Gender-specific Reference Range for Serum Leptin in Omani Population.

Objectives: Leptin is a hormone that contributes to glucose homeostasis and food intake regulation via its action on the hypothalamus. Leptin level increases with obesity and overfeeding and decreases with energy deficiency. Serum leptin levels vary between different ethnic groups with no reports of its reference range in the Arabic population. We sought to determine gender-specific reference ranges for serum leptin in a cohort of the Arabic population and identify the cut-off value for different metabolic derangements. Methods: The study data were obtained from the records of 1198 subjects included in the Oman Family Study. The percentile method was used in the estimation reference range and the receiver operating characteristic to identify cut-off points for multiple metabolic derangements. Results: The reference range of serum leptin was 0.5-90.6 ng/mL, and it was not correlated with the age of the subjects. Higher leptin was observed in females compared to males (p < 0.001), and the reference range for serum leptin in females was 4.9-96.3 ng/mL compared to 0.25-48.8 ng/mL in males. The optimum cut-off value for leptin ranged between 24.1-28.9 ng/mL for metabolic syndrome, obesity, central obesity, and type 2 diabetes. Conclusions: We identified gender-specific reference ranges for serum leptin in a large cohort of Arabs. The optimum cut-off value for serum leptin to determine metabolic derangement with the highest sensitivity and specificity was 24.1-28.9 ng/mL. Future studies are needed to study the relative risk of higher serum leptin using prospective studies.

Heritability and genetic correlations of obesity indices with ambulatory and office beat-to-beat blood pressure in the Oman Family Study.

OBJECTIVE: To more precisely and comprehensively estimate the genetic and environmental correlations between various indices of obesity and BP. METHODS: We estimated heritability and genetic correlations of obesity indices with BP in the Oman family study (n = 1231). Ambulatory and office beat-to-beat BP was measured and mean values for SBP and DBP during daytime, sleep, 24-h and 10 min at rest were calculated. Different indices were used to quantify obesity and fat distribution: BMI, percentage of body fat (%BF), waist circumference and waist-to-height ratio (WHtR). SOLAR software was used to perform univariate and bivariate quantitative genetic analyses adjusting for age, age, sex, age-sex and age--sex interactions. RESULTS: Heritabilities of BP ranged from 30.2 to 38.2% for ambulatory daytime, 16.8--21.4% for sleeping time, 32.1--40.4% for 24-h and 22--24.4% for office beat-to-beat measurements. Heritabilities for obesity indices were 67.8% for BMI, 52.2% for %BF, 37.3% for waist circumference and 37.9% for WHtR. All obesity measures had consistently positive phenotypic correlations with ambulatory and office beat-to-beat SBP and DBP (r-range: 0.14--0.32). Genetic correlations of obesity indices with SBP and DBP were higher than environmental correlations (rG: 0.16--0.50; rE: 0.01--0.31). CONCLUSION: The considerable genetic overlap between a variety of obesity indices and both ambulatory and office beat-to-beat BP highlights the relevance of pleiotropic genes. Future GWAS analyses should discover the specific genes both influencing obesity indices and BP to help unravel their shared genetic background.

Heritability and genetic and environmental correlations of heart rate variability and baroreceptor reflex sensitivity with ambulatory and beat-to-beat blood pressure.

This family study from Oman (n = 1231) explored the heritability and genetic and environmental correlations of heart rate variability (HRV) and baroreceptor reflex sensitivity (BRS) with ambulatory and beat-to-beat blood pressure (BP). Ambulatory BP was measured for 24 hours to calculate mean values for daytime and sleep separately. Time and frequency domain HRV indices, BRS, office beat-to-beat BP, and heart rate (HR) were measured for 10 minutes at rest. SOLAR software was used to perform univariate and bivariate quantitative genetic analyses adjusting for age, age2, sex, their interactions and BMI. Heritability of SBP and DBP ranged from 16.8% to 40.4% for daytime, sleeping, 24-hour and office beat-to-beat measurements. HR and BRS showed a heritability of 31.9% and 20.6%, respectively, and for HRV indices heritability ranged from 11.1% to 20.5%. All HRV measurements and BRS were found to be negatively correlated with BP, but phenotypic correlation coefficients were relatively weak; HR was positively correlated with BP. None of the genetic correlations were statistically significant while environmental factors explained most of the correlations for all HRV indices with BP. Our study found consistent but weak correlations among HRV, HR, BRS and ambulatory/office beat-to-beat BP. However, environmental rather than genetic factors contributed most to those correlations.

Epidemiology of Diabetes Mellitus in Oman: Results from two decades of research.

OBJECTIVES: This study aimed to describe the epidemiology of diabetes mellitus over the past two decades in Oman, particularly in terms of its prevalence and incidence. In addition, the study sought to estimate the future incidence of diabetes in Oman. METHODS: Three national and three regional surveys conducted between 1991 and 2010 were analysed to obtain the age-adjusted prevalence and undiagnosed proportion of type 2 diabetes mellitus (T2DM) among Omani subjects aged ≥20 years. Diabetes mellitus registers and published studies were used to determine incidence rates of both type 1 diabetes mellitus (T1DM) and T2DM in Oman. Linear regression was used to determine trends and projections for diabetes in 2050. RESULTS: The age-adjusted prevalence of T2DM in Oman varied from 10.4% to 21.1%, while the highest prevalence of impaired fasting glucose was found in males (35.1%). In comparison to men, higher incidence rates of T2DM were found in women (2.7 cases compared to 2.3 cases per 1,000 person-years, respectively). No significant trends were observed for the prevalence or incidence of T2DM in both genders. Undiagnosed T2DM was more common in men (range: 33-68%) than women (range: 27-53%). The results of this study show that by 2050, there will be an estimated 350,000 people with T2DM living in Oman (a 174% increase compared to estimates for 2015). CONCLUSION: Health authorities need to prioritise diabetes prevention and control in order to prevent or delay long-term complications and avert a potential epidemic of diabetes in Oman.

The Effect of Residing Altitude on Levels of High-Density Lipoprotein Cholesterol: A Pilot Study From the Omani Arab Population.

Lower mortality rates from coronary heart disease and higher levels of serum high-density lipoprotein cholesterol (HDL-C) have been observed in populations residing at high altitude. However, this effect has not been investigated in Arab populations, which exhibit considerable genetic homogeneity. We assessed the relationship between residing altitude and HDL-C in 2 genetically similar Omani Arab populations residing at different altitudes. The association between the levels of HDL-C and other metabolic parameters was also investigated. The levels of HDL-C were significantly higher in the high-altitude group compared with the low-altitude group. Stepwise regression analysis showed that altitude was the most significant factor affecting HDL-C, followed by gender, serum triglycerides, and finally the 2-hour postprandial plasma glucose. This finding is consistent with previously published studies from other populations and should be taken into consideration when comparing cardiovascular risk factors in populations residing at different altitudes.

Heritability of ambulatory and beat-to-beat office blood pressure in large multigenerational Arab pedigrees: the 'Oman Family study'.

OBJECTIVE: To estimate the heritability of ambulatory blood pressure (BP), heart rate (HR), and beat-to-beat office BP and HR in an isolated, environmentally and genetically homogeneous Omani Arab population. METHODS: Ambulatory BP measurements were recorded in 1,124 subjects with a mean age of 33.8 ± 16.2 years, using the auscultatory mode of the validated Schiller ambulatory BP Monitor. Beat-to-beat BP and HR were recorded by the Task Force Monitor. Heritability was estimated using quantitative genetic analysis. This was achieved by applying the maximum-likelihood-based variance decomposition method implemented in SOLAR software. RESULTS: We detected statistically significant heritability estimates for office beat-to-beat, 24-hour, daytime, and sleep HR of 0.31, 0.21, 0.20, and 0.07, respectively. Heritability estimates in the above mentioned conditions for systolic BP (SBP)/diastolic BP (DBP)/mean BP (MBP)were all significant and estimated at 0.19/0.19/0.19, 0.30/0.44/0.41, 0.28/0.38/0.39, and 0.21/0.18/0.20,respectively. Heritability estimates for 24-hour and daytime ambulatory SBP, DBP, and MBP ranged from 0.28 to 0.44, and were higher than the heritability estimates for beat-to-beat recordings and sleep periods,which were estimated within a narrow range of 0.18-0.21. CONCLUSION: In this cohort, because shared environments are common to all, the environmental influence that occurs is primarily due to the variation in non-shared environment that is unique to the individual. We demonstrated significant heritability estimates for both beat-to-beat office and ambulatory BP and HR recordings, but 24-hour and daytime ambulatory heritabilities are higher than those from beat-to-beat resting levels and ambulatory night-time recordings.

Genome-wide linkage analysis of hemodynamic parameters under mental and physical stress in extended Omani Arab pedigrees: the Oman Family Study.

BACKGROUND: We performed a genome-wide scan in a homogeneous Arab population to identify genomic regions linked to blood pressure (BP) and its intermediate phenotypes during mental and physical stress tests. METHODS: The Oman Family Study subjects (N = 1277) were recruited from five extended families of ~10 generations. Hemodynamic phenotypes were computed from beat-to-beat BP, electrocardiography and impedance cardiography. Multi-point linkage was performed for resting, mental (word conflict test, WCT) and cold pressor (CPT) stress and their reactivity scores (s), using variance components decomposition-based methods implemented in SOLAR. RESULTS: Genome-wide scans for BP phenotypes identified quantitative trait loci (QTLs) with significant evidence of linkage on chromosomes 1 and 12 for WCT-linked cardiac output (LOD = 3.1) and systolic BP (LOD = 3.5). Evidence for suggestive linkage for WCT was found on chromosomes 3, 17 and 1 for heart rate (LOD = 2.3), DBP (LOD = 2.4) and left ventricular ejection time (LVET), respectively. For △WCT, suggestive QTLs were detected for CO on chr11 (LOD = 2.5), LVET on chr3 (LOD = 2.0) and EDI on chr9 (LOD = 2.1). For CPT, suggestive QTLs for HR and LVET shared the same region on chr22 (LOD 2.3 and 2.8, respectively) and on chr9 (LOD = 2.3) for SBP, chr7 (LOD = 2.4) for SV and chr19 (LOD = 2.6) for CO. For △CPT, CO and TPR top signals were detected on chr15 and 10 (LOD; 2.40, 2.08) respectively. CONCLUSION: Mental stress revealed the largest number of significant and suggestive loci for normal BP reported to date. The study of BP and its intermediate phenotypes under mental and physical stress may help reveal the genes involved in the pathogenesis of essential hypertension.

Heritability of hemodynamic reactivity to laboratory stressors in a homogenous Arab population: 'Oman Family Study'.

BACKGROUND: Exaggerated cardiovascular reactivity to stressful stimuli may be a risk factor for the development of hypertension. The genetic influence on blood pressure (BP) reactivity to stress and its control mechanisms has been receiving considerable support. This study aims at examining the heritability of BP and its intermediate hemodynamic phenotypes to acute stress in a homogeneous Arab population. METHODS: Parameters were computed from continuous BP, electrocardiography and impedance cardiography measurements, during rest, word conflict (WCT) and cold pressor (CPT) tests. Heritability estimates (h(2)) were obtained using the variance components-based approach implemented in the SOLAR software package. RESULTS: Reactivity scores for WCT and CPT increased significantly (P < .05) for systolic (SBP), diastolic (DBP), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR). They decreased significantly (P < .05) for stroke volume (SV), left ventricular ejection time (LVET), end diastolic (EDI) and cardiac contractility (IC) indices. Univariate analysis detected heritability estimates that ranged from 0.19-0.35 for rest, 0.002-0.40 for WCT and 0.08-0.35 for CPT. CONCLUSION: In this unique cohort, resting as well as challenged cardiovascular phenotypes are significantly influenced by additive genetic effects. Heritability estimates for resting phenotypes are in a relatively narrow range, while h(2) for their reactivity is somewhat broader with lower estimates. Further analyses of this study may offer important opportunities for gene finding in hypertension. WHAT IS KNOWN ABOUT THE TOPIC: (1) cardiovascular reactivity to stress predicts cardiovascular disease; (2) genetic susceptibility plays an important role in stress reactivity. Family studies using the cold pressure test reported significant heritability for blood pressure. WHAT THIS STUDY ADDS: (1) this cohort is from five highly consanguineous isolated Arab pedigrees with genetically verified genealogical records and environmental homogeneity; (2) This is the first study to estimate heritability of detailed intermediate hemodynamic phenotypes that make up normal blood pressure.

Is performance in pre-clinical assessment a good predictor of the final Doctor of Medicine grade?

OBJECTIVE: To investigate if any correlation exists between students' grades on their final doctor of Medicine (MD) assessment and their overall preclinical grade point average (GPA) and its component parts. METHODS: Student data available from the Deanship of Admissions and Registration were analyzed. Pearson correlation coefficient was obtained to assess the degree of linear relationship between performance in the preclinical and the MD assessment of 529 students who graduated from the College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoud, Oman from June 1998 to June 2005. Simple and multiple regression analyses were performed to evaluate individual and combined impact of the preclinical courses' grades on MD grades. RESULTS: Preclinical GPA correlated highly with MD GPA (r=0.641). The science component taught early in the preclinical phase correlated more strongly (r=0.457) than student electives (r=0.246). This correlation was better in the good English group. Students' performance, however, was best in electives, but worst in English. Most students who had low MD GPA (<2.0) had also preclinical and science GPA of <2.5. The students with low GPA were found to spend longer in the medical program. CONCLUSION: Restricting progression to the clinical phase to those students whose preclinical GPA is >2.5, and limiting the credit hour requirement of electives by the College seems to be justified.

Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies.

Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events. Joubert syndrome is characterized by a specific midbrain-hindbrain malformation ('molar tooth sign'), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly and is included in the newly emerging group of 'ciliopathies'. In individuals with Joubert disease genetically linked to JBTS1, we identified mutations in the INPP5E gene, encoding inositol polyphosphate-5-phosphatase E, which hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3 and PtdIns(4,5)P2. Mutations clustered in the phosphatase domain and impaired 5-phosphatase activity, resulting in altered cellular PtdIns ratios. INPP5E localized to cilia in major organs affected by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. These data link PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly recognized for its role in mediating cell signals and neuronal function.

Differing definition-based prevalence of metabolic syndrome in the women of Oman family study: a function of multiparity.

OBJECTIVE: The aim of this study was to investigate causes of the prevalence of the metabolic syndrome in multiparous Omani Arab women using the International Diabetes Federation definition (IDF). RESEARCH DESIGN AND METHODS: Of 392 married women (mean age 40 years), 354 (90%) were multiparous with an average parity of 8. They were divided into four parity groups: Para 0, Para 1-3, Para 4-6, and Para >6. Body mass index (BMI), waist circumference, fasting, and 2-hour glucose and insulin, plasma lipids, serum leptin, and homeostasis model assessment for insulin resistance (HOMA-IR) and blood pressure (BP) were measured. RESULTS: In the whole cohort, the IDF definition identified 28% women with the metabolic syndrome, whereas it identified 48% in Para >6. In comparison, the National Cholesterol Education Program (NCEP) definition identified 21% and 39%, respectively (kappa = 0.642). Waist circumference was positively associated with the number of live births (beta = 0.78, p = 0.0001). Compared to other individual IDF criteria, only age-adjusted large waist circumference carried the highest risk for having the metabolic syndrome in all groups (odds ratio [OR], 2.3, 95% confidence interval [CI], 1.0-5.4, 3.2, CI, 1.3-8 and 4.8, CI, 2.1-11.2). CONCLUSION: The high prevalence of the metabolic syndrome in multiparous Omani Arab women appeared to be influenced by the parity-related large waist circumference. The high dependency of the IDF criteria on waist circumference for the definition of the metabolic syndrome in this population has led to the misclassification of such women.

Non-dipping blood pressure in the metabolic syndrome among Arabs of the Oman family study.

OBJECTIVE: The objective was to examine the circadian changes in blood pressure and their relation to the metabolic syndrome and its components in Omani Arabs. RESEARCH METHODS AND PROCEDURES: Ambulatory blood pressure (ABPM) was recorded in 1124 subjects from 5 large, extended, consanguineous, and young Arab pedigrees. According to the International Diabetes Federation's definition, 264 subjects had the metabolic syndrome, a prevalence of 23%. Subjects were defined as non-dippers when their nocturnal systolic blood pressure (SBP) fell by <10% from daytime SBP. RESULTS: Non-dippers with the metabolic syndrome were 131 of 264 (50%), compared with 265 of 860 (31%) without the metabolic syndrome. Of the non-dippers, 99 of 131 (76%) were females and 32 of 131 (24%) were males. Daytime and nighttime SBP and DBP and nighttime pulse pressure were significantly higher in non-dipper subjects with the metabolic syndrome. The important determinants of a non-dipping BP in this cohort were high BMI and high serum triglycerides. DISCUSSION: We hypothesize that obesity and nocturnal volume-dependent hypertension may be involved in the pathophysiology of non-dipping in the metabolic syndrome. This study showed that non-dipping BP was common in subjects with the metabolic syndrome. Higher 24-hour blood pressure load may add to the indices of the overall cardiovascular burden already associated with the metabolic syndrome.

Heritability of determinants of the metabolic syndrome among healthy Arabs of the Oman family study.

The metabolic syndrome, as defined by the International Diabetes Federation, was investigated in five large, extended, highly consanguineous, healthy Omani Arab families of a total of 1277 individuals. Heritability (h2) of the phenotypic abnormalities that make up the syndrome and other related traits was estimated by variance decomposition method using SOLAR software. The overall prevalence of the syndrome was 23%. The prevalence of abnormalities making the syndrome in a descending order were: obligatory waist circumference, hypertension, raised fasting blood glucose, low serum high-density lipoprotein (HDL), and raised serum triglycerides (TGs). Highly significant, but widely spread, h2 values were obtained for: height (0.68), weight (0.68), BMI (0.68), serum HDL (0.63), serum leptin (0.55), percentage body fat (0.53), total serum cholesterol (0.53), fasting serum insulin (0.51), homeostasis model assessment-insulin resistance index (0.48), serum TG (0.43), waist circumference (0.40), diastolic blood pressure (0.38), and 2-hour glucose level (0.17), whereas for the metabolic syndrome itself, h2 was 0.38. The wide spread of h2 results (0.07 to 0.68) indicates that some determinants, such as weight, BMI, and HDL level, are under significant genetic influence among the Omani Arabs. Other determinants such as insulin resistance, abdominal obesity, diastolic blood pressure, and TG levels seem to be more environmentally driven.

Insertion-deletion polymorphism in the angiotensin-converting enzyme (ACE) gene among Sudanese, Somalis, Emiratis, and Omanis.

The angiotensin-converting enzyme (ACE) gene in humans contains an insertion-deletion polymorphism in its intron 16. Because of its involvement with the renin-angiotensin system, the insertion-deletion polymorphism of the ACE gene has been widely investigated in different populations and in case-control studies. However, similar studies for Arab populations are limited in number. Therefore we have investigated the frequencies of the *I and *D alleles of the ACE gene among Sudanese, Somalis, and Arab nationals of the United Arab Emirates and Oman using previously described methods. Our data indicate a preponderance of the *D allele among the Arab and African populations studied (Sudanese, 0.64; Somalis, 0.73; Emiratis, 0.61; and Omanis, 0.71).

The genetic basis of inherited primary nocturnal enuresis: A UAE study.

OBJECTIVE: Nocturnal enuresis is defined as involuntary emptying of the bladder in the absence of an organic cause in a child aged 5 years or older. Primary nocturnal enuresis (PNE) is the term used if the child has never been dry. Of several factors implicated in the etiology of PNE, genetic factors appear to be the strongest. In about 75% of affected children, there is a strong family history. The purpose of this study was to examine the genetic basis of nocturnal enuresis among children in the United Arab Emirates (UAE). METHODS: Chromosomes 12 and 13 were genotyped in all family members of 10 affected children in four large families. Linkage to earlier reported microsatellite markers on these two chromosomes was examined. RESULTS: In the four families examined, we did not find evidence for linkage to the two loci reported previously. CONCLUSIONS: Among UAE children examined, no linkage was found between PNE and the loci reported previously on chromosomes 12 and 13, indicating further genetic heterogeneity in PNE.

A potential role of apolipoprotein B in the risk stratification of diabetic patients with dyslipidaemia.

Diabetic dyslipidaemia is characterised by retention of atherogenic particles, which are depleted of cholesterol. Therefore, calculating or measuring LDL or VLDL cholesterol may not reflect the actual number of these atherogenic particles. We examined the potential role of apolipoprotein B in the risk stratification of Omani patients with type 2 diabetes and dyslipidaemia. Two hundred and twenty-one subjects with type 2 diabetes and 67 healthy controls were recruited. Diabetic subjects had significantly higher serum levels of triglycerides (P<0.0001), non-HDL cholesterol (P<0.0001), and total/HDL cholesterol ratio (P<0.04) and lower levels of HDL cholesterol (P<0.0001) and lipoprotein(a) compared to nondiabetic subjects. The ratio of apoB/LDL cholesterol ratio was significantly higher (P<0.002) among diabetic compared to nondiabetic subjects. Sixty percent of the diabetic subjects with abnormal apoB of >1.2g/L had an LDL cholesterol of less than 4.2 mmol/L compared to 7% of the nondiabetic subjects (sensitivity; 40% versus 93%, respectively). Furthermore, diabetic subjects with ischaemic heart disease (IHD) had significantly higher (P<0.003) apoB/non-HDL cholesterol ratio compared to those without IHD. These findings suggest that the ratios of apoB/LDL cholesterol and apoB/non-HDL cholesterol may have a role in the risk stratification of diabetic patients with dyslipidaemia.

Distribution of arylamine N-acetyltransferase 2 (nat2) genotypes among Omanis.

OBJECTIVE: to determine the genotypes of arylamine N-acetyltransferase (NAT2) among 127 unrelated apparently healthy Omanis. METHOD: Identify the most common known polymorphisms of NAT*2 gene namely, G(191)A, C(282)T, C(341)T, C(481)T, G(590)A, A(803)G and G(857)A using PCR-RFLP analysis. RESULTS: Eleven allele variants (3 alternative) and 30 different genotypes were determined. The commonest alleles were found to be NAT*5B, NAT2*6A and NAT*4 with corresponding frequencies of 0.362, 0.248 and 0.189 respectively. The overall frequency of rapid acetylator alleles was 0.25. CONCLUSION: A new allele variant containing G(590)A, C(282)T and T(341)C polymorphisms was found in one subject (was named NAT2*5J). The commonest genotypes were found to be 5B/5B, 5B/6A, 4/5B, 4/6A with frequencies 0.165, 0.157, 0.118, 0.110 and 0.079 respectively.