Obesity-associated genetic variants in young Asian Indians with the metabolic syndrome and myocardial infarction.

OBJECTIVE: Associations between obesity-related polymorphisms and the metabolic syndrome in 485 young ( ≤ 45 Years) Asian Indian patients with acute myocardial infarction (AMI), and 300 matched controls were assessed. METHODS: Genetic variants included the adiponectin 45T→G and 276G→T, LEPR K109R and Q223R, MC4R-associated C→T and FTO A→T polymorphisms. RESULTS: The metabolic syndrome, as defined by NCEP ATP III and IDF criteria, was diagnosed in 61 and 60% of patients, respectively. No relationship was found between the obesity-associated polymorphisms and the metabolic syndrome, or between AMI patients and controls. The MC4R-associated TT genotype occurred more frequently in patients with lower triglyceride levels (p = 0.024), while the adiponectin 45 TT genotype occurred more commonly in patients with normal fasting glucose levels (p = 0.004). The LEPR Q223R TT genotype was associated with low high-density lipoprotein (HDL) cholesterol levels (p = 0.003). CONCLUSION: The metabolic syndrome occurs commonly in young Asian Indian patients with AMI. No relationship was found between any obesity-associated polymorphism and the metabolic syndrome. Particular genotypes may exert protective or disadvantageous effects on individual components of the metabolic syndrome.

Variants in PPARG, KCNJ11, TCF7L2, FTO, and HHEX genes in South African subjects of Zulu descent with type 2 diabetes

Polymorphisms in a number of genes have consistently been associated with type 2 diabetes in various Caucasian populations. Little, however, is known of the association between these genetic risk markers and type 2 diabetes in sub-Saharan African subjects. The aim of the current study was to determine the association between common variants in the PPARG, KCNJ11, TCF7L2, FTO and HHEX genes in African (black) subjects of Zulu descent in KwaZulu-Natal, South Africa. The association between type 2 diabetes and rs1801282 (PPARG), rs5215 (KCNJ11), rs12255372 (TCF7L2), rs7903146 (TCF7L2) rs9939609 (FTO) and rs1111875 (HHEX) was determined in 178 South African Zulu subjects and 200 healthy ethnically matched control subjects. rs1801282 (PPARG) and rs5215 (KCNJ11) were not found to be present in either the subjects with type 2 diabetes or the control subjects. No association between rs12255372 (TCF7L2), rs9939609 (FTO) and type 2 diabetes was found. Heterozygosity at rs7903146 (TCF7L2) was associated with type 2 diabetes (odds ratio 1.84, 95% confidence interval: 1.19­2.83, p=0.0035). Decreased frequency of homozygosity for the common allele at rs7903146 (TCF7L2) was observed in subjects with type 2 diabetes (odds ratio 0.54, 95% confidence interval: 0.34­0.84; p=0.0043). There was an increased frequency of C allele homozygosity in subjects with type 2 diabetes at rs1111875 (HHEX), of borderline significance (odds ratio 1.54, 95% confidence interval 0.97­2.44, p=0.052). Subjects with type 2 diabetes harbouring one or more of the risk alleles did not differ from those without genetic variation at the loci studied, with respect to age at diagnosis, blood pressure, body mass index or serum lipid levels. We conclude that risk polymorphisms identified in Caucasian populations are not associated with type 2 diabetes in this group of South African subjects of Zulu descent, with the exception of rs7903146 (TCF7L2). The genetic risk for type 2 diabetes in sub-Saharan African subjects may reside in other, as yet unidentified, genes

Metabolic syndrome in young Asian Indian patients with myocardial infarction.

OBJECTIVES: This study assessed the prevalence of the metabolic syndrome and its impact on hospital outcomes in young South African Indians (< or = 45 years) with acute myocardial infarction (AMI) using both the National Cholesterol Education Programme Adult Treatment Panel III (NCEP ATP III) and the International Diabetes Federation (IDF) definitions. METHODS AND RESULTS: The study population comprised 389 patients with AMI. The metabolic syndrome as defined by the NCEP ATP III criteria was found in 235 (60%) patients and in 223 (57%) according to the IDF criteria, with only a 79% concordance between the two definitions. However, when ethnic-specific waist circumference cut-offs proposed by the IDF were used as a criterion for obesity in the NCEP ATP III definition, the number of patients with the metabolic syndrome increased significantly to 270 (69%) (p < 0.001). Elevated fasting blood glucose was the major NCEP ATP III determinant present in 86% of individuals. All determinants for both definitions were found more frequently in patients with the metabolic syndrome (p < 0.001). Although 44% of patients had triple-vessel disease on cardiac catheterization studies, the frequency of adverse cardiovascular events during hospital stay was low, and was uninfluenced by the presence or absence of the metabolic syndrome. CONCLUSION: The metabolic syndrome is a common finding in young Indian patients with AMI who frequently present with extensive atherosclerotic disease. Adverse event rate during hospital stay was low, and was unrelated to the presence of the metabolic syndrome. There was no significant difference in the prevalence rate of the metabolic syndrome as determined by either the NCEP ATP III or IDF definitions, but there was only a moderate level of agreement between the two definitions. Inclusion of ethnic-specific waist circumference cut-offs as the determinant of obesity in the NCEP definition may identify more accurately individuals at increased cardiometabolic risk and improve predication of the metabolic syndrome.

Prognostic value of N-terminal-pro-brain natriuretic peptide measurements in patients with acute coronary syndromes.

BACKGROUND: The aim of this study was to examine the prognostic value of admission N-terminal-pro-brain natriuretic peptide (NT-proBNP) measurements for the outcome of adverse events, and to compare it with that of cardiac troponin T in the assessment of risk in patients with acute coronary syndrome (ACS) during the hospital stay and at six months following hospital discharge. METHODS: The study population consisted of 200 Asian Indian patients admitted with a diagnosis of ACS to the Coronary Care Unit at RK Khan Hospital, Durban, South Africa. A reference group comprising 100 healthy Indian individuals drawn from the same community and who did not suffer from cardiovascular disease was also analysed. RESULTS: The majority of patients presented with ST segment elevation myocardial infarction (STEMI) (71%), whereas 14.5% had non-ST segment elevation MI (NSTEMI), and the remaining 14.5% had unstable angina. Patients had multiple risk factors for coronary heart disease (CHD) including hypertension (59%), hypercholesterolaemia (59%), smoking (57%), diabetes mellitus (51%), obesity (46%), and a strong family history of CHD (55%). NT-proBNP levels were significantly increased in patients with STEMI (p = 0.005) and NSTEMI (p = 0.002) who developed adverse events during their hospital stay, compared with those who did not. At the six-month followup, although NT-proBNP levels were higher in patients with STEMI and NSTEMI who developed adverse events, these differences were not statistically significant. No differences in troponin T levels were detected in patients with STEMI and NSTEMI who developed adverse events, compared to those who did not, either during the hospital stay, or at six months after release. At hospital admission, 24% of patients with unstable angina who had elevated NT-proBNP levels and normal troponin T concentrations developed adverse events, compared to 38% at six months. NT-proBNP levels in the reference group were comparable with those reported in other populations. CONCLUSION: This study demonstrated that elevation in admission NT-proBNP levels is an important determinant of acute and intermediate cardiac risk in patients with ACS. NT-proBNP concentrations were superior to those of troponin T as prognostic markers in both STEMI and NSTEMI. In a low-risk group of patients with unstable angina and negative troponin T concentrations, elevated NT-proBNP levels constituted a risk for the development of adverse cardiovascular events. Therefore, NT-proBNP should be included in the risk assessment of ACS to provide guidance for further therapeutic strategies.

Plasminogen activator inhibitor type 1 (PAI-1) and platelet glycoprotein IIIa (PGIIIa) polymorphisms in young Asian Indians with acute myocardial infarction.

BACKGROUND: The relationship between polymorphisms in the genes for plasminogen activator inhibitor type 1(PAI-1) and platelet glycoprotein IIIa (PGIIIa), clinical and environmental features, and the risk of premature coronary heart disease (CHD) in Asian Indian subjects living in South Africa, has been investigated. METHODS: The prevalence of the PAI-1 promoter 4G/5G and the PGIIIa PI A1A2 polymorphisms was examined in 195 unrelated Asian Indian patients (

Coagulation gene polymorphisms as risk factors for myocardial infarction in young Indian Asians.

BACKGROUND: The relationship between pro-coagulant gene polymorphisms, clinical features and the risk of premature coronary heart disease (CHD) in Indian Asian subjects resident in South Africa has been investigated. METHODS: The prevalence of the beta-fibrinogen -455G/A and -148C/T, and the factor VII 10 bp 5' promoter insertion/deletion and R353Q polymorphisms were examined in 195 unrelated Indian Asian patients (< or = 45 years) who presented with myocardial infarction (MI). Results were compared with those from 107 unaffected siblings (18-45 years) and 300 healthy age- and race-matched control subjects. RESULTS: Overall, none of the polymorphisms examined here showed any association with MI. However, when stratified according to obesity, patients with a BMI > 30 kg/m2 had a significantly higher frequency of the beta-fibrinogen variant alleles, compared with non-obese patients (19% vs 9%; p = 0.025) and controls (19% vs 9%; p = 0.003). Furthermore, the highest frequency of variant alleles occurred in obese smokers (24%), compared with 4% in non-obese non-smokers (p = 0.003) and 9% in control subjects (p < 0.001). The factor VII R353Q and promoter insertion variants, on the other hand, were associated with higher HDL and lower LDL levels (p = 0.034 and 0.04, respectively). CONCLUSION: In young Indian Asians who are both obese and smoke, the beta-fibrinogen genetic polymorphisms -455G-->A and -148C-->T, which are in linkage disequilibrium, are significant risk factors for the development of MI. Factor VII genetic variants, namely the 10 bp promoter insertion/deletion and R353Q polymorphisms, may possibly play a protective role through their association with elevated HDL and low LDL levels, respectively.

Demographic data and outcome of acute coronary syndrome in the South African Asian Indian population.

Significant differences in the prevalence of coronary heart disease (CHD) exist with respect to gender, age and ethnicity. The disease has been reported to be higher in Indian populations that have emigrated from the Indian subcontinent. The aim of this study was to examine differences in major cardiovascular risk factors and clinical outcome in South African Asian Indians of different age groups and gender, who presented with acute coronary syndromes (ACS). The study cohort consisted of 2 290 consecutive patients, admitted between 1996 and 2002, who were divided into three age subgroups: young ( 45 to 65 years; 21%). All three age groups were predominantly male, but this was more evident in the younger (88%) and middle age groups (71%), and became less striking as the proportion of females increased with age. Smoking was more common in young men compared with young women (p < 0.01). Diabetes mellitus (21%) and hypertension (18%) were seen less frequently in young patients but this was confined to men only. Total cholesterol was elevated in 65 to 70% of all patients while high-density lipoprotein (HDL) levels were significantly lower in men compared with women for all age subsets. Hospital mortality was extremely low in young (1%) and middle-aged patients (2%), but was expectedly higher in older patients (8%; p < 0.0001). A family history of CHD was the most common familial vascular disease seen. Young patients were more often subjected to diagnostic and therapeutic interventions. They had more aggressive disease, with 48% of those subjected to angiographic studies having triple vessel disease (TVD), and 14% undergoing coronary artery bypass grafting (CABG). Triple vessel disease was also detected most commonly in middle-aged (64%) and old patients (75%). In conclusion, significant differences in risk factor status were found in South African Indians between genders and for different age groups. Also, young Indians in this study differed markedly from other young population groups with CHD, in that they frequently had premature atherosclerosis with diffuse and aggressive disease.

T594M mutation of the epithelial sodium channel beta-subunit gene in pre-eclampsia and eclampsia in Black South African women.

The possible role of the beta-subunit of the epithelial sodium channel T594M polymorphism in hypertensive disorders of pregnancy has not been examined. This study compared Black South African women with pre-eclampsia (n= 204), early onset pre-eclampsia (n= 67), eclampsia (n= 120) and gestational hypertension (n= 78) with 338 women from the same ethnic group who had full-term normotensive pregnancies, for the presence of the T594M polymorphism. The variant allele was detected in 1.7% to 3.8% of the various patient groups and in 3.6% of the control group reflecting no significant difference. These results suggest that the T594M polymorphism in the sodium channel beta-subunit is not associated with the pathogenesis of pre-eclampsia or gestational hypertension.

Lp(a) and apoE polymorphisms in young South African Indians with myocardial infarction.

The lipoprotein(a) [Lp(a)] and apolipoprotein E (apoE) polymorphisms have been shown to be important genetic determinants of cardiovascular risk. Their effect on coronary heart disease (CHD) is less clear, particularly in Asian Indians who are at high risk for this disease. The aim of this study was to examine the association of the Lp(a) promoter pentanucleotide repeat polymorphism and the apoE codon 112 and 158 genotypes in 195 young South African Indian patients (< or = 45 years) with myocardial infarction (MI). Results were compared with 300 healthy age-matched control subjects drawn from the same community and 107 unaffected siblings (18-45 years). In addition, fasting lipograms were performed on all patients and a detailed history of conventional risk factors and family background was obtained. Of the six different Lp(a) alleles detected, the 8-repeat sequence was most frequently seen. However, no difference in frequencies existed between patient and control groups. The most frequently occurring apoE genotype in the three study groups was E3/E3 (patients 71%; siblings 70%; controls 70%). A significant difference in the E3/E4 genotype was seen between patients and controls (23% vs 14%; p = 0.018) and between siblings and controls (24% vs 14%; p = 0.027). These patients were also more likely to have significantly higher low-density lipoprotein (LDL) and lower high-density lipoprotein (HDL) levels (p = 0.005 and 0.045, respectively). No association was observed between any of the Lp(a) or apoE genotypes and conventional risk factors such as smoking, diabetes, hypertension, obesity or a family history of CHD. In conclusion, the apoE3/E4 genotype is strongly associated with the incidence of myocardial infarction in young South African Indians. This genotype also adversely affects LDL and HDL cholesterol levels, both of which contribute to premature atherosclerosis. In contrast, the Lp(a) pentanucleotide repeat polymorphism does not appear to have any aetiological role in MI in this population.

Renin-angiotensin system and associated gene polymorphisms in myocardial infarction in young South African Indians.

The renin-angiotensin system plays an important role in cardiovascular regulation. Abnormalities in genetic components of this system, such as the angiotensin-converting enzyme (ACE) gene, angiotensin II type 1 (AT1) receptor gene and angiotensinogen (AGT) gene, may cause a variety of adverse cardiovascular effects. It was the aim of this study, therefore, to investigate the involvement of the ACE insertion/deletion (I/D), AT1 receptor 1166 A->C and AGT M235T polymorphisms as predisposing factors for myocardial infarction (MI) in 195 young South African Indians (C AT1 receptor polymorphism with respect to both genotype and allelotype (p > 0.70), or in the genotype or allele frequency distribution of the AGT M235T polymorphism (p > 0.44). However, a significant in crease was noted for both the AT1 receptor C variant (p = 0.025) and the AGT T variant (p = 0.047) in hypertensive patients compared with those who were normotensive. In conclusion, results of this study indicate that the ACE I/D, the 1166 A->C AT1 receptor and AGT M235T polymorphisms do not confer any increased risk for MI in young South African Indians.

P53 codon 72 polymorphism and BRCA 1 and 2 mutations in ovarian epithelial malignancies in black South Africans.

Mutations in the BRCA and p53 tumor suppressor genes are implicated in the oncogenesis of ovarian tumors although their exact roles remain unclear. Despite recognized ethnic differences in the frequency of ovarian cancer and in genetic polymorphisms between populations, studies carried out so far have focused almost entirely on Caucasian subjects. In this study, undertaken at King Edward VIII Hospital, Durban, South Africa, we examined blood and/or primary epithelial ovarian tumor tissue from 75 black South African women for the presence of the three most commonly occurring BRCA 1 and 2 mutations (185delAG, 5382insC and 6174delT). The p53 codon 72 allele status was also examined and results were compared to a reference cohort comprising 340 ethnically matched subjects. None of the BRCA 1 or 2 mutations were detected in the patient group. The codon 72 Arg allele frequency in lymphocytic DNA was not significantly different compared with the control group. In contrast, in ovarian tumor DNA, the Arg allele was found significantly more frequently than in the controls; this was observed in terms of both Arg allele frequency (45% vs. 31%; P = 0.017) and Arg homozygosity (20% vs. 9%; P = 0.039). Tumors with the more aggressive serous papillary cystadenomatous histology had a markedly higher Arg frequency (45%) than the mucinous cystadenomas (25%). The higher frequency of the Arg allele detected in this study in black South Africans with ovarian tumors suggests a possible role in malignant transformation and may constitute a risk factor for ovarian and other epithelial cancers through mechanisms yet to be elucidated.

Risk factors and methylenetetrahydrofolate reductase gene polymorphisms in a young South African Indian-based population with acute myocardial infarction.

Although coronary heart disease (CHD) is extremely common in South African Indians, there is little published data on the possible causes leading to myocardial infarction (MI) in young Indians. The aim of this study was to identify common environmental risk factors and to examine the relationship between two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, the 677 C right arrow-hooked T and 1298 A right arrow-hooked C in young South African Indians with MI. Demographic and risk factor data were obtained from245 patients

Absence of Factor V Leiden, thrombomodulin and prothrombin gene variants in Black South African women with pre-eclampsia and eclampsia.

It has been suggested that gene aberrations may contribute to vascular endothelial dysfunction of pre-eclampsia in Caucasian and Japanese women. This study was undertaken to examine the association between pre-eclampsia in Black Zulu speaking South African women and the Factor 5 Leiden mutation. 100 patients with pre-eclampsia comprised the study group. The control group comprised 110 normotensive pregnant women of the same population group. Genotyping was performed to detect the G or A allele at residue 506 of the Factor V gene, and the C or T allele at residue 455 of the thrombomodulin gene. Our findings demonstrate that these particularly genetic loci are of little use in disease association studies for pre-eclampsia in homogenous Zulu speaking Africans.

P53 codon 72 polymorphism and human papillomavirus type in relation to cervical cancer in South African women.

The usefulness of the arginine (Arg) residue at codon 72 of the p53 tumor suppressor gene as a marker for the risk of cervical cancer remains unclear. Studies to date have focused mainly on Caucasian subjects despite marked ethnic variations in both the p53 polymorphism and the frequency of cervical carcinoma. Furthermore, not all studies have taken into account the type of human papillomavirus (HPV) infection present. In this study, undertaken at King Edward VIII Hospital, Durban, South Africa, we determined the p53 codon 72 status in 281 black South African women with cervical cancer and 340 ethnically matched healthy control subjects. In addition, HPV DNA was confirmed in 190 cervical tumors and the viral type determined. Results showed that overall more cancer patients than control subjects had an Arg allele at codon 72 with respect to both genotype and allelotype (P < 0.05). A significantly higher (P < 0.001) Arg allele frequency (55%) was also observed in patients whose tumors contained low or intermediate risk HPV DNA compared with control subjects (31%); the Arg homozygosity rate was 34% and 9% in patients and controls, respectively (P < 0.001). In contrast, patients harboring HPV 16/18 infections showed no differences in p53 status compared with controls. It would appear that, in the absence of HPV 16/18 infections, the Arg allele at codon 72 of the p53 tumor suppressor gene may constitute a risk factor for carcinogenesis of the cervix.

Polymorphisms in various coagulation genes in black South African women with placental abruption.

This pilot study examined Factor V Leiden (R506Q), prothrombin (20210G-->A), thrombomodulin (A455V) and MTHFR (677C-->T) in 100 Zulu-speaking black South African women with placental abruption and 217 controls. The Factor V Leiden and prothrombin variant gene alleles were not detected in either patient or control groups. The thrombomodulin polymorphic variant was not seen in the patient group but three heterozygotes (1%) were found in the controls. No homozygotes for the MTHFR T677 variant were detected in the patients but two (1%) were noted in the controls; the normal and heterozygote genotype and allele frequencies for this polymorphism were similar in the two groups.

Biochemical and molecular diagnosis of glutaric aciduria type 1 in a black South African male child: case report.

Glutaric aciduria type 1 (GA-1) is an inborn error of metabolism caused by a deficiency of the mitochondrial enzyme glutaryl-Co enzyme A dehydrogenase. GA-1 is not uncommon amongst Caucasians but to the best of our knowledge, it has previously not been reported in black African children. We present a case of GA-1 in a black South African boy who was referred to hospital at the age of five years and ten 10 months with dyskinesia and dystonia accompanied by chorea and athetosis. Radiological examination revealed enlarged basal cisterns with bilateral fluid collection around the sylvian fissures suggestive of GA-1. Analysis of urine showed raised levels of glutaric acid at 520 micromol/mmol creatinine (normal <2.0), 3-hydroxyglutaric acid at 113 micromol/mmol creatinine (normal <3.0) and a low blood carnitine level of 31.5 micromol/l (normal 35-84). A definitive diagnosis was reached through DNA analysis which revealed homozygosity for an A293T mutation in the glutaryl-Co-enzyme A dehydrogenase (GCDH) gene.

Collagen Ialpha1 and vitamin D receptor gene polymorphisms in South African whites, blacks and Indians.

OBJECTIVE: To determine whether polymorphic differences exist between black, white and Indian South Africans in genes associated with bone mineral density and osteoporosis. DESIGN: Genes selected were the vitamin D receptor (Apa I and Taq I polymorphisms) and collagen (Sp I transcription factor polymorphism) using standard molecular biology techniques. SETTING: Department of Chemical Pathology, Nelson R Mandela School of Medicine, University of Natal, Durban, South Africa. SUBJECTS: Healthy male and female blood donors living in the Durban metropolitan region, South Africa. The group comprised black Africans (n=264), white Caucasians (n=247) and Asians of Indian origin (n=194). RESULTS: No significant differences in genotypes were seen between white and Indian subjects. Blacks had a significantly higher frequency of the TT Taq I genotype and a significantly lower frequency of the Ss Sp I genotype. No ss genotype was detected in blacks. CONCLUSION: The very low frequency of the collagen Sp I s allele and higher frequency of the VDR T allele in blacks may be associated with the lower incidence of osteoporosis in this ethnic group.

Apolipoprotein E polymorphism in South African Zulu women with preeclampsia.

OBJECTIVES: Apolipoprotein E may contribute to the hypertiglyceridemia and consequent endothelial dysfunction of preeclampsia. We carried out a study to determine whether the apolipoprotein E genotype plays any role as a risk factor for preeclampsia in a black South African population with a high incidence of preeclampsia. DESIGN: A descriptive, prospective study design was used. SETTING: King Edward VIII Hospital, a tertiary care, referral academic hospital in Durban, South Africa. PATIENTS AND PARTICIPANTS: One hundred three South African Zulu women with preeclampsia and 110 healthy normotensive women attending the antenatal clinic were recruited. MAIN OUTCOME MEASURES: The relationship between the apolipoprotein E allele and genotype frequencies to preeclampsia as well as adverse perinatal outcome. RESULTS: The frequencies of varepsilon2 and varepsilon4 alleles (0. 19 and 0.25, respectively) were much higher than those reported in other population groups. However, there was no significant difference in the apolipoprotein E genotype and allele frequencies between the study and the control groups. The varepsilon2/2 genotype was associated with increased risk of perinatal death (p = 0.047). CONCLUSION: The study suggests that, despite the high incidence of both preeclampsia and the varepsilon2 and varepsilon4 alleles in South African Zulu women, apolipoprotein E genotype does not appear to be a risk factor for preeclampsia in this population.

5,10 methylenetetrahydrofolate reductase polymorphism in black South African women with pre-eclampsia.

The polymorphic C677T mutation in the gene encoding 5,10 methylenetetrahydrofolate reductase has been shown to be a risk factor for pre-eclampsia in Japanese and European women when inherited as a homozygous trait. We attempted to verify these findings in a black African population with a high incidence of pre-eclampsia. No difference in frequency of the T-allele was observed in 105 women with pre-eclampsia, compared with 110 healthy pregnant normotensive women. Only one woman with pre-eclampsia was TT homozygous, suggesting that methylenetetrahydrofolate reductase polymorphism is not an important factor in the pathogenesis of pre-eclampsia in black South African women.

PIP: This study aims to determine whether the C677T 5,10 methylenetetrahydrofolate reductase (MTHFR) polymorphism plays any role as a risk factor for preeclampsia in black South African women. A total of 105 pregnant women with preeclampsia were included in the study and were subjected to several tests. Test results showed that the MTHFR genotypes and allele frequencies in the study group and control group have no significant difference in the frequencies of the homozygous TT genotype or the T-allele. Among the respondents, only one woman with preeclampsia was homozygous for the C677T mutation. Findings indicate that preeclampsia in black South African women affects 18% of pregnancies. In addition, the C677T mutation cannot be considered an important factor in the pathogenesis of preeclampsia in this study population. Further studies are required for clarifications concerning these issues.