Vincristine-induced neuropathy in pediatric patients with acute lymphoblastic leukemia in Oman: Frequent autonomic and more severe cranial nerve involvement.

BACKGROUND: Vincristine (VCR) induced peripheral neuropathy is a common complication in children with acute lymphoblastic leukemia (ALL). PROCEDURES: A retrospective data analysis over an interval of 10 years (2006-2016) of all children with ALL seen at Sultan Qaboos University Hospital was carried out. Electronic medical records of eligible patients were reviewed. Patients with clinical evidence of neuropathy and abnormal nerve conduction studies (NCSs) were included in the study. RESULTS: Nineteen (nine females and 10 males) out of 103 pediatric patients developed VCR-related neuropathy, and their age ranged between 2.5 and 14 years. Symptoms started after 2-11 doses of VCR. All 19 patients had documented peripheral neuropathy on NCSs. The autonomic nervous system and cranial nerves affection was relatively common in our patients; two presented with bradycardia, two patients with unexplained tachycardia, and five had abdominal pain and constipation, complicated by typhlitis in two patients. One patient developed unilateral hearing loss. Two patients developed severe life-threatening cranial nerve involvement with bilateral ptosis and recurrent laryngeal nerve involvement presented as vocal cord paralysis, hoarseness of voice, frequent chocking, and aspiration episodes. CONCLUSIONS: Peripheral neuropathy was the commonest form of VCR-related neuropathy. Autonomic neuropathy was relatively common in our patients. Cranial neuropathy is a serious side effect of VCR that can be severe, involving multiple cranial nerves and needs prompt recognition and management. Concomitant administration of pyridoxine and pyridostigmine does not seem to protect against further neurological damage in some patients.

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.

Pulmonary Function Test Outcomes in Adult Omani Patients: Preliminary findings from a single-centre study.

Objectives: This study aimed to document the distribution of PFT outcomes among adult Omani patients. There is limited information regarding the distribution of pulmonary diseases (PD) in Oman. Pulmonary function test (PFT) outcome patterns could indicate an indirect distribution of PD. Methods: This retrospective cross-sectional study was conducted from January to December 2015 at a tertiary hospital in Oman. A total of 1,118 adults referred for PFTs during this period were included. Results: There were 605 (54.1%) female and 513 (45.9%) male patients. The mean age of the patients was 47.11 ± 18.1 years. Most patients underwent spirometry with reversibility (36.8%) or full lung function testing with reversibility (29.7%). Among the 1,064 patients with conclusive PFT outcomes, 39.9% had normal findings, 26.1% had obstructive defects, 19.6% demonstrated restrictive defects and 10.6% had mixed obstructive/restrictive defects. Conclusion: This study generated important preliminary data regarding PFT outcomes (defects) in Omani patients.

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.

The adequacy of informed consent forms in genetic research in Oman: a pilot study.

Genetic research presents ethical challenges to the achievement of valid informed consent, especially in developing countries with areas of low literacy. During the last several years, a number of genetic research proposals involving Omani nationals were submitted to the Department of Research and Studies, Ministry of Health, Oman. The objective of this paper is to report on the results of an internal quality assurance initiative to determine the extent of the information being provided in genetic research informed consent forms. In order to achieve this, we developed checklists to assess the inclusion of basic elements of informed consent as well as elements related to the collection and future storage of biological samples. Three of the authors independently evaluated and reached consensus on seven informed consent forms that were available for review. Of the seven consent forms, four had less than half of the basic elements of informed consent. None contained any information regarding whether genetic information relevant to health would be disclosed, whether participants may share in commercial products, the extent of confidentiality protections, and the inclusion of additional consent forms for future storage and use of tissue samples. Information regarding genetic risks and withdrawal of samples were rarely mentioned (1/7), whereas limits on future use of samples were mentioned in 3 of 7 consent forms. Ultimately, consent forms are not likely to address key issues regarding genetic research that have been recommended by research ethics guidelines. We recommend enhanced educational efforts to increase awareness, on the part of researchers, of information that should be included in consent forms.

Acceptance and Compliance of Continuous Positive Airway Pressure in Patients with Obstructive Sleep Apnea: Local Population Survey.

OBJECTIVES: Continuous positive airway pressure (CPAP) compliance of > 4 hours per night has been considered acceptable to achieve clinical improvements in patients with obstructive sleep apnea (OSA). However, the factors determining CPAP adherence are unclear. This study aims to address the issue of acceptance and adherence to CPAP treatment in the Omani population and to determine the factors affecting adherence to CPAP. METHODS: This retrospective study included adult OSA patients who underwent polysomnography between January 2008 and December 2014 (n = 3046). Demographic information, Epworth Sleepiness Scale (ESS), apnea/hypopnea index (AHI), and desaturation events were collected from the sleep laboratory records. Subjects were grouped as CPAP users and CPAP non-users. CPAP users were divided into compliers (> 4 hours/night) and non-compliers (< 4 hours/night). Student's t-test was used to find differences in CPAP users and non-users, compliers, and gender differences in CPAP users. The association of CPAP compliers and non-compliers with age, gender, AHI, ESS, and comorbidities were assessed using the chi-square test. RESULTS: Out of the 90.0% patients advised CPAP treatment, 34.7% came for regular CPAP follow-up. Total CPAP compliers were 59.3% (n = 274). The CPAP users had higher age, high ESS, baseline AHI, and more oxygen desaturation events than CPAP non-users (p < 0.010). Among the CPAP users, females were significantly older than males and had more oxygen desaturation events. CPAP compliers had significantly higher baseline AHI and more oxygen desaturation events. There was no association between CPAP compliance and age, gender, AHI, ESS, or comorbidities. CONCLUSIONS: CPAP users and compilers have severe OSA. CPAP acceptance and adherence are suboptimal and could not be predicted by age, gender, AHI, ESS, or comorbidities.

Evaluation of Hospital Referral Notes for Pulmonary Function Tests at Tertiary Care Teaching Hospital in Oman.

OBJECTIVES: There is substantial increase in referrals for investigations at Sultan Qaboos University Hospital (SQUH). Evaluating the quality of hospital referral notes (RNs) is necessary from diagnostic, patient, and economic perspectives. RNs for pulmonary function tests (PFTs) can be considered as representative of the array of tests performed at SQUH. METHODS: This cross-sectional study evaluated the quality of RNs based on 'completeness' for all consecutive patients referred for PFTs at SQUH over six months. Evaluation included documentation of demographic features, RNs date, priority for investigation, referral reason, pulmonary and relevant medical and smoking history for spirometry RNs, and addition of hemoglobin level for full lung functions (Full-LuFs) tests. The proportion of complete RNs was determined and analyzed separately to study association of spirometry and full-LuFs tests with source and reasons for referral. RESULTS: Only 644 of 683 RNs were available for analysis. Smoking history was stated in only 3.3% of all RNs; hence, it was excluded from the analysis. RNs were complete only in 12.4% of cases for spirometry and 14.4% for full-LuFs tests. RNs for patients who primarily had pulmonary disease were proportionately incomplete than those for patients with other reasons (p < 0.050). There was no significant association between incompleteness of RNs and referral hospital (SQUH vs. non-SQUH) and SQUH inpatient or outpatient status implying that the overall proportion of completeness of RNs from all concerned referral locations was similar and low in both types of RNs. CONCLUSIONS: There is a need to improve the quality of RNs at SQUH. Referring doctors must be made aware of the importance of completeness of RNs to improve test reporting, patient management and satisfaction, and reduce financial burden on hospital exchequer.

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 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.

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.

An audit of the sleep medicine service in Oman.

OBJECTIVE: To audit the sleep service at Sultan Qaboos University Hospital (SQUH), Muscat, Oman, and to explore deficiencies to introduce new measures of improvement. METHODS: Polysomnography (PSG) reports and SQUH medical records of all patients who underwent sleep studies from January 1995 to December 2006 in the sleep laboratory at SQUH were reviewed and analyzed. RESULTS: Out of a total of 1042 sleep studies conducted in the specified period, 768 PSG recordings were valid for analysis. The audit showed that the Otolaryngology Department was the main referring specialty for PSG (43%). Snoring was the main symptom for 33% of the subjects referred, but suspicion of obstructive sleep apnea was the main reason for referral (38%). Three quarters of the patients were males who were also younger, and with lower body mass index compared to females (p=0.0001 for all). Despite large number of patients with an apnea-hypopnea index of >15 (n=261), only 94 (36%) patients received continuous positive airway pressure titrations and treatment. CONCLUSION: The sleep medicine service in SQUH provided the basic service, and raised the awareness of the importance of this specialty. However, substantial effort is required to bring it to international standards.

Cardio-autonomic functions and sleep indices before and after coronary artery bypass surgery.

BACKGROUND: Earlier studies showed a short-term impairment of cardio-autonomic functions following coronary artery bypass grafting (CABG). There is a lack of consistency in the time of recovery from this impairment. Studies have attributed the post-CABG atrial fibrillation to preexisting obstructive sleep apnea (OSA) without an objective sleep assessment. The aim of this study was to evaluate the effect of CABG on cardio-autonomic and hemodynamic functions and on OSA indices in patients with ischemic heart disease (IHD). METHODS: Cardio-autonomic function using heart rate variability indices, hemodynamic parameters, and sleep studies were performed in 26 patients with stable IHD before, on day-6, and day-30 post-CABG surgery. RESULTS: The high-frequency powers of normalized R-R intervals significantly (P = 0.002) increased from the preoperative value of 46.09 to 66.52 on day-6 and remained unchanged on day-30 postsurgery. In contrary, the low-frequency powers of normalized R-R interval decreased from 53.91 to 33.48 during the same period (P = 0.002) and remained unchanged on day 30 postsurgery. Baroreceptor sensitivity, obstructive and central apnea indices, desaturation index, and lowest O2 saturation were not significantly different between preoperative, day-6, and day-30 postsurgery. CONCLUSION: Our study revealed that recovery of autonomic functions following CABG occurs as early as 30 days of postsurgery. CABG does not seem to have short-term effects on sleep study indices. However, long-term effects need further evaluation.

Heritability and genetic correlations of heart rate variability at rest and during stress in the Oman Family Study.

INTRODUCTION: Individual differences in heart rate variability (HRV) can be partly attributed to genetic factors that may be more pronounced during stress. Using data from the Oman Family Study (OFS), we aimed to estimate and quantify the relative contribution of genes and environment to the variance of HRV at rest and during stress; calculate the overlap in genetic and environmental influences on HRV at rest and under stress using bivariate analyses of HRV parameters and heart rate (HR). METHODS: Time and frequency domain HRV variables and average HR were measured from beat-to-beat HR obtained from electrocardiogram recordings at rest and during two stress tests [mental: Word Conflict Test (WCT) and physical: Cold Pressor Test (CPT)] in the OFS - a multigenerational pedigree consisting of five large Arab families with a total of 1326 participants. SOLAR software was used to perform quantitative genetic modelling. RESULTS: Heritability estimates for HRV and HR ranged from 0.11 to 0.31 for rest, 0.09-0.43 for WCT, and 0.07-0.36 for CPT. A large part of the genetic influences during rest and stress conditions were shared with genetic correlations ranging between 0.52 and 0.86 for rest-WCT and 0.60-0.92 for rest-CPT. Nonetheless, genetic rest-stress correlations for most traits were significantly smaller than 1 indicating some stress-specific genetic effects. CONCLUSION: Genetic factors significantly influence HRV and HR at rest and under stress. Most of the genetic factors that influence HRV at rest also influence HRV during stress tests, although some unique genetic variance emerges during these challenging conditions.

Genetic loci associated with heart rate variability and their effects on cardiac disease risk.

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74

Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk.

This corrects the article DOI: 10.1038/ncomms15805.

Habitual Sleep Deprivation is Associated with Type 2 Diabetes: A Case-Control Study.

OBJECTIVES: It is suggested that a minimum of eight hours of sleep per night is needed for metabolism to work normally. The aim of the study was to determine the association of habitual sleep deprivation and type 2 diabetes mellitus (T2DM). METHODS: We conducted a case-control study comparing patients with T2DM with age and sex matched healthy controls. Standard sleep questionnaires (the Berlin and Epworth Sleepiness Scale) and a weekly diary were used by patients to self-report habitual sleep. RESULTS: A total of 172 diabetics and 188 healthy controls were enrolled in the study. There was a significant difference between T2DM and healthy controls in nocturnal sleep duration (p = 0.033). There was a significant association between nocturnal sleep duration of fewer than six hours and T2DM (χ2 = 14.0; p = 0.0001). There was no significant difference in daytime sleepiness and daytime naps between the T2DM and control groups (p = 0.452; p = 0.581, respectively). CONCLUSIONS: A nocturnal sleep duration < 6 hours is associated with T2DM.

White coat hypertension and masked hypertension among omani patients attending a tertiary hospital for ambulatory blood pressure monitoring.

OBJECTIVES: Our study aimed to estimate the rate of white coat hypertension (WCH) and effect, and masked hypertension in patients attending a tertiary care hospital for 24 hour ambulatory blood pressure monitoring (24-h ABPM). METHODS: A total of 231 adult patients were referred to the Department of Clinical Physiology at Sultan Qaboos University Hospital, Muscat, for ABPM, between January 2010 and June 2012. The following data were gathered and analyzed: demographic data, clinic blood pressure (BP) measurements, and 24-h BP profile from ABPM. Thirty-two patients were excluded and the final analysis included 199 patients. RESULTS: There were 105 (52.8%) women and 94 (47.2%) men studied. The mean age of patients was 46±15 years and most patients were overweight with a mean BMI of 29.6±5kg/m(2). Around half of patients (53.8%) were on one or more antihypertensive medications. WCH was found in 10.6% and white coat effect was found in 16% of patients. The majority of patients (57%) with WCH were aged 40 years or above. Masked hypertension was present in 6% of patients and masked uncontrolled hypertension in 8.5% of patients. CONCLUSIONS: Our study showed that WCH and effect, and masked hypertension are common in hypertensive patients. Identifying these patients will have an impact on their management. However, the results of the study should be interpreted within the context of its limitations. Prospective randomized community and hospital-based studies should be conducted to estimate the true prevalence in the general population as well as in hypertensive patients.

Association of gene variants with susceptibility to type 2 diabetes among Omanis.

AIM: To investigate the association of 10 known common gene variants with susceptibility to type 2 diabetes mellitus (T2D) among Omanis. METHODS: Using case-control design, a total of 992 diabetic patients and 294 normoglycemic Omani Arabs were genotyped, by an allelic discrimination assay-by-design TaqMan method on fast real time polymerase chain reaction system, for the following gene variants: KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398), CDKN2A/B (rs10811661), FTO (rs9939609 and rs8050136), IGF2BP2 (rs4402960), SLC30A8 (rs13266634) CAPN10 (rs3792267) and HHEX (rs1111875). T2D patients were recruited from the Diabetes Clinic (n = 243) and inpatients (n = 749) at Sultan Qaboos Univesity Hospital (SQUH), Muscat, Oman. Adult control participants (n = 294) were volunteers from the community and from those visiting Family Medicine Clinic at SQU, for regular medical checkup. The difficulty in recruiting Omani participants with no family history of diabetes was the main reason behind the small number of control participants in this study. Almost all volunteers questioned had a relative with diabetes mellitus. Inspite of the small number of normoglycemic controls in this study, this sample was sufficient for detection of genes and loci for common alleles influencing T2D with an odds ratio of ≥ 1.3 reaching at least 80% power. Data was collected from June 2010 to February 2012. RESULTS: Using binary logistic regression analysis, four gene variants showed significant association with T2D risk: KCNJ11 (rs5219, P = 5.8 × 10(-6), OR = 1.74), TCF7L2 (rs7903146, P = 0.001, OR = 1.46), CDKAL1 (rs10946398, P = 0.002, OR = 1.44) and CDKN2A/B (rs10811661, P = 0.020, OR = 1.40). The fixation index analysis of these four gene variants indicated significant genetic differentiation between diabetics and controls {[KCNJ11 (rs5219), P < 0.001], [TCF7L2 (rs7903146), P < 0.001], [CDKAL1 (rs10946398), P < 0.05], [CDKN2A/B (rs10811661), P < 0.05]}. The highest genotype variation % between diabetics and controls was found at KCNJ11 (2.07%) and TCF7L2 (1.62%). This study was not able to detect an association of T2D risk with gene variants of IGF2BP2 (rs4402960), SLC30A8 (rs13266634), CAPN10 (rs3792267) and HHEX (rs1111875). Moreover, no association was found between FTO gene variants (rs9939609 and rs8050136) and T2D risk. However, T2D risk was found to be significantly associated with obesity (P = 0.002, OR = 2.22); and with the Waist-to-Hip ratio (n = 532, P = 1.9 ×10(-7), OR = 2.4), [among males (n = 234, P = 1.2 × 10(-4), OR = 2.0) and females (n = 298, P = 0.001, OR = 6.3)]. CONCLUSION: Results confirmed the association of KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398) and CDKN2A/B (rs10811661) gene variants with susceptibility to T2D among Omani Arabs.

Utility of large consanguineous family-based model for investigating the genetics of type 2 diabetes mellitus.

OBJECTIVES: This study examined the utility of a family-based model for replicating the results of genome-wide association studies (GWAS) of type 2 diabetes (T2D). METHODS AND RESULTS: In a total of 232 members of a large consanguineous Omani Arab pedigree (age: 16-80years), there were 27 diabetics and 50 prediabetics (17 with impaired fasting glucose and 33 with impaired glucose tolerance). All 232 individuals underwent anthropometric and biochemical investigations and genotyped for 14 known common gene variants of modest effect on T2D risk. Power analysis at a LOD score of 3, gave 80% power to locate a single specific locus that accounts for 52% of the total phenotypic variation. Measured genotype analysis (MGA) was used to determine heritability of various quantitative traits (QTs) which ranged 25-56%. Using MGA, some common gene variants were found to have little (<5%) but significant impact on the heritability of T2D related QTs [KCNJ11 (rs5219), p=0.004]; [IGF2BP2 (rs4402960), p=0.02]; [SLC30A8 (rs13266634), p=0.05]; [CAPN10 (rs2975760), p=0.031]; [FTO (rs8050136), p=0.023]; [FTO (rs9939609), p=0.018] and [SLC30A8 (rs13266634), p=0.05]. Sib-TDT analysis showed that some gene variants were significantly associated with T2D risk but didn't reach the level of significance after Bonferroni correction [KCNJ11 (rs5219), p=0.047] and [CAPN10 (rs41266971), p=0.035]. CONCLUSION: We have demonstrated that, in principle, a family-based model with minor limitations could be used to replicate some of the results of large GWAS case-control studies. This model could successfully be applied for the future discovery, by deep sequencing, of rare gene variants.

Familial Clustering of Type 2 Diabetes among Omanis.

OBJECTIVE: The aim of this study was to screen Omani individuals for the familial aggregation of type 2 diabetes mellitus. METHODS: A random cohort of 1182 Omani individuals visiting the Family Medicine Clinic at Sultan Qaboos University Hospital (SQUH), Muscat, Oman, for regular medical checkup, aged ≥40 years, were sampled. Patients were categorized into three groups: (1) individuals who claim not to have diabetes and had no family history of diabetes; (2) individuals who claim not to have diabetes but had family history of diabetes; (3) individuals with diabetes. Only 16% of these Omani individuals had no diabetes and no family history of diabetes. Another separate random cohort of 234 Omani type 2 diabetes mellitus patients, from the Diabetes Clinic at SQUH, were interviewed and questioned about their family history of type 2 diabetes mellitus. RESULTS: Ninety five percent of the patients had a family history of diabetes. Eighty percent had first degree relatives with diabetes and 46% had second degree relatives with diabetes. At least one parent with diabetes was reported among 55% of these diabetics, while maternal diabetes (55%) was found to be higher than paternal diabetes (47%). However, only 15% had both parents with diabetes. Furthermore, almost half of the 234 diabetics were having at least one of the following relatives with diabetes: brother, sister, aunt or an uncle. CONCLUSION: The findings of this study confirm familial aggregation of diabetes among the Omani population. Compared to other populations, familial aggregation of type 2 diabetes mellitus among Omanis is relatively very high, and is perhaps due to the very high degree of consanguinity among Omanis. Since almost everyone seems to have a genetic predisposition to diabetes, the dramatic lifestyle changes over the past 25 years, could tip the population into an epidemic of type 2 diabetes mellitus.