Impact of Vitamin D Status Correction on Serum Lipid Profile, Carboxypeptidase N and Nitric Oxide Levels in Saudi Adults.

This study aimed to determine the impact on the lipid profile, carboxypeptidase N (CPN) and nitric oxide (NOx) associated with vitamin D (VD) status correction among Saudi adults with VD deficiency. A total 111 VD deficient (25(OH)D < 50 nmol/L)) adult Saudis aged 18-50 years old (57 females and 54 males) were enrolled in this 6-month interventional study. They were given 50,000 IU VD weekly for the first 2 months and then twice a month for the next 2 months, followed by 1000 IU daily for the last 2 months. The fasting lipid profile and the blood glucose, VD, NOx and CPN concentrations were measured at baseline and after intervention. Post-supplementation, the median VD was significantly higher (p < 0.001) in females [58.3 (50.6-71.2)] and males [57.8 (51.0-71.8)]. HDL cholesterol significantly increased (p = 0.05) and NOx significantly decreased (p = 0.02) in males post-supplementation. Triglycerides were positively associated with NOx in all subjects before (r = 0.44, p = 0.01) and after (r = 0.37, p = 0.01) VD status correction. There was a significant increase in serum levels of CPN2 (p = 0.02) in all subjects. Furthermore, CPN was inversely correlated with NOx (r = -0.35, p = 0.05) in males post-supplementation. In conclusion, VD status correction reduced serum NOx, particularly in males. The inhibition of NOx synthesis may be responsible for the anti-inflammatory effects of VD supplementation. An inverse association was found between NOx and CPN2.

Proanthocyanidins alleviate pentylenetetrazole-induced epileptic seizures in mice via the antioxidant activity.

The role of oxidative stress in the initiation and progress of epilepsy is well established. Proanthocyanidins (PACs), a naturally occurring polyphenolic compound, have been reported to possess a broad spectrum of pharmacological and therapeutic properties against oxidative stress. However, the protective effects of proanthocyanidins against epilepsy have not been clarified. In the present study, we used the pentylenetetrazole (PTZ)-induced epilepsy mouse model to explore whether proanthocyanidins could help to reduce oxidative stress and protect against epilepsy. Mice were allocated into four groups (n = 14 per each group): control, PTZ (60 mg/kg, intraperitoneally), PACs + PTZ (200 mg/kg, p.o.) and sodium valproate (VPA) + PTZ (200 mg/kg, p.o.). PTZ injection caused oxidative stress in the hippocampal tissue as represented by the elevated lipid peroxidation and NO synthesis and increased expression of iNOS. Furthermore, depleted levels of anti-oxidants, GSH, GR, GPx, SOD, and CAT also indicate that oxidative stress was induced in mice exposed to PTZ. Additionally, a state of neuroinflammation was recorded following the developed seizures. Moreover, neuronal apoptosis was recorded following the development of epileptic convulsions as confirmed by the elevated Bax and caspase-3 and the decreased Bcl2 protein. Moreover, AChE activity, DA, NE, 5-HT, brain-derived neurotrophic factor levels, and gene expression of Nrf2 have decreased in the hippocampal tissue of PTZ exposed mice. However, pre-treatment of mice with PACs protected against the generation of oxidative stress, apoptosis, and neuroinflammation in the PTZ exposed mice brain as the biomarkers for all these conditions was bought to control levels. In addition, the gene expression of Nrf2 was significantly upregulated following PACs treatment. These results suggest that PACs can ameliorate oxidative stress, neuroinflammation, and neuronal apoptosis by activating the Nrf2 signaling pathway in PTZ induced seizures in mice.

Associations of Bone Mineral Density with RANKL and Osteoprotegerin in Arab Postmenopausal Women: A Cross-Sectional Study.

Background and objective: There is limited information as to the association of several key bone markers with bone mineral density (BMD) in understudied ethnic groups. This study investigated the relationship between circulating levels of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-Β ligand (RANKL) with BMD in Arab postmenopausal women. Materials and methods: In this cross-sectional study, a total of 617 Saudi postmenopausal women from the Osteoporosis Registry of the Chair for Biomarkers of Chronic Diseases were included. Anthropometric data, BMD, and biochemical data were retrieved from the registry. Participants were stratified into three groups based on T-score; n = 169 with osteoporosis, n = 282 with osteopenia, and n = 166 normal. Analysis of bone markers including RANKL, OPG, osteocalcin, and N-terminal telopeptide (NTx) was completed using commercially available bioassays. Results: The results suggested that OPG was significantly and positively correlated with age in the osteoporosis group (r = 0.29, p < 0.05), while it was inversely correlated with BMD femoral neck left (r = −0.56, p < 0.001) and BMD femoral neck right (r = −0.37, p < 0.05) in the same group. Moreover, RANKL showed a significant inverse correlation with NTx in the osteopenia group (r = −0.37, p < 0.05). Furthermore, the RANKL/OPG ratio had a positive and significant correlation with BMI (r = 0.34, p < 0.05), BMD femoral neck left (r = 0.36, p < 0.05) and BMD femoral neck right (r = 0.35, p < 0.05) in the osteopenia group. By contrast, it showed a significant inverse correlation with waist to hip ratio in the osteoporosis group (r = −0.38, p < 0.05). Multiple regression analysis showed that OPG contributes to BMD variations in the osteopenia group (p = 0.03). Conclusions: In conclusion, changes in circulating levels of RANKL and OPG might be a protective mechanism contrary to the increased bone loss in postmenopausal women.

Vitamin D Receptor Gene Variants Susceptible to Osteoporosis in Arab Post-Menopausal Women.

Post-menopausal osteoporosis (PMO) is a multifactorial bone disorder in elderly women. Various vitamin D receptor (VDR) gene variants have been studied and associated with osteoporosis in other populations, but not in a homogenous Arab ethnic group. Herein, the current study explores the association between VDR polymorphisms and susceptibility to osteoporosis in Saudi postmenopausal women. In total, 600 Saudi postmenopausal women (N = 300 osteoporosis; N = 300 control) were genotyped for VDR gene variants (rs7975232, rs1544410, rs731236) using TaqMan® SNP genotyping assays. Bone mineral density (BMD) for the lumbar spine and femur was assessed using dual-energy X-ray absorptiometry (DEXA). The heterozygous frequency distributions AC of rs7975232, CT of rs1544410, and AG of rs731236 were significantly higher in the osteoporosis group than controls (p < 0.05). Heterozygous AC of rs7975232 (1.6; 95% CI 1.1-2.3; p < 0.023), CT of rs1544410 (1.6; 95% CI 1.1-2.4; p < 0.022), and AG of rs731236 (1.6; 95% CI 1.1-2.4; p < 0.024) were significantly associated with increased risk of osteoporosis, independent of age and BMI. In conclusion, VDR gene variants rs7975232, rs1544410, rs731236 had a significant effect on BMD and were associated with osteoporosis risk in Saudi postmenopausal women.

Sex differences in the glutamate signaling pathway in juvenile rats.

Females have been found to be at lower risk for the development of neurodevelopmental disorders than males. The greater neuroprotection in females is mostly due to female sex hormones. Estrogen is hypothesized to provide neuroprotection by suppressing the neuro-excitotoxicity induced by glutamate (Glu). This study was conducted to understand the effect of sex in modulating Glu signaling in juvenile rats. Brain tissue homogenate of 15 Wistar albino rats (9 males, 6 females) weighing 60 to 80 g and aged approximately 28 days was used. Biochemical parameters related to Glu signaling, such as the absolute and relative concentrations of Glu, gamma aminobutyric acid (GABA), and glutamine, as well as glutamate transporter 1 (GLT1), glutamine synthetase (GS), glutaminase (GLN), and glutamate decarboxylase-67 (GAD-67), were measured by ELISA. The data obtained demonstrated that compared with the levels in males, female rats exhibited significantly lower levels of Glu (p = .001) and GLN/GS (p = .021). The Glu/GABA and Glu/GLT1 ratios as well as the levels of GAD-67 were also lower in female rats, although the difference was not significant. The GLN/GAD-67 ratio (p = .027) and levels of GS (p = .019) were significantly higher in female rats than in males. Multiple regression analysis confirmed the role of GLN/GS, together with the much higher affinity of GLT1 to Glu, in avoiding excitotoxicity in females. In conclusion, there was a significant difference in Glu signaling between female and male rats. The females exhibited a lower susceptibility to develop Glu-induced excitotoxicity, an etiological mechanism for multiple neurodevelopmental disorders.

Hepatokines Fetuin-A and Fetuin-B status in obese Saudi patient with diabetes mellitus type 2.

The present study aims to investigate the association of the serum levels of Fetuin-A and Fetuin-B with type 2 diabetes mellitus (T2DM) in obese Saudi patients and explore the mechanism that links obesity and T2DM in Saudi patients. In this study, a total of 240 adult Saudis (116 men and 124 women) in the age group of 42.7±11.6 years were divided into three groups based on fasting blood glucose (FBG) levels: controls, T2DM and prediabetic. The levels of FBG, lipid profile and serum insulin were measured. Enzyme-linked immunosorbent assay (ELISA) was done to measure Fetuin-A, Fetuin-B and C-reactive protein (CRP). The results show that participants of the prediabetic and T2DM groups had significantly higher body mass index (BMI) values and elevated blood pressure (BP), FBG, total cholesterol (TC), triglyceride (TG), insulin, homeostatic model assessment-IR (HOMA-IR) and homeostatic model assessment-ß (HOMA-ß) as compared to the control group (P<0.001). The T2DM group participants exhibited significantly higher BMI, BP, FBG, TG, insulin, HOMA-IR and HOMA-ß as compared to the prediabetic group participants (P<0.001). The serum levels of high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) were not significantly different among the three tested groups. The serum concentrations of CRP, Fetuin-A and Fetuin-B were slightly higher in T2DM patients as compared to the control group, but the difference failed to reach statistical significance (P>0.05). When results were segregated according to gender, FBG and HDL-C were significantly elevated (P=0.043 and P=0.002, respectively) in T2DM women (12.6±3.6 mmol/l and 1.0±0.3 mmol/l, respectively) compared to T2DM men (11.0±3.3 mmol/l and 0.86±0.2 mmol/l, respectively). However, the diastolic BP and waist-hip ratio (WHR) were significantly increased (P=0.010 and P=0.006, respectively) in T2DM men. The BMI and TC and all other measured parameters were similar between the two genders. Fetuin-A was significantly and positively associated with insulin levels (R=0.19, P=0.05), HOMA-IR (R=0.25, P=0.01) and TG (R=0.20, P=0.01) among overall participants of this study. The T2DM participants exhibited a significantly positive correlation with body weight. Fetuin-A was significantly and positively correlated with Fetuin-B in prediabetic participants, but this relation was not observed in the T2DM participants. Fetuin-B correlated inversely (P<005) with systolic BP (R=-0.20, P=0.01) and diastolic BP (R=-0.18, P=0.05). Interestingly, a strong inverse correlation was observed between Fetuin-B and TG in overall participants (R=-0.21, P=0.01) and specifically in T2DM women (R=-0.41, P=0.01). In conclusion, our study did not find a significant association of Fetuin-A or Fetuin-B levels in serum with T2DM. However, our results suggest that Fetuin-A may influence insulin resistance and serum Fetuin-B concentrations were inversely associated with TG in the general adult Saudi population.

Ziziphus spina-christi Leaf Extract Mitigates Mercuric Chloride-induced Cortical Damage in Rats.

BACKGROUND: Mercuric chloride (HgCl2) severely impairs the central nervous system when humans are exposed to it. AIMS: We investigated the neuroprotective efficiency of Ziziphus spina-christi leaf extract (ZSCLE) on HgCl2-mediated cortical deficits. METHODS: Twenty-eight rats were distributed equally into four groups: the control, ZSCLE-treated (300 mg/kg), HgCl2-treated (0.4 mg/kg), and ZSCLE+HgCl2-treated groups. Animals received their treatments for 28 days. RESULTS: Supplementation with ZSCLE after HgCl2 exposure prevented the deposition of mercury in the cortical slices. It also lowered malondialdehyde levels and nitrite and nitrate formation, elevated glutathione levels, activated its associated-antioxidant enzymes, glutathione reductase, and glutathione peroxidase, and upregulated the transcription of catalase and superoxide dismutase and their activities were accordingly increased. Moreover, ZSCLE activated the expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 when compared with the HgCl2 group. Notably, post-treatment with ZSCLE increased the activity of acetylcholinesterase and ameliorated the histopathological changes associated with HgCl2 exposure. Furthermore, ZSCLE blocked cortical inflammation, as observed by the lowered mRNA expression and protein levels of interleukin-1 beta and tumor necrosis factor-alpha, as well as decreased mRNA expression of inducible nitric oxide synthase. In addition, ZSCLE decreased neuron loss by preventing apoptosis in the cortical tissue upon HgCl2 intoxication. CONCLUSION: Based on the obtained findings, we suggest that ZSCLE supplementation could be applied as a neuroprotective agent to decrease neuron damage following HgCl2 toxicity.

Endotoxemia, vitamin D and premature biological ageing in Arab adults with different metabolic states.

There are limited studies on the association of endotoxin, a potent mediator of gut-derived inflammation and telomere length (TL). We investigated (1) the influence of adiposity on endotoxin and TL amongst Saudi adults according to type 2 diabetes mellitus (T2DM) status and (2) the influence vitamin D may have on TL attrition. Anthropometric data and fasting blood samples were taken from 775 Saudi adults visiting different primary care centers in Riyadh [387 T2DM and 388 non-T2DM]. TL, derived from peripheral blood mononuclear cells, was analyzed by Quantitative real-time polymerase chain reaction and circulating endotoxin levels by Limulus Amebocyte Lysate assay. Subjects were stratified based on obesity and T2DM status. A significant lower TL was observed in the non-obese T2DM group as compared with their non-obese, non-T2DM counterparts (p = 0.002). Significant inverse associations between TL, endotoxin and endotoxin activity were observed in the cohort with obesity. Regression analysis showed that endotoxin was a significant predictor for TL in all subjects and even after stratification according to subgroups; with variances perceived in circulating TL stronger among non-T2DM obese (10%; p = 0.003) than non-T2DM non-obese (12%; p = 0.007). Also, in the non-T2DM group, TL and HDL-cholesterol predicted 29% of the variances perceived in 25(OH)D (p < 0.001). Taken together these findings show that circulating endotoxin and 25(OH)D are associated with premature biological ageing influenced by adiposity and metabolic state; suggesting future intervention studies to manipulate gut microbiome and or vitamin D levels may offer ways to mitigate premature TL attrition.

Insights of Noncanonical Splice-site Variants on RNA Splicing in Patients With Congenital Hypothyroidism.

CONTEXT: Congenital hypothyroidism (CH) is caused by mutations in the genes for thyroid hormone synthesis. In our previous investigation of CH patients, approximately 53% of patients had mutations in either coding exons or canonical splice sites of causative genes. Noncanonical splice-site variants in the intron were detected but their pathogenic significance was not known. OBJECTIVE: This work aims to evaluate noncanonical splice-site variants on pre-messenger RNA (pre-mRNA) splicing of CH-causing genes. METHODS: Next-generation sequencing data of 55 CH cases in 47 families were analyzed to identify rare intron variants. The effects of variants on pre-mRNA splicing were investigated by minigene RNA-splicing assay. RESULTS: Four intron variants were found in 3 patients: solute carrier family 26 member 4 (SLC26A4) c.1544+9C>T and c.1707+94C>T in one patient, and solute carrier family 5 member 5 (SLC5A5) c.970-48G>C and c.1652-97A>C in 2 other patients. The c.1707+94C>T and c.970-48G>C caused exons 15 and 16 skipping, and exon 8 skipping, respectively. The remaining variants had no effect on RNA splicing. Furthermore, we analyzed 28 previously reported noncanonical splice-site variants (4 in TG and 24 in SLC26A4). Among them, 15 variants (~ 54%) resulted in aberrant splicing and 13 variants had no effect on RNA splicing. These data were compared with 3 variant-prediction programs (FATHMM-XF, FATHMM-MKL, and CADD). Among 32 variants, FATHMM-XF, FATHMM-MKL, and CADD correctly predicted 20 (63%), 17 (53%), and 26 (81%) variants, respectively. CONCLUSION: Two novel deep intron mutations have been identified in SLC26A4 and SLC5A5, bringing the total number of solved families with disease-causing mutations to approximately 45% in our cohort. Approximately 46% (13/28) of reported noncanonical splice-site mutations do not disrupt pre-mRNA splicing. CADD provides highest prediction accuracy of noncanonical splice-site variants.

Association of Alzheimer's Disease with Genetic Variants of Apolipoprotein E, Clusterin, TNF-α, and IL-6 Among Elderly Saudis.

BACKGROUND: In the wake of the warning by WHO that the prevalence of dementia may have a rise of 125% in the Middle East by 2050, identification of the genetic risk factors in Arab populations is urgent. OBJECTIVES: To investigate the association of Single Nucleotide Polymorphisms (SNPs) in apolipoprotein E (ApoE), clusterin (CLU), tumor necrotic factor- α (TNF-α) and interleukin-6 (IL-6) genes, with risk of Alzheimer's disease (AD) in Saudi Arabian participants. METHODS: A total of 42 Saudi AD patients and 23 age-matched control participants were genotyped for eight SNPs: rs429358, rs7412 (ApoE); rs11136000, rs1532278 (CLU); rs1800629, rs1799724 (TNF-α) and rs1800796, rs1800795(IL-6), by RT-PCR using the TaqMan assay. Serum concentrations of amyloid beta peptide 1-40(Aß1-40), amyloid beta peptide 1-42(Aß1- 42), CLU and some other biochemical markers were measured. RESULTS: A significant increase (p=0.004) in the serum CLU level was detected in the AD group (340.4 ± 74.6) compared with control group (265.0 ± 80.9). For rs1532278 (CLU), genotype GA was significantly higher in AD patients (57.1%) than in the control participants (26.1%), [p=0.024, OR = 4.00, 95% CI (1.20-13.28)]. For the ApoE SNP rs7412, 40.4% of patients carried a TT genotype, whereas it was completely absent in the controls [p = 0.020, OR = 30.53, 95% CI (1.73 - 540.05)].For rs429358 (ApoE), patients showed a significantly increased frequency of the TC genotype [p = 0.006, OR = 9.33, 95% CI (1.89-46.19)] and TT [p = 0.045, OR = 19.76, 95% CI (1.07-366.0)] genotype than controls. AD patients with CC genotype for ApoE rs429358 had significantly lower levels of Aß1-40 (p=0.04) in AD patients than controls. Carriers of genotype GG for rs1800629 (TNF-α) showed significantly higher levels of serum IL-6 (p = 0.04) in AD patients. CONCLUSION: Genetic variants in ApoE and CLU may influence susceptibility to AD among Saudi Arabian participants.

Gut-Derived Endotoxin and Telomere Length Attrition in Adults with and without Type 2 Diabetes.

Premature aging, as denoted by a reduced telomere length (TL), has been observed in several chronic inflammatory diseases, such as obesity and type 2 diabetes mellitus (T2DM). However, no study to date has addressed the potential inflammatory influence of the gut-derived Gram-negative bacterial fragments lipopolysaccharide, also referred to as endotoxin, and its influence on TL in low-grade inflammatory states such as type 2 diabetes mellitus (T2DM). The current study therefore investigated the influence of endotoxin and inflammatory factors on telomere length (TL) in adults with (T2DM: n = 387) and without (non-diabetic (ND) controls: n = 417) obesity and T2DM. Anthropometric characteristics were taken, and fasted blood samples were used to measure biomarkers, TL, and endotoxin. The findings from this study highlighted across all participants that circulating endotoxin (r = -0.17, p = 0.01) was inversely associated with TL, noting that endotoxin and triglycerides predicted 18% of the variance perceived in TL (p < 0.001). Further stratification of the participants according to T2DM status and sex highlighted that endotoxin significantly predicted 19% of the variance denoted in TL among male T2DM participants (p = 0.007), where TL was notably influenced. The influence on TL was not observed to be impacted by anti-T2DM medications, statins, or anti-hypertensive therapies. Taken together, these results show that TL attrition was inversely associated with circulating endotoxin levels independent of the presence of T2DM and other cardiometabolic factors, suggesting that low-grade chronic inflammation may trigger premature biological aging. The findings further highlight the clinical relevance of mitigating the levels of circulating endotoxin (e.g., manipulation of gut microbiome) not only for the prevention of chronic diseases but also to promote healthy aging.

PTHR1 Genetic Polymorphisms Are Associated with Osteoporosis among Postmenopausal Arab Women.

The parathyroid hormone 1 receptor (PTHR1) plays a crucial role in calcium homeostasis and bone metabolism. However, its genetic role in regulating bone turnover markers (BTMs) in postmenopausal osteoporosis (PMO) remains unclear. Herein, we explored parathyroid hormone (PTH) and PTHR gene variant susceptibility to osteoporosis and their association with various circulating BTM and inflammatory markers in postmenopausal women of Arab ethnicity. In total, 600 postmenopausal Arab women (300-PMO and 300-control) were genotyped for selected SNPs in PTH (rs1459015, rs307253, rs6054, rs307247, rs10500783 and rs10500784), PTHR1 (rs6442037, rs1138518, and rs724449 SNPs) and PTHR2 (rs9288393, rs10497900, and rs897083). Anthropometrics, BTMs, and inflammatory markers were measured. Bone mineral density (BMD) was measured at the lumbar spine L1-L4 and the femoral neck using dual-energy X-ray absorptiometry (DXA). PTHR1 rs1138518 genotype C/T was found to be a significant risk factor for PMO (OR = 1.49, 95% CI 1.0-2.1, P = 0.03). The genotypes C/T and T/T of PTHR1 rs1138518 were associated with 25-hydroxy-vitamin D (25(OH)D) regulation. In the PMO group, carriers of the C/T genotype had significantly lower 25(OH)D levels than carriers of the same genotypes in the control group (59.9 (36.7-92.4) nmol/l and 66.4 (43.5-87.8) nmol/l, respectively; P = 0.048]. Our study concludes that the PTHR1 rs1138518 genotype could be a potential risk factor for osteoporosis and 25(OH)D regulation in Arab women with PMO.

Association of RANKL and OPG Gene Polymorphism in Arab Women with and without Osteoporosis.

Receptor activator of the nuclear factor-κB ligand (RANKL) and osteoprotegerin genes (OPG) were identified as susceptible loci for postmenopausal osteoporosis (PMO) in various ethnicities, but neither have been studied in an Arabian population. Hence, the current study aimed to fill this gap. A total of 372 postmenopausal women (174 osteoporosis (OP) and 198 control group (CTRs)) were genotyped for four SNPs: rs2277438A/G and rs9533156T/C (RANKL), and rs2073618C/G and rs3102735T/C (OPG). Anthropometrics, bone mineral density, 25(OH)D and several other bone markers were measured. The frequency distribution of the heterozygous CG genotype of rs2073618 (OPG) was lower in the OP (36.8%) than in CTRs (47%) (OR: 0.6, 95% CI: 0.3-0.97; p = 0.041). No differences in the allelic/genotypic frequencies were detected between the two groups for all other studied SNPs. However, the heterozygous TC genotype of rs3102735 (OPG) was associated significantly with lower BMD at the femoral neck in OP subjects (p = 0.04). The homozygous rare CC genotype of rs9533156 (RANKL) was associated with lower 25(OH)D levels in CTRs (p = 0.032). In contrast, heterozygous AG genotype of rs2277438 (RANKL) is associated with lower 25(OH)D in the OP group (p = 0.02). Our results suggest that RANKL SNPs may impact 25(OH)D levels and that OPG SNP rs2073618A/G is a significant genetic risk factor for PMO Saudi Arabian women.

Serum minerals (Ca, P, Co, Mn, Ni, Cd) and growth hormone (IGF-1 and IGF-2) levels in postmenopausal Saudi women with osteoporosis.

Osteoporosis is reported to be common among Saudi women. Several minerals appear to be important determinants of insulin-like growth factor (IGF), the bioactivity of which regulates bone and mineral metabolism. Here we proposed that mineral status may alter the IGF system among individuals with osteoporosis. This study aims to evaluate the relationships between essential elements and IGF levels among postmenopausal Saudi women with osteoporosis. A total of 128 postmenopausal Saudi women aged ≥50 years old were recruited in this study. Diagnosis of osteoporosis was done by using dual-energy x-ray absorptiometry to determine the bone minerals density (BMD). Serum calcium and phosphate were determined using routine chemical analyzer. Serum Co, Mn, Ni, Cd were measured using inductively coupled plasma mass spectrometry. Serum IGF-1 and IGF-2 were determined using Luminex xMAP. Using stepwise linear regression analysis, only Cd was identified to be significantly associated with IGF1 in osteoporosis, explaining 3% (confidence interval 0.01-0.05; P = 0001) of the variance perceived. Our results suggest that Cd exposure indirectly affects BMD which may increase the risk of osteoporosis in postmenopausal women. Further longitudinal study using a larger sample size is recommended to determine causality of Cd levels and IGF-1.

Association of Polymorphisms in RANK and RANKL Genes with Osteopenia in Arab Postmenopausal Women.

The RANKL/RANK/OPG pathway regulates bone remodelling and turnover. However, the genetic background of bone mineral density (BMD) and osteopenia in Saudi postmenopausal women is yet to be studied. We studied the genetic polymorphism of RANKL/RANK/OPG with BMD and other associated factors in Saudi postmenopausal osteopenic women. A total of 439 (223 osteopenia and 216 control) postmenopausal women were recruited from the orthopaedic department of the King Khalid University Hospital, Riyadh, KSA. Genetic variants of RANK (rs1805034 and rs35211496), RANKL (rs2277438 and rs9533156), and OPG (rs2073618 and rs3102735) were genotyped using RT-PCR. Anthropometrics, bone mineral density, and other bone markers were measured. The levels of bone turnover markers, PTH, and RANKL were found to be significantly different between control and the osteopenia group. The odds ratio of 2.37 (1.00-5.69) for RANK SNP (rs1805034) indicates that subjects with CC genotype are more vulnerable to developing osteopenia as compared to subjects with TT genotype. Similarly, for RANKL SNP (rs2277438), the significant odds ratio of 20.56 (9.82-43.06) indicates that the subjects with GG genotype are at significantly higher risk of having osteopenia compared with the AA genotype subjects. In addition, G allele in rs2277438 also found to be a risk factor for osteopenia 4.54 (3.18-6.49) compared with A allele. However, none of the OPG genotypes shows association with osteopenia. The association of RANK polymorphisms with osteopenia shows its clinical importance in the diagnosis and prognosis of the bone diseases; here, we suggest that the subjects with RANK and RANKL polymorphisms may develop osteoporosis.

Efficacy of vitamin D supplementation according to vitamin D-binding protein polymorphisms.

OBJECTIVES: The aim of this study was to determine the influence of vitamin D-binding protein (DBP) gene polymorphisms in vitamin D metabolites before and after vitamin D supplementation. METHODS: In all, 234 participants (126 women; 108 men) with vitamin D deficiency [25(OH)D <50 nmol/L] were given 50 000 IU of vitamin D supplements for 8 wk followed by daily maintenance of 1000 IU for 4 mo. Two single-nucleotide polymorphisms (rs4588 and rs7041) in DBP coding gene were assessed. RESULTS: Baseline 25(OH)D was significantly in higher in participants with homozygous major genotype of rs7041 than other genotypes (P = 0.02). Postsupplementation 25(OH)D was significantly higher in participants with homozygous major genotypes of either rs4588 and rs7041 than other genotypes (P < 0.001). Participants with the minor allele of either rs4588 or rs7041 were 2.9 (1.9-4.5) times and 3.7 (2.1-6.6) times, respectively, more likely to be non-responders (postsupplementation 25 OHD <50 nmol/L) than those homozygous for the major allele at these locations (P < 0.001). Furthermore, participants with homozygous minor and heterozygous genotype of rs7041 were 6.2 and 4.2times more likely to be non-responders than those with the homozygous major genotype (P < 0.001) even after adjustments for age, sex, body mass index, baseline 25(OH)D concentration, and other alleles. Participants with homozygous minor and heterozygous genotypes of rs4588 were 4.1 and 12.4times more likely to be non-responders than those with homozygous major genotypes. These significant risks, however, were lost after adjustment. CONCLUSIONS: rs7041 and rs4588 variants of the DBP gene are associated with variations in 25(OH)D levels and efficacy of response to vitamin D supplementation in Saudi Arabian adults.

Novel Associations between BRCA1 Variants C.181 T>G (Rs28897672) and Ovarian Crisk in Saudi Females.

BACKGROUND: Mutations in BRCA1 gene have been implicated in ovarian cancers, and BRCA testing may be conducted in high-risk women. This study was designed to determine the frequency of three single nucleotide polymorphisms (SNPs) variants in BRCA1 gene and BRCA1 expression in Saudi females with ovarian cancer. METHODS: Expression levels of mRNA of BRCA1 gene were studied in 10 ovarian cancer and 10 normal ovarian tissues, by quantitative real time polymerase chain reaction (qPCR). The study also included 28 females who had suffered from ovarian cancer and had been successfully operated upon and 90 healthy females with no history of cancer. Blood was drawn in EDTA tubes and used for extraction of DNA. The genotyping was carried out using Taqman® SNP Genotyping kit by RT-PCR. The variants investigated included c.871 T>C (rs799917), c.1040 G>A (rs4986852), c.181 T>G (rs28897672) in BRCA1 gene. RESULTS: The c.181 T>G (rs28897672) showed significantly different genotype and allele frequencies between the patients and the control subjects (p value = 0.002 and 0.02, respectively). The genotype TG was significantly protective (OR = 0.36, p value = 0.024). The mRNA expression of BRCA1 gene was found to be low in the ovarian cancer tissues. CONCLUSIONS: This study showed that c.181 T>G in BRCA1 genes is associated with the development of ovarian cancer in Saudis. More studies are needed to unveil other SNPs that may be associated with ovarian cancer and to understand the mechanism(s) involved in reducing the expression of BRCA1 gene in ovarian cancer tissues.