Biomedical subjects

Mohammed F Saad

Publications and source records attributed to Mohammed F Saad.

At least 19 recordsLinked to original sources

PubMed2007

LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Previous studies showing that smaller low-density lipoprotein (LDL) size is associated with greater atherosclerotic risk did not adequately control for small and large LDL particle correlation. METHODS AND RESULTS: We studied the association of lipoproteins measured by proton nuclear magnetic resonance spectroscopy with carotid intima-media thickness (IMT) in apparently healthy individuals (N = 5538, 38% White, 28% African American, 22% Hispanic, 12% Chinese). Small and large LDL particle concentrations (LDL-p) were inversely correlated (r = /-0.63, P < 0.0001). Controlling for risk factors but not for LDL subclass correlation, LDL size and small LDL-p separately were associated with IMT (-20.9 and 31.7 microm change in IMT per 1-S.D., respectively, both P < 0.001), but large LDL-p was not (4.9 microm, P = 0.27). When LDL subclasses were included in the same model, large and small LDL-p were both associated with IMT (36.6 and 52.2 microm higher IMT per 1-S.D., respectively, both P < 0.001; 17.7 and 11.6 microm per 100 nmol/L, respectively). LDL size was not significant after accounting for LDL subclasses and risk factors (P = 0.10). CONCLUSION: Both LDL subclasses were significantly associated with subclinical atherosclerosis, with small LDL confounding the association of large LDL with atherosclerosis. Future studies of LDL size should account for the strong inverse correlation of LDL subclasses.

Aged↗

PubMed2006

Hypertension and smoking are associated with reduced regional left ventricular function in asymptomatic: individuals the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVES: This study sought to test the hypothesis that reduced regional left ventricular (LV) function is associated with traditional risk factors including hypertension, hypercholesterolemia, and smoking in asymptomatic individuals. BACKGROUND: Coronary artery disease is the main etiology of congestive heart failure in the U.S. and Europe. However, the relationship between risk factors for coronary artery disease and decreased myocardial function has not been studied systematically in asymptomatic individuals. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) is a cohort study designed to investigate the nature of atherosclerosis in asymptomatic individuals. A total of 1,184 participants (45 to 84 years old) underwent tagged cardiac magnetic resonance imaging. Regional LV function was quantified by analyzing peak systolic circumferential strain (Ecc) in regions corresponding to the left anterior descending (LAD), circumflex (LCX), and right coronary (RCA) territories. The association between risk factors and strains was studied using multiple linear regression. RESULTS: Higher diastolic blood pressure (DBP) was associated with lower Ecc (p < or = 0.002). The Ecc's in the LAD territory of participants with DBP <80, 80 to 84, 85 to 89, and > or =90 mm Hg were -15.6%, -14.8%, -14.2%, and -13.7%, respectively (p < 0.001). Similar results were documented in other territories and after multivariable analysis. Smokers had lower Ecc in the LAD and RCA regions compared with nonsmokers. Furthermore, dose response relationship between cigarette consumption measured in pack-years and regional LV dysfunction by Ecc was noted (p < or = 0.01 in LAD and RCA territories). Finally, combined diastolic hypertension and smoking was associated with a greater reduction of regional LV function. CONCLUSIONS: Higher diastolic blood pressure and smoking are associated with decreased regional LV function in asymptomatic individuals.

Aged↗

PubMed2006

Association between levels of blood pressure and measures of subclinical disease multi-ethnic study of atherosclerosis.

BACKGROUND: High blood pressure (BP) is associated with the presence and severity of subclinical disease. Less is known about associations between normal levels of BP and various measures of subclinical disease. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled 6814 participants free of clinical cardiovascular disease (38% white, 28% African American, 22% Hispanic, and 12% Asian). The baseline examination included standardized measures of BP, common carotid intimal-medial thickness determined by ultrasonography, coronary artery calcium by computed tomography, and left ventricular mass by magnetic resonance imaging. Participants with treated hypertension (n = 2173) were excluded. Statistical methods included analysis of variance, linear regression, and chi(2) tests. RESULTS: Among the 4640 participants, BP was strongly related to age and African American ethnicity. Carotid intimal-medial thickness was directly associated with systolic BP (SBP) and inversely associated with diastolic BP (DBP, P < .001 for both). For SBP in men, for instance, the adjusted regression coefficient was 0.058 mm per 1 SD (21 mm Hg; 95% CI, 0.045 to 0.070), and for SBP in women it was 0.043 (95% CI, 0.033 to 0.052). Left ventricular mass was directly related to SBP and DBP. The proportion with non-zero calcium scores increased with SBP but decreased with DBP. CONCLUSIONS: The range of BP examined in this study fell largely within the normal or prehypertension stage. In cross-sectional analysis of data from a population-based study, these untreated levels of BP were associated with a variety of measures of subclinical cardiovascular disease.

Black or African American↗

PubMed2006

Prevalence of age-related macular degeneration in 4 racial/ethnic groups in the multi-ethnic study of atherosclerosis.

OBJECTIVE: To describe the prevalence of age-related macular degeneration (AMD) in 4 racial/ethnic groups (white, black, Hispanic, and Chinese) that participated in the second examination of the Multi-ethnic Study of Atherosclerosis (MESA). DESIGN: Prospective cohort study. PARTICIPANTS: Six thousand one hundred seventy-six 45- to 85-year-old subjects selected from 6 United States communities. METHODS: Fundus images were taken using a 45 degrees digital camera through dark-adapted pupils and were graded for drusen size, type, area, increased retinal pigment, retinal pigment epithelial depigmentation, neovascular lesions, and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System. MAIN OUTCOME MEASURE: Age-related macular degeneration. RESULTS: Prevalences of AMD were 2.4% (black), 4.2% (Hispanic), 4.6% (Chinese), to 5.4% (white) (P<0.001 for any differences among groups). The highest prevalence of any AMD occurred in those 75 to 84 years old, varying from 7.4% in blacks to 15.8% in whites and Chinese (P = 0.03). Estimated prevalences of late AMD were 0.3% (black), 0.2% (Hispanic), 0.6% (white), and 1.0% (Chinese). These differences were marginally significant (age and gender adjusted, P = 0.08). The frequency of exudative AMD was highest in Chinese (age- and gender-adjusted odds ratio, 4.30; 95% confidence interval, 1.30-14.27) compared with whites. Differences in age, gender, pupil size, body mass index, smoking, alcohol drinking history, diabetes, and hypertension status did not explain the variability among the 4 racial/ethnic groups. CONCLUSIONS: Low prevalences of AMD were found in the MESA cohort in all groups. A lower prevalence of AMD was found in blacks compared with whites. The higher prevalence of exudative AMD in Chinese needs further study.

Age Distribution↗

PubMed2006

Genome-wide linkage of plasma adiponectin reveals a major locus on chromosome 3q distinct from the adiponectin structural gene: the IRAS family study.

Adiponectin (APM1) is an adipocyte-derived peptide that contributes to glucose, lipid, and energy homeostasis. We assessed the genetic basis of plasma adiponectin in Hispanic-American and African-American families enrolled through the Insulin Resistance Atherosclerosis Study Family Study. A 10-cM genome scan was performed in two batches: an original set (set 1) consisting of 66 families (45 Hispanic American and 21 African American) and a replication set (set 2) consisting of 66 families (45 Hispanic American and 21 African American). Adiponectin levels were measured by radioimmunoassay in 1,727 individuals from 131 of 132 families. Linkage analysis was carried out in Hispanic Americans and African Americans separately in set 1, set 2, and the pooled set (set 1 plus set 2), with and without diabetic subjects. A major gene was mapped to 3q27 with a logarithm of odds (LOD) score of 8.21 in the Hispanic-American sample. Ninety-six unrelated individuals were screened for polymorphisms in the APM1 gene, and 18 single nucleotide polymorphisms (SNPs) were genotyped in the Hispanic-American sample. Plasma adiponectin level was modestly associated with two SNPs and their accompaning haplotypes. Incorporating each or both SNPs in the linkage analysis, however, did not significantly reduce the LOD score. Therefore, a quantitative trait locus at 3q27, likely distinct from the APM1 gene, contributes to the variation of plasma adiponectin levels in the Hispanic-American population.

Adiponectin↗

PubMed2006

Decreased hepatic futile cycling compensates for increased glucose disposal in the Pten heterodeficient mouse.

Despite altered regulation of insulin signaling, Pten(+/-) heterodeficient standard diet-fed mice, approximately 4 months old, exhibit normal fasting glucose and insulin levels. We report here a stable isotope flux phenotyping study of this "silent" phenotype, in which tissue-specific insulin effects in whole-body Pten(+/-)-deficient mice were dissected in vivo. Flux phenotyping showed gain of function in Pten(+/-) mice, seen as increased peripheral glucose disposal, and compensation by a metabolic feedback mechanism that 1) decreases hepatic glucose recycling via suppression of glucokinase expression in the basal state to preserve hepatic glucose production and 2) increases hepatic responsiveness in the fasted-to-fed transition. In Pten(+/-) mice, hepatic gene expression of glucokinase was 10-fold less than wild-type (Pten(+/+)) mice in the fasted state and reached Pten(+/+) values in the fed state. Glucose-6-phosphatase expression was the same for Pten(+/-) and Pten(+/+) mice in the fasted state, and its expression for Pten(+/-) was 25% of Pten(+/+) in the fed state. This study demonstrates how intra- and interorgan flux compensations can preserve glucose homeostasis (despite a specific gene defect that accelerates glucose disposal) and how flux phenotyping can dissect these tissue-specific flux compensations in mice presenting with a "silent" phenotype.

Animals↗

PubMed2006

Lipin deficiency impairs diurnal metabolic fuel switching.

Fatty liver is a common feature of both obesity and lipodystrophy, reflecting compromised adipose tissue function. The lipin-deficient fatty liver dystrophy (fld) mouse is an exception, as there is lipodystrophy without a fatty liver. Using a combination of indirect calorimetry and stable-isotope flux phenotyping, we determined that fld mice exhibit abnormal fuel utilization throughout the diurnal cycle, with increased glucose oxidation near the end of the fasting period and increased fatty acid oxidation during the feeding period. The mechanisms underlying these alterations include a twofold increase compared with wild-type mice in tissue glycogen storage during the fed state, a 40% reduction in hepatic glucose production in the fasted state, and a 27-fold increase in de novo fatty acid synthesis in liver during the fed state. Thus, the inability to store energy in adipose tissue in the fld mouse leads to a compensatory increase in glycogen storage for use during the fasting period and reliance upon hepatic fatty acid synthesis to provide fuel for peripheral tissues during the fed state. The increase in hepatic fatty acid synthesis and peripheral utilization provides a potential mechanism to ameliorate fatty liver in the fld that would otherwise occur as a consequence of adipose tissue dysfunction.

Animals↗

PubMed2006

Feasibility of automating insulin delivery for the treatment of type 1 diabetes.

An automated closed-loop insulin delivery system based on subcutaneous glucose sensing and subcutaneous insulin delivery was evaluated in 10 subjects with type 1 diabetes (2 men, 8 women, mean [+/-SD] age 43.4 +/- 11.4 years, duration of diabetes 18.2 +/- 13.5 years). Closed-loop control was assessed over approximately 30 h and compared with open-loop control assessed over 3 days. Closed-loop insulin delivery was calculated using a model of the beta-cell's multiphasic insulin response to glucose. Plasma glucose was 160 +/- 66 mg/dl at the start of closed loop and was thereafter reduced to 71 +/- 19 by 1:00 p.m. (preprandial lunch). Fasting glucose the subsequent morning on closed loop was not different from target (124 +/- 25 vs. 120 mg/dl, respectively; P > 0.05). Mean glucose levels were not different between the open and closed loop (133 +/- 63 vs. 133 +/- 52 mg/dl, respectively; P > 0.65). However, glucose was within the range 70-180 mg/dl 75% of the time under closed loop versus 63% for open loop. Incidence of biochemical hypoglycemia (blood glucose <60 mg/dl) was similar under the two treatments. There were no episodes of severe hypoglycemia. The data provide proof of concept that glycemic control can be achieved by a completely automated external closed-loop insulin delivery system.

Adult↗

PubMed2006

Diabetic cardiomyopathy and subclinical cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA).

OBJECTIVE: Studies have demonstrated increased left ventricular mass (LVM) and diastolic dysfunction among diabetic patients without clinical cardiovascular disease (CVD), but few have assessed the potential contribution of subclinical CVD to ventricular abnormalities in diabetes. We examined whether diabetic cardiomyopathy is associated with subclinical atherosclerosis and if abnormalities are found with impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS: LVM, end-diastolic volume (EDV), and stroke volume were measured by magnetic resonance imaging (MRI), and atherosclerosis was assessed by coronary artery calcium and carotid intima-media wall thickness in 4,991 participants in the Multi-Ethnic Study of Atherosclerosis, a cohort study of adults aged 45-84 without prior CVD. Multivariable linear regression was used to analyze the association between MRI measures and glucose status. RESULTS: Increased LVM was observed in white, black, and Hispanic participants with diabetes but not among Chinese participants. After adjustment for weight, height, CVD risk factors, and subclinical atherosclerosis, ethnicity-specific differences in ventricular parameters were present. Among whites and Chinese with diabetes, LVM was similar to that in normal subjects; EDV and stroke volume were reduced. In blacks with diabetes, EDV and stroke volume were reduced, and LVM was increased (+5.6 g, P < 0.05). Among Hispanics with diabetes, EDV and stroke volume were similar to normal, but LVM was increased (+5.5 g, P < 0.05). After adjustment, IFG was associated with a decrease in EDV and stroke volume in whites and blacks only; however, no significant differences in LVM were observed. CONCLUSIONS: Ethnicity-specific differences in LVM, EDV, and stroke volume are associated with abnormal glucose metabolism and are independent of subclinical CVD.

Aged↗

PubMed2005

Smoking, diabetes, and blood cholesterol differ in their associations with subclinical atherosclerosis: the Multiethnic Study of Atherosclerosis (MESA).

Previous reports suggest that low-density lipoprotein cholesterol (LDLc) is associated with atherosclerosis plaque initiation while cigarette smoking is more associated with plaque progression. The role of diabetes in plaque initiation and progression is not clear. The aim of this study was to confirm and extend these findings. Among 6384 men and women aged 45-84 free of clinical cardiovascular disease, subclinical atherosclerosis severity was classified on the basis of ultrasound measures of carotid stenosis and thickness and the ankle-brachial blood pressure index of lower extremity arterial disease. Carotid plaques were classified as echolucent or echogenic. Distensibility was calculated from the change in carotid diameter over the cardiac cycle. The smoking association with minimal, moderate, and more severe disease was progressive, estimated as equivalent to LDLc effects of 40, 85 and 238 mg/dl respectively. LDLc was relatively more associated with echolucent plaques; smoking with echogenic plaques. Diabetes was associated with carotid stiffness, whereas smoking was associated with greater distensibility. The results, together with pathological literature, suggest that LDLc may be of key importance both in plaque initiation and vulnerability to rupture, whereas smoking may relate to plaque progression to thicker, more fibrous lesions. Diabetes contributes uniquely to arterial stiffness.

Aged↗

PubMed2005

Ankle-brachial index and subclinical cardiac and carotid disease: the multi-ethnic study of atherosclerosis.

The authors studied associations between ankle-brachial index (ABI) and subclinical atherosclerosis in the Multi-Ethnic Study of Atherosclerosis. Participants included 3,458 women (average age = 62.6 years) and 3,112 men (average age = 62.8 years) who were free of clinically evident cardiovascular disease. Measurements included ABI, carotid artery intima-media thickness, and coronary artery calcium assessed with computed tomography. Five ABI categories were defined: <0.90 (definite peripheral arterial disease (PAD)), 0.90-0.99 (borderline ABI), 1.00-1.09 (low-normal ABI), 1.10-1.29 (normal ABI), and > or =1.30 (high ABI). Compared with that in men with normal ABI, significantly higher internal carotid artery intima-media thickness was observed in men with definite PAD (1.58 vs. 1.09; p < 0.001), borderline ABI (1.33 vs. 1.09; p < 0.001), and low-normal ABI (1.18 vs. 1.09; p < 0.001) after adjustment for confounders. Fully adjusted odds ratios for a coronary artery calcium score greater than 20 decreased across progressively higher ABI categories in both women (2.85 (definite PAD), 1.27 (borderline ABI), 1.11 (low-normal ABI), 1.00 (normal ABI; referent), and 0.78 (high ABI); p for trend = 0.0002) and men (3.26 (definite PAD), 1.72 (borderline ABI), 1.14 (low-normal ABI), 1.00 (normal ABI; referent), and 1.43 (high ABI); p for trend = 0.0002). These findings indicate excess coronary and carotid atherosclerosis at ABI values below 1.10 (men) and 1.00 (women) and may imply increased risk of cardiovascular events in persons with borderline and low-normal ABI.

Aged↗

PubMed2005

Urine albumin excretion and subclinical cardiovascular disease. The Multi-Ethnic Study of Atherosclerosis.

We examined the association between urine albumin excretion (UAE) and common and internal carotid artery intima-media thickness (IMT), end-diastolic left ventricular (LV) mass, and coronary artery calcification (CAC) scores using data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based study of 6814 adults aged 45 to 85 years without clinical cardiovascular disease (CVD). The mean age of the MESA participants was 62.7 years, 47% were male, and 15% had diabetes mellitus (DM). Sex-specific spot urine albumin/creatinine ratios were used to define 4 UAE categories: normal, high normal, microalbuminuria, and macroalbuminuria. CAC scores were log-transformed after adding 1 to all scores. Mean values of subclinical CVD measures were computed by level of UAE after adjustment for blood pressure, DM, and other covariates. After adjustment for all covariates, geometric mean CAC scores were higher among participants with high normal UAE (8.8; P=0.07), microalbuminuria (9.9; P=0.002), and macroalbuminuria (13.1; P=0.02) compared with normal UAE (7.4), but only microalbuminuria reached statistical significance. Mean LV mass (g/m2.7) was significantly higher in participants with high normal UAE (37.0; P=0.001), microalbuminuria (38.3; P< or =0.0001), and macroalbuminuria (42.3; P< or =0.0001) compared with normal UAE (36.0) after adjustment for all covariates. No significant difference in mean carotid IMT was found after adjustment for all covariates. Similar results were noted in MESA participants with and without DM. In conclusion, higher UAE, including levels below microalbuminuria, may reflect the presence of subclinical CVD among adults without established CVD.

Aged↗

PubMed2005

Genetic analysis of adiponectin and obesity in Hispanic families: the IRAS Family Study.

Adiponectin, coded for by the APM1 gene, is a novel adipocyte-derived hormone implicated in energy homeostasis and obesity. Several genetic studies have observed evidence of association between APM1 gene polymorphisms and features of the metabolic syndrome, such as insulin resistance and obesity. As part of a comprehensive genetic analysis of the APM1 gene, we have screened 96 unrelated individuals for polymorphisms in the promoter, coding regions, and 3'untranslated region (UTR). Three promoter single-nucleotide polymorphisms (SNPs), two rare coding SNPs (G113A and T1233C), and 13 SNPs in the 3'UTR were identified. Eighteen SNPs were genotyped in 811 Hispanic individuals from 45 families in the IRAS Family Study (IRASFS). SNPs were tested for association with six obesity quantitative traits (body mass index, waist, waist:hip ratio, subcutaneous adipose tissue, visceral adipose tissue, and visceral:subcutaneous ratio). Significant evidence of association to at least one of the obesity traits was identified in seven of the 18 SNPs (<0.001-0.05). The promoter SNP INS CA-11156 was the most consistently associated SNP and was associated significantly with all measures of obesity, except the visceral:subcutaneous ratio (P-values 0.009-0.03). Haplotype analysis supported this evidence of association, with haplotypes containing an insertion of one CA repeat at position -11156 consistently being associated with lower obesity values (P-value <0.001-0.05). The adiponectin polymorphisms, in particular those in the promoter region, thus show significant association with obesity measures in the Hispanic population. Additional studies are needed to confirm our findings and determine which polymorphism causes the functional effect.

3' Untranslated Regions↗

PubMed2005

Ethnic differences in coronary calcification: the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: There is substantial evidence that coronary calcification, a marker for the presence and quantity of coronary atherosclerosis, is higher in US whites than blacks; however, there have been no large population-based studies comparing coronary calcification among US ethnic groups. METHODS AND RESULTS: Using computed tomography, we measured coronary calcification in 6814 white, black, Hispanic, and Chinese men and women aged 45 to 84 years with no clinical cardiovascular disease who participated in the Multi-Ethnic Study of Atherosclerosis (MESA). The prevalence of coronary calcification (Agatston score >0) in these 4 ethnic groups was 70.4%, 52.1%, 56.5%, and 59.2%, respectively, in men (P<0.001) and 44.6%, 36.5%, 34.9%, and 41.9%, respectively, (P<0.001) in women. After adjustment for age, education, lipids, body mass index, smoking, diabetes, hypertension, treatment for hypercholesterolemia, gender, and scanning center, compared with whites, the relative risks for having coronary calcification were 0.78 (95% CI 0.74 to 0.82) in blacks, 0.85 (95% CI 0.79 to 0.91) in Hispanics, and 0.92 (95% CI 0.85 to 0.99) in Chinese. After similar adjustments, the amount of coronary calcification among those with an Agatston score >0 was greatest among whites, followed by Chinese (77% that of whites; 95% CI 62% to 96%), Hispanics (74%; 95% CI 61% to 90%), and blacks (69%; 95% CI 59% to 80%). CONCLUSIONS: We observed ethnic differences in the presence and quantity of coronary calcification that were not explained by coronary risk factors. Identification of the mechanism underlying these differences would further our understanding of the pathophysiology of coronary calcification and its clinical significance. Data on the predictive value of coronary calcium in different ethnic groups are needed.

Black or African American↗

PubMed2005

Cosegregation of albuminuria and blood pressure: the Insulin Resistance Atherosclerosis (IRAS) family study.

BACKGROUND: Albuminuria was shown to be heritable and to share common genetic determinants with blood pressure (BP) in individuals of white ethnicity. Our aim in this study was to examine the familial aggregation of albuminuria and its phenotypic, genetic, and environmental correlations with BP in nondiabetic individuals of Hispanic (HA) and African American (AA) ethnicity. METHODS: The study included 129 large HA and AA families, providing 1405 nondiabetic individuals; those on antihypertensive medications were excluded. The albumin/creatinine ratio (ACR) in a random urine sample was used as a measure of albuminuria. A variance component approach was used in the analysis. RESULTS: After adjusting for age, sex, and body mass index (BMI), the heritabilities of ACR, systolic BP (SBP) and diastolic BP (DBP) were 11%, 26%, and 28%. The phenotypic correlations between ACR and each of SBP and DBP in HA (r = 0.17 and r = 0.16 respectively) and AA (r = 0.26 and r = 0.16) were significant. When partitioned into genetic and environmental factors, the genetic correlations between ACR and each of SBP and DBP were significant in HA (r(g) = 0.49 for each), whereas the environmental correlations were not. Conversely, the genetic correlations between ACR and SBP/DBP were not significant in AA (although with DBP it was not significantly different from that of HA), whereas a significant environmental correlation was observed between ACR and SBP (r(e) = 0.28, P < .001). CONCLUSIONS: Both albuminuria and BP exhibit familial aggregation in nondiabetic HA and AA. In HA, but not in AA, ACR and especially SBP share common genetic determinants. The mechanism of this ethnic heterogeneity is unclear but merits further investigation.

Adult↗

PubMed2005

Association of proopiomelanocortin gene polymorphisms with obesity in the IRAS family study.

Proopiomelanocortin (POMC) has been found to be associated with rare Mendelian forms of obesity in children, and, in linkage studies, genomic regions containing the POMC locus have been linked to leptin levels, a predictor of obesity, in white, Mexican-American, and African-American families. POMC polymorphisms have not been investigated in detail for association with obesity in the general population. Five single nucleotide polymorphisms (SNPs) (G-3460C, C17T, G3473A, C3755T, and A7069G) were genotyped on 811 Hispanic individuals in the Insulin Resistance Atherosclerosis Family Study and tested for association with multiple obesity quantitative traits. General and family-based association analyses for each individual SNP and for haplotypes were performed using the generalized estimating equation and quantitative pedigree disequilibrium test (QPDT), respectively. Modest but consistent associations were observed for SNP C3755T, with p values ranging from 0.011 to 0.045 for association with BMI, waist, visceral adipose tissue, and subcutaneous adipose tissue. G-3460C, G3473A, and A7069G were also found to be associated with additional obesity measurements (p value 0.025 to 0.04), with comparable levels of evidence observed for linkage disequilibrium between these traits and these SNPs. Results of the haplotype analyses were also consistent with the single SNP analysis, with haplotypes containing C3755T showing the greatest evidence of association (p values ranging 0.004 to 0.048). Monte Carlo simulations (gene dropping) that account for the number of comparisons and the correlation structure indicate that the multivariate significance for these obesity traits with these polymorphisms was p = 0.0091. Collectively, the POMC polymorphisms showed consistent evidence for association with obesity traits in Hispanic Americans across several analytical approaches using SNP and haplotype analysis. These results support the hypothesis that POMC contributes genetically to the development of obesity.

Adult↗

PubMed2005

A genome scan for fasting insulin and fasting glucose identifies a quantitative trait locus on chromosome 17p: the insulin resistance atherosclerosis study (IRAS) family study.

Plasma insulin and glucose concentrations are important quantitative phenotypes related to diabetes and the metabolic syndrome. Reports purporting to identify quantitative trait loci (QTLs) that contribute to the variation in fasting insulin and glucose concentrations are discrepant. As part of the Insulin Resistance Atherosclerosis Study (IRAS) Family Study, a genome scan was performed in African-American (n = 42) and Hispanic (n = 90) extended families to identify regions that may contain positional candidate genes for fasting insulin and fasting glucose (n = 1,604 subjects). There was significant evidence for linkage of fasting insulin to the short arm of chromosome 17 (logarithm of odds [LOD] = 3.30; 54 cM between D17S1294 and D17S1299, P = 1.0 x 10(-4)). The strongest evidence for linkage over all pedigrees for fasting glucose was also observed in this region (LOD = 1.44; 58 cM, P = 9.9 x 10(-3)). The results of this study provide impetus for future positional cloning of QTLs regulating insulin and glucose levels. Identifying genes in these regions should provide insight into the nature of genetic factors regulating plasma glucose and insulin concentrations.

Black or African American↗

PubMed2004

Insulin resistance and hypertension: the Insulin Resistance Atherosclerosis study.

The association between insulin resistance and insulinemia and hypertension is controversial. We examined the relation between insulin resistance and hypertension in 564 non-Hispanic whites (NHW), 505 Hispanics (H), and 413 African Americans (AA) who participated in the Insulin Resistance Atherosclerosis Study (IRAS). Insulin sensitivity was measured with a frequently sampled intravenous glucose tolerance test with minimal model analysis. The prevalence of hypertension was 32.5%, 49.4%, and 32.3% in NHW, AA, and H, respectively (P<0.001). When subjects without diabetes in all ethnic groups were combined, age, male sex, race (AA), body mass index (BMI), and insulin resistance, but not fasting insulin, were significantly associated with hypertension. When each ethnic group was analyzed separately, insulin resistance was significantly associated with hypertension in NHW and H, but not AA. After excluding subjects taking antihypertensive medications, male sex, BMI, fasting glucose, and insulin resistance, but not fasting insulin, were significant determinants of blood pressure. When the 3 ethnic groups were analyzed separately, insulin resistance was significantly associated with blood pressure in H, but not NHW, or AA. Neither insulin resistance nor fasting insulin was significantly associated with hypertension or blood pressure in subjects with diabetes of the 3 ethnic groups after adjusting for age, sex, BMI, and waist. In conclusion, insulin resistance, but not insulinemia, was related to hypertension and blood pressure in subjects without diabetes, but ethnic differences in these relations appear to exist. Neither insulin resistance nor insulinemia was related to hypertension or blood pressure in patients with type 2 diabetes in the 3 ethnic groups.

Black or African American↗