Biomedical subjects

Ahmed H Kissebah

Publications and source records attributed to Ahmed H Kissebah.

8 recordsLinked to original sources

PubMed2007

SEPS1 protects RAW264.7 cells from pharmacological ER stress agent-induced apoptosis.

Selenoprotein S (SEPS1) is a novel endoplasmic reticulum (ER) resident protein and it is known to play an important role in production of inflammatory cytokines. Here, we show evidence that SEPS1 is stimulated by pharmacological ER stress agents in RAW264.7 macrophages as well as other cell types. Overexpression studies reveal a protective action of SEPS1 in macrophages against ER stress-induced cytotoxicity and apoptosis, resulting in promoting cell survival during ER stress. The protective action of SEPS1 is largely dependent on ER stress-mediated cell death signal with less effect on non-ER stress component cell death signals. Conversely, suppression of SEPS1 in macrophages results in sensitization of cells to ER stress-induced cell death. These findings suggest that SEPS1 could be a new ER stress-dependent survival factor that protects macrophage against ER stress-induced cellular dysfunction.

Animals↗

PubMed2005

Genetic variation in selenoprotein S influences inflammatory response.

Chronic inflammation has a pathological role in many common diseases and is influenced by both genetic and environmental factors. Here we assess the role of genetic variation in selenoprotein S (SEPS1, also called SELS or SELENOS), a gene involved in stress response in the endoplasmic reticulum and inflammation control. After resequencing SEPS1, we genotyped 13 SNPs in 522 individuals from 92 families. As inflammation biomarkers, we measured plasma levels of IL-6, IL-1beta and TNF-alpha. Bayesian quantitative trait nucleotide analysis identified associations between SEPS1 polymorphisms and all three proinflammatory cytokines. One promoter variant, -105G --> A, showed strong evidence for an association with each cytokine (multivariate P = 0.0000002). Functional analysis of this polymorphism showed that the A variant significantly impaired SEPS1 expression after exposure to endoplasmic reticulum stress agents (P = 0.00006). Furthermore, suppression of SEPS1 by short interfering RNA in macrophage cells increased the release of IL-6 and TNF-alpha. To investigate further the significance of the observed associations, we genotyped -105G --> A in 419 Mexican American individuals from 23 families for replication. This analysis confirmed a significant association with both TNF-alpha (P = 0.0049) and IL-1beta (P = 0.0101). These results provide a direct mechanistic link between SEPS1 and the production of inflammatory cytokines and suggest that SEPS1 has a role in mediating inflammation.

Adult↗

PubMed2005

Genetic linkage and association of the growth hormone secretagogue receptor (ghrelin receptor) gene in human obesity.

The growth hormone secretagogue receptor (GHSR) (ghrelin receptor) plays an important role in the regulation of food intake and energy homeostasis. The GHSR gene lies on human chromosome 3q26 within a quantitative trait locus strongly linked to multiple phenotypes related to obesity and the metabolic syndrome. Because the biological function and location of the GHSR gene make it an excellent candidate gene, we tested the relation between common single nucleotide polymorphisms (SNPs) in the GHSR gene and human obesity. We performed a comprehensive analysis of SNPs, linkage disequilibrium (LD), and haplotype structure across the entire GHSR gene region (99.3 kb) in 178 pedigrees with multiple obese members (DNA of 1,095 Caucasians) and in an independent sample of the general population (MONICA Augsburg left ventricular hypertrophy substudy; DNA of 1,418 Caucasians). The LD analysis revealed a disequilibrium block consisting of five SNPs, consistent in both study cohorts. We found linkage among all five SNPs, their haplotypes, and BMI. Further, we found suggestive evidence for transmission disequilibrium for the minor SNP alleles (P < 0.05) and the two most common haplotypes with the obesity affection status ("susceptible" P = 0.025, "nonsusceptible" P = 0.045) in the family cohort using the family-based association test program. Replication of these findings in the general population resulted in stronger evidence for an association of the SNPs (best P = 0.00001) and haplotypes with the disease ("susceptible" P = 0.002, "nonsusceptible" P = 0.002). To our knowledge, these data are the first to demonstrate linkage and association of SNPs and haplotypes within the GHSR gene region and human obesity. This linkage, together with significant transmission disequilibrium in families and replication of this association in an independent population, provides evidence that common SNPs and haplotypes within the GHSR region are involved in the pathogenesis of human obesity.

Body Mass Index↗

PubMed2004

Major quantitative trait locus for resting heart rate maps to a region on chromosome 4.

Multiple studies have identified resting heart rate as a risk factor for cardiovascular disease independent of other cardiovascular disease risk factors (such as dyslipidemia and hypertension). Previous studies have examined heart rate in hypertensive individuals, but little is known about the genetic determination of resting heart rate in a normal population. Therefore, our objective was to perform a genome screen on a population containing normotensive and hypertensive individuals. We performed variance decomposition linkage analysis using maximum likelihood methods at approximately 10 cM intervals in 2209 individuals of predominantly North European ancestry. We estimated the heritability of resting heart rate to be 26% and obtained significant evidence of linkage (logarithm of the odds [LOD]=3.9) for resting heart rate on chromosome 4q. This signal is in the same region as a quantitative trait locus (QTL) for long QT syndrome 4 and a QTL for heart rate in rats. Within the 1-LOD unit support interval, there are 2 strong candidates: ankyrin-B and myozenin 2.

Animals↗

PubMed2004

Genetic determinants of obesity-related lipid traits.

In our ongoing effort to identify genes influencing the biological pathways that underlie the metabolic disturbances associated with obesity, we performed genome-wide scanning in 2,209 individuals distributed over 507 Caucasian families to localize quantitative trait loci (QTLs), which affect variation of plasma lipids. Pedigree-based analysis using a quantitative trait variance component linkage method that localized a QTL on chromosome 7q35-q36, which linked to variation in levels of plasma triglyceride [TG, logarithm of odds (LOD) score = 3.7] and was suggestive of linkage to LDL-cholesterol (LDL-C, LOD = 2.2). Covariates of the TG linkage included waist circumference, fasting insulin, and insulin:glucose, but not body mass index or hip circumference. Plasma HDL-cholesterol (HDL-C) levels were suggestively linked to a second QTL on chromosome 12p12.3 (LOD = 2.6). Five other QTLs with lower LOD scores were identified for plasma levels of LDL-C, HDL-C, and total cholesterol. These newly identified loci likely harbor genetic elements that influence traits underlying lipid adversities associated with obesity.

Blood Glucose↗

PubMed2004

A novel pathway to the manifestations of metabolic syndrome.

Pathways leading from obesity to the manifestations of metabolic syndrome involve a number of metabolic risk factors, as well as adipokines, mediators of inflammatory response, thrombogenic and thrombolytic parameters, and vascular endothelial reactivity. Increased adipose tissue mass contributes to augmented secretion of proinflammatory adipokines, particularly tumor necrosis factor-alpha (TNF alpha), along with diminished secretion of the "protective" adiponectin. In our view, TNF alpha and adiponectin are antagonistic in stimulating nuclear transcription factor-kappa B (NF-kappa B) activation. Through this activation, TNF alpha induces oxidative stress, which exacerbates pathological processes leading to oxidized low-density lipoprotein and dyslipidemia, glucose intolerance, insulin resistance, hypertension, endothelial dysfunction, and atherogenesis. NF-kappa B activation further stimulates the formation of additional inflammatory cytokines, along with adhesion molecules which promote endothelial dysfunction. Elevated free fatty acid, glucose, and insulin levels enhance this NF-kappa B activation and further downstream modulate specific clinical manifestations of metabolic syndrome.

Adiponectin↗

PubMed2002

Gallstones: genetics versus environment.

OBJECTIVE: The aim of this study was to determine if a significant genetic component contributes to the pathogenesis of symptomatic gallstones. SUMMARY BACKGROUND DATA: Gallstones represent a polygenic disorder that affects more than 30,000,000 Americans and results in more than 750,000 cholecystectomies in the United States annually. Risk factors include age, gender, race, parity, obesity, and diabetes. A family history of gallstones also has been identified as a risk factor suggesting that genetics play a role in gallstone formation. However, the role of genetics in the pathogenesis of gallstone formation has not been determined. METHODS: A gallbladder disease-specific questionnaire was administered to 904 healthy unrelated adult volunteers (association study). The questionnaire ascertained a history of cholecystectomy and gallstone disease in first-degree relatives, as well as medical history, demographic, and anthropometric data. A logistic regression model was used to identify risk factors for symptomatic gallstone disease in a multivariate analysis. A maximum likelihood based variance decomposition approach was then used in 1,038 individuals from 358 families (family study) to estimate the additive genetic heritability of symptomatic gallstone disease. RESULTS: In the association study significant risk factors for symptomatic gallstone disease were female gender (relative risk 8.8, P <.003), obesity (BMI > 30, relative risk 3.7, P <.001), age > 50 (relative risk 2.5, P <.001), and a positive family history of previous cholecystectomy in a first-degree family member (relative risk 2.2, P <.01). In the family study the additive genetic heritability of symptomatic gallstones was 29% (P <.02), age and gender were significant covariates and explained 9.3% of the phenotypic variation in gallbladder disease. CONCLUSIONS: These data suggest that genetic factors are responsible for at least 30% of symptomatic gallstone disease. However, the true role of heredity in gallstone pathogenesis is probably higher because data based on symptomatic gallbladder disease underestimates the true prevalence in the population.

Adolescent↗

PubMedDate not supplied

Insulin resistance causes human gallbladder dysmotility.

Obesity, diabetes, and hyperlipidemia are known risk factors for the development of gallstones. A growing body of animal and human data has correlated insulin resistance with organ dysfunction. The relationship among obesity, diabetes, hyperlipidemia, and abnormal gallbladder motility remains unclear. Therefore, we designed a study to investigate the association among obesity, insulin resistance, hyperlipidemia, and gallbladder dysmotility. One hundred ninety-two healthy adult nondiabetic volunteers were studied. Gallbladder ultrasounds were performed before and after a standardized fatty meal. A gallbladder ejection fraction (EF) was calculated, and an EF of < 25% was considered abnormal. Serum was analyzed for cholesterol, triglycerides, cholecystokinin, leptin, glucose, and insulin. The homeostasis assessment model (HOMA) was used to determine insulin resistance. The volunteers had a mean age of 38 years (range, 18-77), and 55% were female. Thirty subjects (15%) had gallstones and were excluded from the study. Thirty subjects (19%) had abnormal gallbladder motility (EF < 25%). In lean subjects (n = 96) fasting glucose was significantly increased in the 16 subjects with gallbladder EF < 25% versus the 80 subjects with gallbladder EF > 25% (109 +/- 20 mg/dl versus 78 +/- 2 mg/dl, P < 0.05). Similarly, the HOMA index was significantly greater in subjects with gallbladder EF < 25% versus gallbladder EF >25% (3.3 +/- 1.2 versus 2.0 +/- 0.2, P < 0.05). In obese subjects (n = 66), fasting glucose, insulin, and insulin resistance were not associated with a gallbladder EF < 25%. These data suggest that in lean, nondiabetic volunteers without gallstones, gallbladder dysmotility is associated with an elevated fasting glucose as well as a high index of insulin resistance. We conclude that insulin resistance alone may be responsible for gallbladder dysmotility that may result in acalculous cholecystitis or gallstone formation.

Adolescent↗