/year), faster with higher baseline AVC score (P<0.01). Compared with participants remaining free of AVC, de novo acquisition of AVC was associated with higher LDL-cholesterol (141+/-31 versus 121+/-27 mg/dL, P<0.05) and faster CAC progression (+78+/-87 versus +28+/-47 U/year, P<0.05). In multivariate analysis, LDL-cholesterol independently determined AVC acquisition while higher baseline AVC scores determined faster progression of existing AVC. CONCLUSION: In the population, AVC is frequent with aging and atherosclerotic risk factors. AVC is a marker of subclinical CAD. AVC is progressive, appearing de novo with progressive atherosclerosis whereas established AVC progresses independently of atherosclerotic risk factors and faster with increasing initial AVC loads.

Age Distribution↗

PubMed2006

Family-based association study of matrix metalloproteinase-3 and -9 haplotypes with susceptibility to ischemic white matter injury.

Susceptibility to ischemic damage to the subcortical white matter of the brain has a strong genetic basis. Dysregulation of matrix metalloproteinases (MMPs) contributes to loss of cerebrovascular integrity and white matter injury. We investigated whether sequence variation in the genes encoding MMP3 and MMP9 is associated with variation in leukoaraiosis volume, determined by magnetic resonance imaging, in non-Hispanic whites and African-Americans using family-based association tests. Seven hundred and fifty-six white and 671 African-American individuals from sibships ascertained through two or more siblings with hypertension were genotyped for 7 and 8 haplotype-tagging polymorphisms in the MMP3 and MMP9 genes, respectively. MMP3 sequence variation was significantly associated with variation in leukoaraiosis volume in Whites. Two common haplotypes with opposing relationships to leukoaraiosis volume were identified. MMP9 sequence variation was also significantly associated with variation in leukoaraiosis volume in both African-Americans and Whites. Different haplotypes contributed to these associations in the two racial groups. These findings add to the growing body of evidence from animal models and human clinical studies suggesting a role of MMPs in ischemic white matter injury. They provide the basis for further investigation of the role of these genes in susceptibility and/or progression to clinical disease.

Black or African American↗

PubMed2006

Influence of genomic loci on measures of chronic kidney disease in hypertensive sibships.

Genomewide linkage analyses were conducted of serum creatinine, estimated GFR (eGFR), and urine albumin-creatinine ratio (UACR) in search of genetic susceptibility loci for chronic kidney disease in 1351 black (median age 63 yr, 70% women, 79% hypertensive) and 1022 white individuals (median age 61 yr, 56% women, 75% hypertensive) from sibships in which two or more members had essential hypertension diagnosed before age 60 yr. After adjustment for gender, age, diabetes, and use of angiotensin inhibitors, the logarithm-transformed measure of serum creatinine was heritable in both ethnic groups (0.45 in black individuals [P < 0.001]; 0.39 in white individuals [P < 0.001]), as was eGFR (0.52 in black individuals [P < 0.001]; 0.39 in white individuals [P < 0.001]). Log UACR was heritable in black individuals (0.30, P < 0.001) but not in white individuals (0.12; P = 0.059). In black individuals, the univariate maximum multipoint logarithm of odds scores (MLS) were observed on chromosome 7 for log serum creatinine (MLS = 3.65, at 43 cM from pter; P = 0.00002) and eGFR (MLS = 2.52, at 45 cM from pter; P = 0.00033) and for log UACR (MLS = 2.91, at 112 cM from pter; P = 0.00012). In white individuals, only one MLS for log serum creatinine and one for eGFR achieved the logarithm of odds score criterion for "suggestive" evidence of linkage (2 < or = MLS < 3), both on chromosome 3 (at 211 and 209 cM, respectively); however, none did so for log UACR. In black individuals, bivariate linkage analyses of log serum creatinine and pulse pressure (i.e., systolic-diastolic BP) provided "suggestive" evidence of a region on chromosome 5 with pleiotropic effects on both traits (MLS = 3.62, at 85 cM from pter; P = 0.00023). These findings support the utility of genetic linkage analyses for identification of novel risk factors that influence measures of chronic kidney disease, particularly among black individuals.

Black or African American↗

PubMed2006

Dietary sodium restriction and beta2-adrenergic receptor polymorphism modulate cardiovascular function in humans.

Dietary Na+ intake influences beta2-adrenergic receptor (beta2AR) responsiveness. While receiving a normal Na+ diet (150 mmol day(-1)), subjects homozygous for glycine at amino acid 16 (Gly16) have greater forearm beta2AR-mediated vasodilatation than subjects homozygous for arginine (Arg16), an effect that is mediated by endothelial NO. We tested the hypothesis that dietary Na+ restriction eliminates genotype differences in forearm and systemic beta2AR-mediated dilatation in these groups. We measured heart rate, mean arterial pressure and cardiac output (CO, acetylene breathing) responses to administration of intravenous terbutaline (TRB) before and after 5 days of low dietary Na+ intake (10 mmol day(-1)) in healthy Gly16 (n = 17; age, 31 +/- 7 year) and Arg16 homozygotes (n = 15; age, 29 +/- 8 year). After the low-Na+ diet, a catheter was placed in the brachial artery to measure forearm blood flow (FBF, plethysmography) responses to administration of isoprenaline (isoproterenol) before and after NO inhibition with NG-mono-methyl-L-arginine (L-NMMA). In the Gly16 group, the low-Na+ diet decreased baseline CO from 6.4 +/- 1.4 to 5.5 +/- 1.2 l min(-1) (P = 0.003, paired t test), tended to decrease stroke volume from 97.0 +/- 20.6 to 86.9 +/- 21.7 ml (P = 0.06) and increased peripheral resistance from 1106 +/- 246 to 1246 +/- 222 dynes s cm(-5) (P = 0.02); significant effects of the low-Na+ diet were not observed in Arg16 subjects. In a repeated measures ANOVA, the responses of all cardiovascular measures to systemic administration of TRB were not influenced by genotype or diet. Additionally, the FBF response to incremental doses of isoprenaline did not differ between genotype groups before or after administration of L-NMMA. We conclude that dietary Na+ restriction blunted the increased forearm NO-mediated beta2AR responsiveness in Gly16 homozygotes observed in a previous study after normal dietary Na+ intake, while baseline CO decreased and peripheral resistance increased in this group. This study provides evidence that dietary Na+ modulates effects of the Arg16Gly polymorphism on cardiovascular function.

Adult↗

PubMed2006

Novel genomic loci influencing plasma homocysteine levels.

BACKGROUND AND PURPOSE: Genetic factors that influence interindividual variation in levels of plasma homocysteine, a risk factor for vascular disease, are not fully understood. We performed linkage analyses to identify genomic regions that influence homocysteine levels in blacks and non-Hispanic whites. METHODS: Subjects (n=2283) belonged to hypertensive sibships and included 1319 blacks (63+/-10 years, 70% women) and 964 non-Hispanic whites (61+/-7 years, 57% women). Fasting plasma homocysteine was measured by high-pressure liquid chromatography. Genotypes were measured at 366 microsatellite marker loci distributed across the 22 autosomes. Plasma homocysteine adjusted for age, sex, body mass index, serum creatinine, and estrogen use (in women) was used in the genetic analyses. Heritability and linkage analyses were performed using a variance components approach. RESULTS: Mean (+/-SD) homocysteine levels were 10.4+/-5.27 mumol/L in blacks and 10.0+/-2.84 micromol/L in non-Hispanic whites (P=0.58 for difference). Homocysteine levels were significantly (P<0.0001) heritable in blacks (h2=0.70) and in non-Hispanic whites (h2=0.49). Linkage analyses demonstrated significant evidence of linkage (multipoint logarithm of odds> or =3.0) for homocysteine on chromosomes 1q42, 14q32, and 19p13 in blacks and on chromosomes 9q34 and 12q24 in non-Hispanic whites. Tentative evidence of linkage (logarithm of odds 1.3 to 2.0) was present on chromosomes 2q32, 7p15, 8q24, 18q21, and 20p12 in blacks and chromosomes 6q26 and 18q21 in non-Hispanic whites. Four genes in the homocysteine metabolism pathway (MTR, DNMT1, GAMT, and CARM1) were present under 2 of the significant linkage signals in blacks (chromosomes 1q42 and 19p13). CONCLUSIONS: Plasma homocysteine is a significantly heritable trait. Linkage analyses reveal several unique genomic loci that may influence circulating levels of homocysteine and therefore susceptibility to vascular diseases including stroke.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed2006

The Arg16Gly polymorphism of the beta2-adrenergic receptor and the natriuretic response to rapid saline infusion in humans.

The beta2-adrenergic receptors (beta2ARs) play a role in renal Na+ regulation. Subjects homozygous for glycine at amino acid 16 (Gly16) of the beta2AR have been shown to have enhanced beta2-mediated vascular relaxation when compared to subjects homozygous for arginine (Arg16). However, Gly16 subjects have been shown to have higher blood pressure than Arg16 subjects. Given the dominant role of the kidneys in long-term blood pressure regulation, we sought to determine whether there were differences in renal Na+ handling between Gly16 (n = 17) and Arg16 (n = 14) subjects (Gly16: age, 30 +/- 2 years; body mass index (BMI), 25 +/- 11 kg m(-2); Arg16: age, 30 +/- 2 years; BMI, 25 +/- 1 kg m(-2)). We measured urinary Na+ content before and for 3 h following rapid intravenous saline infusion (30 ml kg(-1) in approximately 16 min). Prior to the infusion, there were no differences in 24-h Na+ excretion between Gly16 and Arg16 subjects (Gly16, 183 +/- 21 mmol; Arg16, 184 +/- 20 mmol); however, systolic blood pressure (SBP) was significantly higher in Gly16 than Arg16 subjects with no differences observed in diastolic blood pressure (DBP) or mean arterial pressure (MAP) (SBP: Gly16, 117 +/- 3 mmHg; Arg16, 109 +/- 2 mmHg; DBP: Gly16, 78 +/- 2 mmHg; Arg16, 77 +/- 2 mmHg; MAP: Gly16, 90 +/- 2 mmHg; Arg16, 89 +/- 2 mmHg). With rapid saline infusion, MAP increased in both genotype groups (Gly16, 6.7%; Arg16, 3.4%; P > 0.05). In the 3 h following Na+ infusion, Na+ excretion was less in Gly16 when compared to Arg16 subjects, with a trend towards significance when expressed as total Na+ excreted (Gly16, 66 +/- 7 mmol; Arg16, 85 +/- 9 mmol; P = 0.07), and a significant difference when expressed as a fraction of the administered load (Gly16, 0.18 +/- 0.02; Arg16, 0.28 +/- 0.03; P < 0.01). These results suggest that the Arg16Gly polymorphism of the beta2AR is associated with differences in natriuretic response to rapid saline infusion, which may influence long-term regulation of blood pressure.

Adult↗

PubMed2006

Quantitative trait loci influencing low density lipoprotein particle size in African Americans.

Genomic regions that influence LDL particle size in African Americans are not known. We performed family-based linkage analyses to identify genomic regions that influence LDL particle size and also exert pleiotropic effects on two closely related lipid traits, high density lipoprotein cholesterol (HDL-C) and triglycerides, in African Americans. Subjects (n = 1,318, 63.0 +/- 9.5 years, 70% women, 79% hypertensive) were ascertained through sibships with two or more individuals diagnosed with essential hypertension before age 60. LDL particle size was measured by polyacrylamide gel electrophoresis, and triglyceride levels were log-transformed to reduce skewness. Genotypes were measured at 366 microsatellite marker loci distributed across the 22 autosomes. Univariate and bivariate linkage analyses were performed using a variance components approach. LDL particle size was highly heritable (h(2) = 0.78) and significantly (P < 0.0001) genetically correlated with HDL-C (rho(G) = 0.32) and log triglycerides (rho(G) = -0.43). Significant evidence of linkage for LDL particle size was present on chromosome 19 [85.3 centimorgan (cM), log of the odds (LOD) = 3.07, P = 0.0001], and suggestive evidence of linkage was present on chromosome 12 (90.8 cM, LOD = 2.02, P = 0.0011). Bivariate linkage analyses revealed tentative evidence for a region with pleiotropic effects on LDL particle size and HDL-C on chromosome 4 (52.9 cM, LOD = 2.06, P = 0.0069). These genomic regions may contain genes that influence interindividual variation in LDL particle size and potentially coronary heart disease susceptibility in African Americans.

Adult↗

PubMed2006

Epistatic effects between two genes in the renin-angiotensin system and systolic blood pressure and coronary artery calcification.

BACKGROUND: Coronary artery calcification (CAC) is an important indicator of future coronary artery disease events. Since elevated blood pressure (BP) is an important predictor of CAC, genetic polymorphisms in the renin-angiotensin system and their interaction may play a role in explaining CAC quantity variation. MATERIAL/METHODS: As part of the Epidemiology of Coronary Artery Calcification Study, 166 asymptomatic women and 166 asymptomatic men were genotyped for the insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene and the -6 promoter polymorphism of the angiotensinogen (AGT) gene. We used a novel method to detect gene-gene interaction and compared it to the standard two-way analysis of variance (ANOVA) method. RESULTS: Based on a two-way ANOVA model, there was no evidence for epistasis for either systolic BP or CAC in either men or women. However, using a novel method, we found evidence of significant gene-gene interaction in systolic BP in men and gene-gene interaction in both systolic BP levels and CAC quantity in women. CONCLUSIONS: Our study demonstrates that new methods of assessing epistasis maybe important in understanding the complex genetics of systolic blood pressure as well as subclinical coronary atherosclerosis.

Adult↗

PubMed2006

Beta-2 adrenergic receptor polymorphisms and the forearm blood flow response to mental stress.

Circulating epinephrine plays an important role in skeletal muscle vasodilation during mental stress. Normotensive adults homozygous for glycine (Gly) of the Arg16/Gly beta2-adrenergic receptor polymorphism have a greater forearm beta2-receptor mediated vasodilation and a higher cardiac output response to isometric handgrip than arginine (Arg) homozygotes. To test the hypothesis that the Arg16/Gly beta2-adrenergic receptor polymorphism affects the forearm blood flow (FBF) and hemodynamic response to mental stress, and whether venous catecholamine concentrations predicted these responses, we measured venous epinephrine, norepinephrine, heart rate (HR), arterial pressure (Finapres), and FBF during mental stress in healthy subjects homozygous for Gly16 (n = 30; mean age +/- SE: 30 +/- 1.2, 13 women) and Arg16 (n = 17, age 30 +/- 1.6, 11 women). Resting HR, blood pressure, and FBF responses to mental stress were similar between genotype groups. There were positive correlations between epinephrine and peak FBF (r = 0.694, P < 0.001), peak forearm vascular conductance (r = 0.677, P < 0.001) and the change in epinephrine to the change in HR (r = 0.456, P = 0.002) in all subjects. These correlations were not significantly different in the Gly16 and Arg16 groups. We conclude that venous epinephrine predicts the FBF response to mental stress, and the increase in epinephrine is also correlated with the increase in HR. Furthermore, the Arg16/Gly beta2-receptor polymorphism has no significant influence on the FBF or cardiovascular responses to mental stress.

Adult↗

PubMed2006

A comparison of serum creatinine-based methods for identifying chronic kidney disease in hypertensive individuals and their siblings.

BACKGROUND: The Modification of Diet in Renal Disease (MDRD) equation is often used to determine an estimated glomerular filtration rate (eGFR) from serum creatinine. This study compared kidney disease as defined by reduced eGFR, elevated serum creatinine, or elevated urinary albumin-to-creatinine ratio (ACR). METHODS: As part of the Genetic Epidemiology Network of Arteriopathy study, a community-based sample was ascertained through sibships having at least two members with essential hypertension. Kidney disease was defined by reduced eGFR (<60 mL/min/1.73 m(2)), elevated serum creatinine (>97.5(th) percentile for sex-specific normal individuals), or elevated ACR (>95(th) percentile for sex-specific normal individuals). RESULTS: The sample (n = 2653) was 65% female, 61% African American, and 77% hypertensive, with a mean (+/- SD) age of 61 +/- 10 years. There was greater agreement between kidney disease defined by elevated ACR and an elevated serum creatinine level (kappa = 0.19) than between kidney disease defined by elevated ACR and a reduced eGFR (kappa = 0.07). The multivariable-adjusted odds ratio of kidney disease for male versus female sex was 0.92 (95% CI, 0.75 to 1.12) by reduced eGFR, but was 2.08 (95% CI, 1.62 to 2.67) by elevated serum creatinine and 2.11 (95% CI, 1.63 to 2.74) by elevated ACR. The multivariable-adjusted odds ratio of kidney disease for subjects of African American versus white ethnicity was 0.27 (95% CI, 0.22 to 0.33) by reduced eGFR but was 1.17 (95% CI, 0.91 to 1.51) by elevated serum creatinine and 3.87 (95% CI, 2.89 to 5.25) by elevated ACR. CONCLUSION: In a predominantly hypertensive population, kidney disease identified by elevated ACR was more concordant with elevated serum creatinine than with reduced eGFR. The MDRD equation, derived using kidney disease patients, may misrepresent the gender- and ethnicity-specific risk of kidney disease.

Adult↗

PubMed2006

Monogenic forms of low-renin hypertension.

Hypertension is an important public health problem affecting more than 50 million individuals in the US alone. The most common form, essential hypertension, results from the complex interplay between genetic predisposition and environmental influences. In contrast, monogenic (mendelian) forms of hypertension are caused by single gene mutations that are influenced little, if at all, by environmental factors. Most monogenic forms of hypertension affect either electrolyte transport in the distal nephron, or the synthesis or activity of mineralocorticoid hormones, leading to the common pathogenic mechanisms of increased distal tubular reabsorption of sodium and chloride, volume expansion and hypertension. In young patients with a family history of hypertension who present with severe or refractory hypertension and characteristic hormonal and biochemical abnormalities, the differential diagnosis should include monogenic forms of hypertension. Genetic testing, which is increasingly available, can facilitate timely diagnosis and treatment of these relatively uncommon disorders, such that the underlying defect can be corrected or ameliorated and the long-term consequences of poorly controlled hypertension prevented.

Biological Transport↗

PubMed2006

Genotype related differences in beta2 adrenergic receptor density and cardiac function.

INTRODUCTION: Several common polymorphisms of the beta2 adrenergic (ADRB2) have been described including a Glycine (Gly) for arginine (Arg) substitution at amino acid 16. In vivo studies have attributed phenotypic differences in the Arg16Gly polymorphism of the ADRB2 to differences in agonist-mediated desensitization. Some studies, however, have shown differences between genotype groups under non-agonist-mediated conditions suggesting baseline differences in receptor function or in receptor density. We sought to determine whether genetic variation of the ADRB2 influenced ADRB2 density and, consequently, resting cardiovascular function. METHODS: We measured ADRB2 density on isolated lymphocytes in 30 healthy subjects (15 homozygous for Arg, Arg16, and 15 homozygous for Gly, Gly16) matched for age, cardiovascular fitness, BMI, and gender. In addition, we measured cardiac output (Q), heart rate (HR), and stroke volume (SV) after 5 min of quiet rest in these same subjects. RESULTS: Arg16 subjects had lower receptor density (1220 +/- 78 vs 1574 +/- 110, mean +/- SE, P < 0.01) as well as lower resting cardiac output due to a reduced stroke volume, but a higher HR when compared with the Gly16 subjects (Q = 4.3 +/- 0.2 vs 5.0 +/- 0.3 L.min(-1), SV = 65 +/- 6 vs 86 +/- 7 mL.beat(-1), HR = 70 +/- 4 vs 60 +/- 3 beats.min(-1), for the Arg16 and Gly16 groups, respectively, P < 0.01). In addition, ADRB2 density for all subjects was positively associated with cardiac output (r = 0.428, P = 0.009) and stroke volume (r = 0.407, P = 0.001). CONCLUSIONS: These data suggest that the Arg16Gly polymorphism of the ADRB2 influences receptor density, which, in turn, contributes to resting differences in cardiac output and stroke volume.

Adult↗

PubMed2006

Influence of beta2-adrenergic receptor genotype on airway function during exercise in healthy adults.

BACKGROUND: In humans, beta(2)-adrenergic receptors (beta(2)ARs) influence airway tone. There are known functional polymorphisms of the beta(2)AR, such as substitution of glycine for arginine at codon 16. We sought to determine if this variation in genotype differentially influences airway function during exercise. METHODS: Healthy subjects without asthma who were either homozygous for Arg16 (n = 16; mean age, 29 +/- 2 years [+/- SD]; mean maximum oxygen uptake [Vo(2)], 32 +/- 2 mL/kg/min) or the Gly16 allele (n = 26; mean age, 30 +/- 1 years; mean maximum Vo(2), 33 +/- 1 mL/kg/min) participated in the study. Baseline testing included spirometry and maximal symptom-limited exercise. On a separate day, an arterial cannula was placed to measure catecholamine levels. Subjects then performed exercise at two work levels (40% and 75% of peak work) for 9 min each and performed spirometry at 3-min intervals for assessment of airway function. RESULTS: There were no statistically significant differences between groups in maximum Vo(2) or baseline spirometry (p > 0.05). With both light and heavy exercise, the groups had similar increases in the forced expiratory flow at 50% of vital capacity (FEF(50)). FEF(50) increased by 14 +/- 4% and 15 +/- 3% in arginine and glycine groups, respectively, by end exercise (p > 0.05). During recovery (5 min and 10 min after), the Gly16 homozygotes demonstrated persistent bronchodilation (10 min after FEF(50) = + 7 +/- 2% over pre-exercise) while the Arg16 subjects had a rapid return to baseline (10 min after FEF(50) = - 3 +/- 3%, p = 0.007 between groups). No differences were observed in the catecholamine responses between genotypes, although the increase in epinephrine in the arginine group tended to be higher (p = 0.07). CONCLUSIONS: These data suggest that the Arg16Gly polymorphism of the beta(2)AR does not influence airway function during short-duration low- and high-intensity exercise. However, during recovery, the Arg16 genotype is associated with a reduced bronchodilation, possibly due to increased catecholamine desensitization.

Adult↗

PubMed2006

Beta2-adrenergic receptor genotype and pulmonary function in patients with heart failure.

OBJECTIVE: Chronic heart failure (CHF) is associated with neurohumoral activation and decrements in pulmonary function (PF). The beta2-adrenergic receptor (ADRB2) modulates airway smooth muscle tone and influences lung fluid clearance. Common polymorphisms of the ADRB2 are associated with differences in ADRB2 function and therefore could differentially influence PF in patients with CHF. METHODS: We studied baseline PF according to genetic variations of the ADRB2 at amino acid 16 (ie, arginine [Arg] or glycine [Gly]) in 126 CHF patients (mean [+/- SEM] age, 56 +/- 1 years; left ventricular ejection fraction [LVEF], 29 +/- 1%; body mass index [BMI], 28 +/- 0.4 kg/m2) and in 100 healthy control subjects (mean age, 50 +/- 2 years; LVEF, 63 +/- 0.7%; BMI, 25 +/- 0.3 kg/m2). RESULTS: Venous epinephrine levels did not differ between CHF patients and control subjects or across genotype groups; however, norepinephrine levels were higher in CHF patients and was greater in ArgArg patients compared to GlyGly patients (p < 0.05). PF did not differ according to genotype in control subjects; however, CHF patients who were homozygous for Arg had reduced PF relative to heterozygotes or those subjects who were homozygous for Gly (vital capacity: ArgArg group, 82 +/- 3% predicted; ArgGly group, 92 +/- 2% predicted; GlyGly group, 93 +/- 2% predicted; FVC: ArgArg group, 77 +/- 3% predicted; ArgGly group, 89 +/- 2% predicted; GlyGly group, 90 +/- 2% predicted; FEV1: ArgArg group, 75 +/- 4% predicted; ArgGly group, 86 +/- 3% predicted; GlyGly group, 87 +/- 2% predicted; diffusing capacity of the lung for carbon monoxide: ArgArg group, 76 +/- 4% predicted; ArgGly group, 83 +/- 2% predicted; GlyGly group, 85 +/- 2% predicted; p < 0.05). In addition, there was a modest correlation between mitral valve inflow deceleration time and PF in CHF patients (r = 0.42; p < 0.01), but not in control subjects. CONCLUSIONS: These data suggest that genetic variation of the ADRB2 is associated with differences in PF in CHF patients but not in healthy subjects, which may be related to an increased susceptibility of the homozygous Arg subjects to agonist-mediated desensitization of ADRB2s in the lungs, or related to an influence of this polymorphism on cardiac diastolic properties.

Adult↗

PubMed2006

Correspondence between the adult treatment panel III criteria for metabolic syndrome and insulin resistance.

OBJECTIVE: The aim of the present study was to assess the diagnostic accuracy of the Adult Treatment Panel III (ATP-III) definition of the metabolic syndrome in identifying insulin-resistant individuals and to explore alternative approaches to improve identification of insulin-resistant individuals among asymptomatic adults from the general population. RESEARCH DESIGN AND METHODS: The sample consisted of 256 non-Hispanic white subjects without treated hypertension or diabetes, from the Rochester (Minnesota) Heart Family Study (123 men and 133 women; aged 20-60 years). Frequently sampled intravenous glucose tolerance tests were performed in all subjects. The reference standard for insulin resistance was determined by Bergman's minimal model; insulin resistance was defined as an insulin sensitivity index <2 x 10 min(-1) . microU(-1) . ml(-1). Component metabolic syndrome measures included blood pressure determined by sphygmomanometer; fasting serum triglycerides, HDL cholesterol, and glucose concentrations determined enzymatically; and waist circumference determined by tape measure. RESULTS: By ATP-III criteria, the prevalence of metabolic syndrome was 15.6% (16.3% in men and 15.1% in women; P = 0.465). The presence of metabolic syndrome had low sensitivity to identify insulin resistance (45% in men and 39% in women; sex difference, P = 0.137) but high specificity (93% in men and 95% in women; sex difference, P = 0.345). Based on the area under the receiver operating characteristic curve (AUC) constructed by counting metabolic syndrome components as recommended by ATP-III, diagnostic accuracy was fair (AUC = 0.797 in men and 0.747 in women). When component metabolic syndrome measures were considered as quantitative traits rather than dichotomized, use of waist circumference alone, rather than counting metabolic syndrome components, improved diagnostic accuracy for insulin resistance (in men, AUC = 0.906, P = 0.001; in women, AUC = 0.822, P = 0.10). CONCLUSIONS: Application of the ATP-III metabolic syndrome criteria provides good specificity but low sensitivity to screen asymptomatic white adults for insulin resistance. Measuring just waist circumference is simpler and may provide greater accuracy for identifying insulin resistance.

Adult↗

PubMed2006

Limitations of estimating glomerular filtration rate from serum creatinine in the general population.

OBJECTIVE: To compare estimated glomerular filtration rate (GFR) in the general population on the basis of equations derived from different subsets of the general population. PARTICIPANTS AND METHODS: Adults (ages _45 years) were randomly selected from 1997 to 2000 from the Olmsted County, Minnesota, population and had their serum creatinine levels measured. The GFR was estimated using previously reported equations derived from a sample of patients with chronic kidney disease (CKD), a sample of healthy persons, and the combined samples. Serum creatinine was measured with the same assay used to derive these equations. RESULTS: Of 4203 subjects, 2042 (47% participation rate) were enrolled and studied. Serum samples from 1982 subjects were used to measure creatinine levels. The prevalence of a reduced estimated GFR (<60 mL/min per 1.73 m2) was 12% (95% confidence interval [CI], 10%-13%) based on an equation derived with all CKD patients, and this finding was similar to prior reports. However, the prevalence of a reduced estimated GFR was 5.7% (95% CI, 4.8%-6.8%) based on an equation derived with both CKD patients and healthy persons and 0.2% (95% CI, 0.1%-0.5%) based on an equation derived with all healthy persons. Women had a higher risk of reduced estimated GFR according to an equation derived with all CKD patients, but men had a higher risk with an equation derived with both CKD patients and healthy persons.

Aged↗