Relevance of Serum Levels and Functional Genetic Variants in Vitamin D Receptor Gene among Saudi Women with Gestational Diabetes Mellitus.

Background: This study explored the association between ApaI-TaqI Single Nucleotide Polymorphisms (SNPs) in a Vitamin D receptor (VDR) and the risk of Gestational Diabetes Mellitus (GDM) in Saudi women, along with the serum levels of vitamin D. Methods: Ninety women with GDM and 90 non-GDM women were enrolled, based on the inclusion and exclusion criteria for pregnant women enrolled in a single-center study. Blood samples were retrieved from 180 pregnant women using ethylenediaminetetraacetic acid (EDTA) tubes. Serum samples were used to measure the vitamin D, 25-hydroxyvitamin D (25(OH)D or calcidiol), and lipid profiles. Blood was used to measure the hemoglobin A1c levels and to isolate the DNA. The polymerase chain reaction (PCR) was performed for the ApaI (rs79785232), BsmI (rs1544410), FokI (rs2228570), and TaqI (rs731236) SNPs in the VDR gene using restriction fragment length polymorphism analysis. Validation was performed using Sanger sequencing. Statistical analyses were performed between the patients with and without GDM using various statistical software packages. Results: The Hardy-Weinberg equilibrium analysis was statistically significant (p > 0.05). The ApaI, BsmI, and TaqI SNPs were associated with alleles, genotypes, and different genetic models (p < 0.05). Vitamin D levels were associated with deficient levels (p = 0.0002), as well as with a normal and overweight body mass index (p = 0.0004). When vitamin D levels were measured with GDM covariates, the fasting plasma glucose (FPG) (p = 0.0001), postprandial blood glucose (PPBG) (p < 0.0001), oral glucose tolerance test (OGTT)-1 h (p = 0.005), high-density lipoprotein (p = 0.022), and low-density lipoprotein cholesterol (LDLc) (p = 0.001) levels were significantly different. When similar vitamin D levels were measured for each genotype, we confirmed that the ApaI SNP was associated with sufficient levels (p < 0.0001), whereas the BsmI, FokI, and TaqI (p < 0.05) were associated with insufficient levels. The logistic regression model confirmed that the first hour of the OGTT (p = 0.005) was strongly associated with GDM, whereas the analysis of variance confirmed that FPG and PPBG (p < 0.05) were strongly associated with all the SNPs evaluated in the VDR gene. Additionally, the second hour of the OGTT (p = 0.048) and LDLc (p = 0.049) were associated with the ApaI and FokI SNP. Moreover, the first hour OGTT (p = 0.045) and lipid profile parameters (p < 0.05) were associated. Haplotype analysis revealed positive associations among the examined SNPs, which seemed compatible with the hypothesis that variants and combinations of multiple SNP genotypes enhance the risk of GDM in women. Haplotype analysis revealed that different combinations of alleles, such as AGCC, CATT, CGTC, AGTC, and CATT (p < 0.05), were strongly associated. The linkage disequilibrium (LD) analysis showed a strong association with all combinations (p < 0.05). Among the gene-gene interactions, all possible combinations showed a positive association (p < 0.05). Conclusions: Low vitamin D levels were observed in women with GDM. The ApaI, BsmI, and TaqI SNPs were associated with genotype and allele frequencies (p < 0.05). Vitamin D and the SNPs in the VDR gene were associated, according to the ANOVA, logistic regression, haplotype analysis, LD analysis, and the generalized multifactor dimensionality reduction model (p < 0.05).

Dissecting the Molecular Role of ADIPOQ SNPs in Saudi Women Diagnosed with Gestational Diabetes Mellitus.

The traditional definition of gestational diabetes mellitus (GDM) is the leading cause of carbohydrate intolerance in hyperglycemia of varying severity, with onset or initial detection during pregnancy. Previous studies have reported a relationship among obesity, adiponectin (ADIPOQ), and diabetes in Saudi Arabia. ADIPOQ is an adipokine that is produced and secreted by adipose tissue involved in the regulation of carbohydrate and fatty acid metabolism. This study investigated the molecular association between rs1501299, rs17846866, and rs2241766 single-nucleotide polymorphisms (SNPs) in ADIPOQ and GDM in Saudi Arabia. Patients with GDM and control patients were selected, and serum and molecular analyses were performed. Statistical analyses were performed on clinical data, Hardy Weinberg Equilibrium, genotype and allele frequencies, multiple logistic regression, ANOVA, haplotype, linkage disequilibrium, as well as MDR and GMDR analyses. The clinical data showed significant differences in various parameters between the GDM and non-GDM groups (p < 0.05). In GDM women with alleles, genotypes, and different genetic models, the rs1501299 and rs2241766 SNPs showed a strong association (p < 0.05). Multiple logistic regression analysis revealed a negative correlation (p > 0.05). This study concluded that rs1501299 and rs2241766 SNPs were strongly associated with GDM in women in Saudi Arabia.

Saudi Community-Based Screening Study on Genetic Variants in ß-Cell Dysfunction and Its Role in Women with Gestational Diabetes Mellitus.

BACKGROUND: Diabetes (hyperglycemia) is defined as a multifactorial metabolic disorder in which insulin resistance and defects in pancreatic ß-cell dysfunction are two major pathophysiologic abnormalities that underpin towards gestational diabetes mellitus (GDM). TCF7L2, KCNQ1, and KCNJ11 genes are connected to the mechanism of ß-cell dysfunction. The purpose of this study was to investigate the genes associated with ß-cell dysfunction and their genetic roles in the rs7903146, rs2237892, and rs5219 variants in Saudi women diagnosed with type 2 diabetes mellitus and GDM. MATERIALS AND METHODS: In this case-control study, 100 women with GDM and 100 healthy volunteers (non-GDM) were recruited. Genotyping was performed using polymerase chain reaction (PCR), followed by restriction fragment length analysis. Validation was performed using Sanger sequencing. Statistical analyses were performed using multiple software packages. RESULTS: Clinical studies showed a ß-cell dysfunction positive association in women with GDM when compared to non-GDM women (p < 0.05). Both rs7903146 (CT vs. CC: OR-2.12 [95%CI: 1.13-3.96]; p = 0.01 & T vs. C: (OR-2.03 [95%CI: 1.32-3.11]; p = 0.001) and rs5219 SNPs (AG vs. AA: OR-3.37 [95%CI: 1.63-6.95]; p = 0.0006 & G vs. A: OR-3.03 [95%CI: 1.66-5.52]; p = 0.0001) showed a positive association with genotype and allele frequencies in women with GDM. ANOVA analysis confirmed that weight (p = 0.02), BMI (p = 0.01), and PPBG (p = 0.003) were associated with rs7903146 and BMI (p = 0.03) was associated with rs2237892 SNPs. CONCLUSIONS: This study confirms that the SNPs rs7903146 (TCF7L2) and rs5219 (KCNJ11) are strongly associated with GDM in the Saudi population. Future studies should address the limitations of this study.

Screening of mitochondrial mutations in Saudi women diagnosed with gestational diabetes mellitus: A non-replicative case-control study.

INTRODUCTION: Among metabolic disorders, gestational diabetes mellitus (GDM) is specified as hyperglycemia caused by glucose or carbohydrate intolerance defects. GDM is distinguished by oxidative stress, and has been connected to mitochondrial dysfunction. Previous studies have documented the relation between A12026G, A8344G and A3243G mutations in ND4, tRNALeu(UUR), and tRNALys genes in different modes of diabetes. AIM: The purpose of this study was to investigate into the relationship between GDM women and common mitochondrial mutations including A12026, A8344G, and A3243G in Saudi women. METHODS: In this case-control study, we have opted 96 GDM and 102 non-GDM pregnant women and DNA was extracted using EDTA blood and based on specific primers, Polymerase Chain Reaction was followed and then Restriction Fragment Length Polymorphism (RFLP) analysis was performed. Restriction enzymes was cross-checked with Lambda DNA and 10% of the purified PCR products were performed the Sanger sequencing analysis to reconfirm the RFLP analysis of the studied results. RESULTS: None of the heterozygous and homozygous mutations were not observed in our study. All the subjects were turned to be homozygous normal genotypes. CONCLUSION: This study confirms that A12026, A8344G, and A3243G mutations have no role in the Saudi women with GDM.

Insertion and deletion polymorphism in the alpha-2B adrenoceptor gene in pregnant women ripens gestational diabetes mellitus.

There are no earlier studies that reported the association of the 12Glu9 polymorphism in the alpha-2B adrenoceptor (ADRA2B) gene with gestational diabetes mellitus (GDM). We examined the potential association between the ADRA2B gene insertion/deletion (I/D) polymorphism in the Saudi population with GDM. Pregnant women with GDM have been reported to exhibit the same susceptibility as that observed in type 2 diabetes mellitus (T2DM). We have selected I/D polymorphism of the ADRA2B gene located in chromosome 2q11.1 that has been extensively related to T2DM and cardiovascular diseases. This case-control study was conducted with 200 GDM and 300 non-GDM pregnant women. Genotyping of I/D polymorphism was performed by conventional PCR method. Biochemical analyses were found to be significantly different between GDM and non-GDM subjects (p < 0.05). Genotype (ID + DD vs II, p = 0.0002) and allele (D vs I, p = 0.0002) frequencies of the 12Glu9 polymorphism were found to be statistically significant. However, a significant difference was found between allele and genotypes of I/D polymorphism of the ADRA2B gene or the clinical characteristics of the subjects. Our results obtained in this study indicate the ADRA2B gene in the Saudi women was associated with the development of GDM.

The genetic polymorphism in the STK11 does not affect gestational diabetes.

Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance of variable severity that develops during pregnancy. Recent studies indicate that GDM onset is rapid, and that women with GDM will develop other metabolic disorders such as obesity, type 2 diabetes, and cardiovascular disease in their future. Serine/threonine kinase 11 (STK11) is engaged in the insulin signaling pathway and encoded protein is an important activator of adenosine monophosphate activated protein kinase. Based on the previously reported association between the STK11 gene and diabetes, we aimed to investigate whether the rs8111699 polymorphism in STK11 has any role in gestation diabetes in Saudi women. In this case-control study, we recruited pregnant Saudi women based on biochemical analysis of their blood samples. Genomic DNA was obtained from confirmed subjects (200 GDM cases and 300 non-GDM). PCR-RFLP analysis was performed to detect the C528G polymorphism in the STK11 gene. The anthropometric and clinical data were similar between the GDM and non-GDM subjects (p > 0.05), whereas the biochemical analysis was significantly different between the cases and controls (p < 0.05). The genotype and allele frequencies between of the STK11 gene were not statistically significant difference between the GDM and non-GDM groups (OR=0.82; 95% CI:=0.6-1.0; p=0.12). Our study suggests that the rs8111699 polymorphism has no role in the development of GDM in pregnant Saudi women.

Implication of SH2B1 gene polymorphism studies in gestational diabetes mellitus in Saudi pregnant women.

Genome-wide association studies have identified loci that are firmly associated with obesity. The Src-homology-2 B adaptor protein 1 (SH2B1) loci is abundantly expressed in the brain, liver, heart, muscle, and fat tissues. Gestational diabetes mellitus (GDM) is a growing health concern that usually appears during the latter half of pregnancy, and it is characterized by carbohydrate intolerance of variable severity. The SH2B1 gene polymorphism has been linked with an increased risk of weight gain in several but not all population studies. This study aimed to investigate the genetic association of rs4788102 variants in the SH2B1 gene with GDM in Saudi pregnant women. Genomic DNA samples from 200 women with GDM and 300 women without GDM were genotyped using the TaqMan method. The distribution of the GG, GA, and AA genotypes was significantly different between GDM and non-GDM women (p < 0.05). Thus, we identified rs4788102 variants as additional risk factors for GDM in Saudi women, and we suggest that these variants may have a prognostic value.

Relationship between the paraoxonase 1 gene glutamine 192 to arginine polymorphism and gestational diabetes mellitus in Saudi women.

OBJECTIVES: Gestational diabetes mellitus (GDM) is recognized as an imbalance between insulin resistance and insulin secretion, leading to maternal hyperglycemia. Previous studies in a Saudi population indicated a high frequency of Paraoxonase 1 glutamine 192 to arginine (PON1 Q192R) polymorphism, suggesting this polymorphism as an additional risk factor. The present study was designed to explore the possible association between the PON1 Q192R polymorphism and GDM in a Saudi population. METHODS: This case-control study was carried out in 500 pregnant women, including 200 GDM cases and 300 non-GDM women. Genotyping for PON1 Q192R (rs662) variants was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The results of the present study indicates that Q192R polymorphism was significantly associated with GDM in a Saudi population with the minor allele frequency (MAF) (p=0.0007). Q192R genotypes and alleles showed a strong association with GDM (p=0.009 and p=0.0007, respectively). CONCLUSION: In conclusion, these findings suggest that the PON1 Q192R polymorphism has high MAF in GDM in the studied Saudi population.

Insulin receptor substrate-1 (IRS-1) Gly927Arg: correlation with gestational diabetes mellitus in Saudi women.

Pregnant women with gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) share a common pathophysiology associated with similar risk factors. Genetic variants used to determine the risk of developing T2DM might also be associated with the prevalence of GDM. The aim of the present study was to scrutinize the relationship between the G972R polymorphism of the insulin receptor substrate-1 (IRS-1) gene with GDM in the Saudi female population. This is a case-control study that monitored 500 Saudi women. Subjects with GDM (n = 200) were compared with non-GDM (n = 300) controls. We opted to evaluate rs1801278 polymorphism in the IRS1 gene, which plays a critical role in the insulin-signaling pathway. Genotyping was performed with the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. The frequency of the rs1801278 polymorphism was significantly higher in women with GDM than in women with non-GDM (for TT + CT versus CC: P = 0.02). Additionally, there was a significant increase in the frequency of the Arg-encoding mutant allele from GDM to non-GDM (for T versus C: P = 0.01). Our results suggest that the rs1801278 polymorphism in the IRS-1 gene is involved in the occurrence of GDM in the Saudi population.

Radical vaginal trachelectomy after laparoscopic staging and neoadjuvant chemotherapy in women with early-stage cervical cancer over 2 cm: oncologic, fertility, and neonatal outcome in a series of 20 patients.

OBJECTIVES: The aim of the study was to assess oncologic and fertility outcome of treatment in patients with cervical cancer of more than 2 cm seeking parenthood. METHODS: The regimen consisted of laparoscopic lymphadenectomy as a staging procedure to confirm no lymph node metastases before neoadjuvant chemotherapy (NACT) consisting of 2 or 3 cycles of paclitaxel/ifosfamide/cisplatin followed by radical vaginal trachelectomy (RVT). Oncologic and fertility outcome was evaluated prospectively. RESULTS: Twenty women were enrolled up to now. The mean age was 32 years (range, 26-41 years), and mean tumor size was 3 cm (range, 2.1-5.0 cm). Lymphadenectomy was performed before NACT without complications. During NACT, hematologic toxicity grade 3 was observed in 2 of 20 patients, and renal toxicity grade 3 in 1 of 20 patients. Radical vaginal trachelectomy was performed in 18 women until now with 2 intraoperative complications (ureter injury and injury of internal iliac vein). There were no severe postoperative or long-term complications. Complete pathologic remission was found in 9 of 18 patients. In 2 of 18 patients, chemoradiation was recommended because of insufficient pathologic response in the RVT specimen. After a mean follow-up of 23 months (range, 1-88 months), 1 relapse was observed. After RVT, 7 women tried to conceive until now. Seven pregnancies occurred in 5 women. Four children were born, 2 of whom were premature (31 weeks 2 days and 33 weeks 4 days of gestation); 1 pregnancy is ongoing. CONCLUSIONS: Laparoscopic lymphadenectomy followed by NACT and RVT in pN0 patients with cervical cancer of more than 2 cm seems to be an oncologically safe procedure with promising fertility outcomes.

Refractory Noninfectious Anterior Uveitis Associated With Systemic Mastocytosis.

A 10-year-old boy with biopsy-proven systemic mastocytosis presented with bilateral nongranulomatous anterior uveitis associated with high intraocular pressure. Anterior chamber paracentesis was performed for cytological evaluation, which demonstrated monocytes and macrophages but no evidence of mast cells. His uveitis was partially controlled with frequent topical steroid drops and weekly oral methotrexate therapy. The glaucoma was controlled with topical antiglaucoma medications in the right eye. Deep sclerectomy was required in the left eye to control the intraocular pressure. To the best of the authors' knowledge, this is the first report of such an association.

Pregnancy outcome of gestational diabetic mothers: experience in a tertiary center.

BACKGROUND: Carbohydrate intolerance is the most common metabolic complication of pregnancy. Gestational Diabetes Mellitus (GDM) poses numerous problems for both mother and fetus. The objectives of this study are to find out the incidence of gestational diabetes mellitus in pregnant women and their pregnancy outcomes. It was also to discover the risk factors for the admission of neonates to the Neonatal Intensive Care Unit (NICU). DESIGN AND PATIENTS: A hospital-based prospective study performed at King Khalid University hospital (KKUH), where 685 pregnant women who were diagnosed with gestational diabetes mellitus, out of 8000 pregnant women registered between January 2000 - December 2001, were followed and their outcomes studied. RESULTS: The incidence of gestational diabetes mellitus was found to be 8.6% (95% C.I: 8.1, 9.3). There were 511 (74.6%) spontaneous vertex deliveries, and 148 (21.6%) were delivered by lower segment cesarean section. Maternal morbidity in these women was 1.2%. A total of 697 babies were delivered by these 685 women, out of whom 675 were singleton pregnancies, 9 sets of twins and one set of quadruplets. Six-hundred-eighty-seven babies were born alive, 7 babies died in utero and 3 died in the neonatal period. The incidence of neonatal intensive care admission was 4.9%. The mean length of stay in the NICU was 16 days. The commonest cause of neonatal NICU admission was hyperbilirubinemia (41.2%). The risk factors for NICU admission were delivery by non SVD procedure (RR: 4.6, 95% C.I:2.8, 7.7), preterm deliveries, (RR: 4.6, 95% C.I.:2.7, 7.7), and induction of labor (RR: 2.5, 95% C.I: 1.4, 4.5). CONCLUSION: The observation and quantification of maternal outcomes with gestational diabetes mellitus are necessary, so that proper measures could be taken to reduce complications during delivery and the neonatal period and thereby, minimize particularly NICU admission rate.

Frequency of isolated positive sputum cultures among pulmonary tuberculosis patients.

OBJECTIVE: The occurrence of isolated positive sputum cultures among pulmonary tuberculosis (PTB) patients during treatment is not widely reported. This study describes the frequency of isolated positive sputum cultures among PTB patients after initiation of chemotherapy. METHODS: Fifty sputum culture positive PTB patients, consisting of 38 (76%) males and 12 (24%) females with a mean age of 34.31 +/- 19.54 (13-75) years, were studied prospectively over a period of 10 months (September 1999 to June 2000) at Sahary Chest Hospital, Riyadh, Kingdom of Saudi Arabia. The majority of patients received standard 4-drug short-course antimicrobial chemotherapy. Weekly sputum smears and cultures were carried out for each patient during the treatment. RESULTS: Isolated positive sputum cultures were encountered in 4 (8%) of the studied patients. Two of them had 2 consecutive positive smears and cultures in their third and fourth week during treatment and were attributed to poor compliance to the treatment. Of the remaining 2 patients, one had single isolated culture in his fourth week, while the fourth patient showed a slight growth in the fifth week of the treatment. Due to the undetermined status of the smear and very few colonies in the culture, these 2 isolated cultures were attributed to the carry-over contamination during the laboratory procedures. The same treatment was continued with strict monitoring of compliance to the treatment and laboratory protocols. All of the 4 patients converted to negative before leaving the hospital. CONCLUSION: Isolated positive sputum cultures might appear (infrequently) during treatment either due to the treatment noncompliance or carry over contamination. However, under either circumstance, the same treatment should be continued along with strict monitoring of treatment compliance and specimen decontamination and related laboratory protocols.

Multiple pregnancy and preterm labor.

OBJECTIVE: Multiple gestations are high risk pregnancies, which may be complicated by pre-maturity, low birth weight infants, pre-eclampsia, anemia, postpartum hemorrhage, intrauterine growth restriction, neonatal morbidity and high perinatal, neonatal and infant mortality. This study was carried out to determine the incidence and effect of multiple pregnancies on pre-term labor in tertiary care hospitals. METHODS: Retrospective case record analysis of 375 cases of multiple pregnancies that were reported at Armed Forces Hospital and King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia, between January 2000 and December 2001. The data was analyzed to determine the incidence of multiple pregnancies and its effect on pre-term delivery. RESULTS: The over whole incidence of twins was 14/1000 births. Premature labor in multiple pregnancies was 7 times greater than singletons (42% versus 6.4%). Almost half of multiple pregnancy cases were delivered by cesarean section (49% versus 14%). Pregnancy was induced in 34% of cases. Cervical cerclage was applied in only 8% of cases and betamemetics were administered to only 11% of cases. Fetal distress in labor, abnormal presentation and previous uterine scar were the main indications for cesarean section. Fifty percent had no antenatal complications, gestational diabetes complicated 16%, and anemia was reported in 22% of cases. CONCLUSION: Preterm delivery remains the most serious complication of multiple pregnancies. Multiple gestation children may suffer long term sequel of prenatal complications, including cerebral palsy and hearing disabilities. Every effort should be made to reduce the risk of multiple gestation and pre-term labor through proper control and close monitoring of fertility drugs, limiting number of embryo transfer to maximum of 3 or only 2, improving the socioeconomic status of expectant mothers, reduce cigarette smoking, relieve maternal stress, restriction of maternal activity, frequent contact with health care personnel and treatment of any obstetric or medical disorders.

Uterine didelphus with obstructed hemivagina.

Complex congenital anomalies of the mullerian ducts can occur in isolation or in association with other developmental disorders. They result from non-development or non-fusion of the mullerian ducts or the failure of reabsorption of the uterine septum. Early diagnosis is necessary to relieve symptoms, optimize preservation of the genital organs and prevent the development of endometriosis. We present a case report to highlight this phenomenon.