Habiba S. Al Safar

A Genome-Wide Search for Type 2 Diabetes Susceptibility Genes in an Extended Arab Family

Twenty percent of people aged 20 to 79 have type 2 diabetes (T2D) in the United Arab Emirates (UAE). Genome‐wide association studies (GWAS) to identify genes for T2D have not been reported for Arab countries. We performed a discovery GWAS in an extended UAE family (N = 178; 66 diabetic; 112 healthy) genotyped on the Illumina Human 660 Quad Beadchip, with independent replication of top hits in 116 cases and 199 controls. Power to achieve genome‐wide significance (commonly P = 5 × 10−8) was therefore limited. Nevertheless, transmission disequilibrium testing in FBAT identified top hits at Chromosome 4p12‐p13 (KCTD8: rs4407541, P = 9.70 × 10−6; GABRB1: rs10517178/rs1372491, P = 4.19 × 10−6) and 14q13 (PRKD1: rs10144903, 3.92 × 10−6), supported by analysis using a linear mixed model approximation in GenABEL (4p12‐p13 GABRG1/GABRA2: rs7662743, Padj‐agesex = 2.06 × 10−5; KCTD8: rs4407541, Padj‐agesex = 1.42 × 10−4; GABRB1: rs10517178/rs1372491, Padj‐agesex = 0.027; 14q13 PRKD1: rs10144903, Padj‐agesex = 6.95 × 10−5). SNPs across GABRG1/GABRA2 did not replicate, whereas more proximal SNPs rs7679715 (Padj‐agesex = 0.030) and rs2055942 (Padj‐agesex = 0.022) at COX7B2/GABRA4 did, in addition to a trend distally at KCTD8 (rs4695718: Padj‐agesex = 0.096). Modelling of discovery and replication data support independent signals at GABRA4 (rs2055942: Padj‐agesex‐combined = 3 × 10−4) and at KCTD8 (rs4695718: Padj‐agesex‐combined = 2 × 10−4). Replication was observed for PRKD1 rs1953722 (proxy for rs10144903; Padj‐agesex = 0.031; Padj‐agesex‐combined = 2 × 10−4). These genes may provide important functional leads in understanding disease pathogenesis in this population.

Evaluation of different sources of DNA for use in genome wide studies and forensic application.

In the field of epidemiology, Genome-Wide Association Studies (GWAS) are commonly used to identify genetic predispositions of many human diseases. Large repositories housing biological specimens for clinical and genetic investigations have been established to store material and data for these studies. The logistics of specimen collection and sample storage can be onerous, and new strategies have to be explored. This study examines three different DNA sources (namely, degraded genomic DNA, amplified degraded genomic DNA and amplified extracted DNA from FTA card) for GWAS using the Illumina platform. No significant difference in call rate was detected between amplified degraded genomic DNA extracted from whole blood and amplified DNA retrieved from FTA™ cards. However, using unamplified–degraded genomic DNA reduced the call rate to a mean of 42.6% compared to amplified DNA extracted from FTA card (mean of 96.6%). This study establishes the utility of FTA™ cards as a viable storage matrix for cells from which DNA can be extracted to perform GWAS analysis.

Association of Diabetes Related Complications with Heart Rate Variability among a Diabetic Population in the UAE.

Microvascular, macrovascular and neurological complications are the key causes of morbidity and mortality among type II diabetes mellitus (T2DM) patients. The aim of this study was to investigate the alterations of cardiac autonomic function of diabetic patients in relation to three types of diabetes-related complications. ECG recordings were collected and analyzed from 169 T2DM patients in supine position who were diagnosed with nephropathy (n = 55), peripheral neuropathy (n = 64) and retinopathy (n = 106) at two hospitals in the UAE. Comparison between combinations of patients with complications and a control diabetic group (CONT) with no complication (n = 34) was performed using time, frequency and multi-lag entropy measures of heart rate variability (HRV). The results show that these measures decreased significantly (p<0.05) depending on the presence and type of diabetic complications. Entropy, (median, 1st- 3rd interquartile range) for the group combining all complications (1.74,1.37–2.09) was significantly lower than the corresponding values for the CONT group (1.77, 1.39–2.24) with lag-1 for sequential beat-to-beat changes. Odds ratios (OR) from the entropy analysis further demonstrated a significantly higher association with the combination of retinopathy and peripheral neuropathy versus CONT (OR: 1.42 at lag 8) and an even OR for the combination of retinopathy and nephropathy (OR: 2.46 at lag 8) compared to the other groups with complications. Also, the OR of low frequency power to high frequency power ratio (LF/HF) showed a higher association with these diabetic-related complications compared to CONT, especially for the patient group combining all complications (OR: 4.92). This study confirms that the type of microvascular or peripheral neuropathy complication present in T2DM patients have different effects on heart rate entropy, implying disorders of multi-organ connectivity are directly associated with autonomic nervous system dysfunction. Clinical practice may benefit from including multi-lag entropy for cardiac rhythm analysis in conjunction with traditional screening methods in patients with diabetic complications to ensure better preventive and treatment outcomes in the Emirati Arab population.

Vitamin D receptor gene polymorphisms among Emirati patients with type 2 diabetes mellitus

At a prevalence rate close to 19.5%, the UAE has one of the highest rates of Type 2 Diabetes Mellitus (T2DM) in the world. Genome wide association studies (GWAS) have led to the identification of several genetic variants that are associated with T2DM. Recently, genes involved in vitamin D metabolism have gained interest because of the association between vitamin D deficiency (VDD) and increased risk for T2DM. Among these, the Vitamin D receptor (VDR) gene is a good candidate for T2DM susceptibility. The aim of this study was to investigate the association between VDR polymorphisms and T2DM among a representative sample of the Emirati population. In this cross sectional study, two hundred and sixty four patients with T2DM and ninety-one healthy controls were enrolled. The study population was genotyped for the three VDR gene mutations, TaqI (rs731236), FokI (rs2228570) and BsmI (rs1544410). VDR alleles and haplotypes were compared between patients and their healthy controls. The mean age of the T2DM cohort was 60±11.59years and 48.21±12.17years for the healthy controls. The G-allele and GG genotype of rs2228570 and T-allele and TT genotype of rs1544410 SNPs were associated with T2DM. In regards to T2DM-related metabolic complications, the AG and GG genotypes of rs731236 were significantly associated with higher total cholesterol (p=0.011) and LDL-cholesterol (p=0.009) levels in the patients with T2DM. In contrast, the CT genotype of rs1544410 was significantly associated with lower BMI (p=0.031) and the TT genotype was associated with lower LDL-cholesterol level (p=0.007). The frequency of AAT and GGC haplotypes was also different between groups (p=0.014; p=0.032, respectively), implying that these haplotypes of the VDR gene are associated with the susceptibility to T2DM in the Emirati population. To conclude, an association between SNPs in the VDR gene (except for rs731236) and T2DM per se was demonstrated. The rs731236 variant was shown to be associated with high cholesterol and LDL-cholesterol levels in T2DM patients, while rs1544410 was associated with lower BMI and lower LDL cholesterol levels. Our results imply that alleles and haploypes of the VDR gene are associated with the susceptibility to T2DM in the Emirati population.

Relationship between MTHFR C677T and A1298C gene polymorphisms and complications of type 2 diabetes mellitus in an Emirati population.

Purpose Type 2 diabetes mellitus (T2DM) is the most common form of diabetes with clinical consequences giving rise to chronic multiple organ complications. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms are genetic variations that have been linked to T2DM, and micro/macrovascular complications. The link between MTHFR and T2DM however is strongly dependent on the ethnic group studied. The objective of this study was to investigate the possible association between two MTHFR polymorphisms (C677T and A1298C) and T2DM and specifically examine if there are any associations with clinical and demographic characteristics among patients in the United Arab Emirates (UAE). Methods The study included 169 T2DM patients and 209 healthy controls. Genomic DNA was isolated and genotyped using TaqMan real-Time PCR assays for the MTHFR C677T and A1298C polymorphisms. Results There were no significant differences in genotype and haplotype distributions observed between groups. A significant association was observed between the C677T polymorphism and history of cerebrovascular accident (CVA) (p = 0.0330), history of nephropathy (p = 0.0280) and levels of LDL cholesterol (p = 0.0409). Also, the A1298C polymorphism was associated with hypertriglyceridemia (p = 0.0305) in T2DM patients. Conclusion These findings demonstrate that the MTHFR gene polymorphisms are not related to T2DM in the Emirati population. However, these polymorphisms can be used as risk markers for CVA, nephropathy, high LDL cholesterol and triglycerides in T2DM patients and allow timely treatment.

Novel dynamic peak and distribution plantar pressure measures on diabetic patients during walking.

Diabetic peripheral neuropathy (DPN) is a common complication leading to foot ulceration and amputation. Several kinematic, kinetic and plantar pressure measures have been proposed for DPN detection, however findings have been inconsistent. In this work, we present new shape features that capture variations in the plantar pressure using shape and entropy measures to the study of patients with retinopathy, DPN and nephropathy, and a control diabetic group with no complications. The change in the peak plantar pressure (PPP) position with each step for both feet was represented as a convex polygon, asymmetry index, area of the convex polygon, 2nd wavelet moment (WM2) and sample entropy (SamEn). WM2 and the SamEn were more sensitive in capturing variations due to presence of complications than the area and asymmetry measures. WM2 of the left heel (median: 1st IQ, 3rd IQ): 8.27 (4.6,14.8) and left forefoot: 9.2 (2.4,16) were significantly lower for the DPN group compared to the control (CONT) group (heel 11.9 (5.0,16.4); forefoot: 10.3 (4.4,21.3), p < 0.05). SamEn for the DPN group was significantly lower in the right foot compared to the left foot (1.3 (1.26, 1.37) and 1.33 (1.26,1.4), p < 0.01) compared to CONT (right foot: 1.37 (1.24,1.45) and left foot: 1.34 (1.25,1.42), P < 0.05). These new shape and regularity features have shown promising results in detecting diabetic peripheral neuropathy and warrant further investigation.

Gait alterations in the UAE population with and without diabetic complications using both traditional and entropy measures

Diabetic foot, one of the most common and debilitating manifestations of type 2 diabetes mellitus (T2DM), is the leading cause of worldwide non-traumatic lower extremity amputations. Diabetics who are at risk of ulceration are currently mainly identified by a thorough clinical examination of the feet, which typically does not show clear symptoms during the early stages of disease progression. In this study, we used a non-linear dynamics tool, gait entropy (GaitEN), in addition to traditional linear gait analysis methods, to investigate gait alterations amongst diabetic patients with combinations of three types of T2DM related complications: retinopathy, diabetic peripheral neuropathy (DPN) and nephropathy. Peak plantar pressure (PPP) was not significantly different in the group with DPN as compared to the control group (diabetics with no complications, CONT) in the forefoot region (DPN: mean±SD: 396±69.4kPa, CONT: 409±68.9kPa), although it was significantly lower in the heel region (DPN: mean±SD: 285±43.1.4kPa, CONT: 295±61.8kPa). On the other hand, gait entropy was significantly lower for the DPN compared to CONT group (DPN: 0.95±0.34, CONT: 1.03±0.28, p<0.05). The significant low entropy was maintained when neuropathy was combined with either retinopathy or nephropathy. For the group with all three complications (ALL-C), the entropy was higher than CONT (ALL-C: 1.07±0.26). This may indicate an intrinsic sensorimotor feedback mechanism for the DPN patients to regulate their gait. However, this feedback gets weaker as patients develop multiple complications. Further analysis with longer walking time and different speeds is needed to verify the entropy results.

Landmarks detection on 3D face scans using local histogram descriptors

In this work, we exploit 3D Constrained Local Model (CLM) for facial landmark detection. Our approach integrates the geometric information of 3D face scans. The fast increase demand of 3D data invite to develop 3D image processing methods for many applications and especially for automatic landmark detection. The new step in this paper is the introduction of mesh histogram of gradients (meshHOG) as local descriptors around every landmark location. The proposed work is evaluated on the publicly available Bosphorus database. A comparison with the other descriptors mesh LBP and mesh SIFT are also depicted.

Mesh LBP features for 3D constrained local model

We propose an automatic facial landmarks detection in 3D mesh manifold. The method is based on 3D Constrained Local Model (CLM) which learns both global variations in 3D face scan and local ones around every vertex landmark. Differently from the other approaches of CLM, our contribution is a full 3D mesh. The framework exploits the intrinsic 3D features around the mesh vertices by utilizing histogram-based mesh Local Binary Patterns (mesh-LBP). The experiments are conducted on publicly available 3D face scans Bosphorus database.