Influence of KISS1 gene polymorphisms on the risk of polycystic ovary syndrome and its associated variables, in Saudi women.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder, affecting millions of women worldwide. The role of genetic polymorphisms of the KISS1 gene on the development of PCOS is still obscure. This study was designed to investigate the probable influence of KISS1 gene polymorphisms on PCOS and its associated variables: BMI, waist-hip ratio, kisspeptin, LH, FSH, and LH-FSH ratio. METHODS: The study comprised 104 PCOS women and 109 controls, with age ranging from 19 to 36 years. BMI, waist-hip ratio, and circulating levels of kisspeptin, LH, and FSH were measured. DNA was extracted, and genotyping of the KISS1 gene was carried out by nucleotide sequencing. The PCOS-associated variables were analyzed in different genotypes of single nucleotide polymorphisms (SNPs) of the KISS1 gene. RESULTS: The values of waist-hip ratio (WHR), LH, and LH-FSH ratio were significantly higher in PCOS women than controls. BMI, kisspeptin, and FSH levels exhibited no significant difference between the groups. Six novel SNPs of KISS1 gene were identified. Three: rs372790354G > A, rs12998G > A, and rs35431622A > T were investigated. Among these SNPs, the genotype and allele frequencies of rs372790354 showed significant association with PCOS (GA: p = 0.018, AA: p = 0.022, mutant allele-A: p = 0.021) and the G allele was protective. The values of LH, kisspeptin, and WHR of PCOS women were significantly influenced (p < 0.05) by the AA genotype of rs372790354. The other two SNPs rs12998G > A and rs35431622A > T revealed no significant influence on PCOS and associated variables. Haplotypes were constructed, but there was no significant difference between the patients and controls. CONCLUSION: In conclusion, this is the first study, which reports a significant influence of KISS1 gene polymorphism (rs372790354G > A) on PCOS and its associated variables. However, more extensive research is necessary to confirm these findings.

rs4889 polymorphism in KISS1 gene, its effect on polycystic ovary syndrome development and anthropometric and hormonal parameters in Saudi women.

BACKGROUND: Kisspeptin is involved in female reproduction. This study was designed to i- estimate kisspeptin levels in women with polycystic ovary syndrome (PCOS), in comparison with controls, ii- study the correlations between kisspeptin and PCOS-related reproductive hormones, and iii- investigate the relation between KISS1 gene polymorphisms and hormone levels in women suffering from PCOS. METHODS: The investigation was a clinically designed study on 28 women with PCOS, and 30 normal, healthy women with no signs of PCOS as controls. Blood samples were collected between day 3 and day 6 of the menstrual cycle in both groups at 8:00 a.m., and circulating levels of LH, FSH and kisspeptin were estimated. DNA was extracted from whole blood and all coding exons of KISS1 gene were sequenced. RESULTS: Women with PCOS had higher LH levels and BMI compared to controls. Plasma kisspeptin levels were positively correlated with LH levels. There was no statistically significant difference between the groups in terms of kisspeptin and FSH levels. The SNP rs4889 C/G, a non-synonymous SNP, was investigated in the PCOS group. The frequency of GG genotype was significantly higher in the PCOS compared to the controls. These patients were more obese, had higher kisspeptin and FSH levels. CONCLUSION: The results of the study show that the genetic variation of KISS1 gene may be a factor contributing to PCOS development. The association between the gene and the gene variation and PCOS need further validation in large-scaled and functional studies.

Polymorphisms in proinflammatory cytokine genes, effect on gene expression and association with preterm delivery in Saudi females.

Genetic polymorphism in proinflammatory cytokine genes may be associated with the etiology of preterm birth (PTB). The current study was designed with the aim to explore the association of genetic polymorphisms and mRNA expression of IL-1α, IL-1ß, and TNF-α gene with preterm birth in the Saudi population. Genotyping of genomic DNA of 50 PTB patients and an equal number of controls were carried out using TaqMan Genotyping assay kits. Gene expression of each gene was carried out using quantitative RT-PCR. The cytokine levels in the serum of PTB patients and controls were measured by ELISA. A statistically significant association was observed between the rs361525 alleles (G and A) of TNF-α and PTB, where the mutant A allele was significantly protective against PTB development (OR= 0.362; χ2=4.31; p=0.038). The gene expression of all studied genes (IL1α, IL-1ß, IL-6, and TNF-α) was higher in the PTB patients, but the results reached significance only for IL-1ß (p=0.035). Elevated gene expression was also evident from the level of these proteins in plasma, where the level of IL1α, IL-ß were significantly higher in the serum of PTB patients compared to the controls, however, IL6 and TNF-α were significantly lower despite higher gene expression. For IL6, the lower level could be due to tocolytic treatment that was given to all women suffering from PTB. Receiver operating curves (ROC) were drawn for the studied cytokines. In conclusion, this study revealed that rs361525 polymorphism plays a role as a protective marker for PTB and the levels of IL-1α, IL-6, TNF- α can be used as predicative biomarkers for PTB I Saudi women.

Sickle cell disease in Middle East Arab countries.

The sickle cell (HbS) gene occurs at a variable frequency in the Middle Eastern Arab countries, with characteristic distribution patterns and representing an overall picture of blood genetic disorders in the region. The origin of the gene has been debated, but studies using ß-globin gene haplotypes have ascertained that there were multiple origins for HbS. In some regions the HbS gene is common and exhibits polymorphism, while the reverse is true in others. A common causative factor for the high prevalence and maintenance of HbS and thalassaemia genes is malaria endemicity. The HbS gene also co-exists with other haemoglobin variants and thalassaemia genes and the resulting clinical state is referred to as sickle cell disease (SCD). In the Middle Eastern Arab countries, the clinical picture of SCD expresses two distinct forms, the benign and the severe forms, which are related to two distinct ß-globin gene haplotypes. These are referred to as the Saudi-Indian and the Benin haplotypes, respectively. In a majority of the Middle Eastern Arab countries the HbS is linked to the Saudi-Indian haplotype, while in others it is linked to the Benin haplotype. This review outlines the frequency, distribution, clinical feature, management and prevention as well as gene interactions of the HbS genes with other haemoglobin disorders in the Middle Eastern Arab countries.

Lack of Association between Angiotensin Converting Enzyme I/D Polymorphism and Unexplained Recurrent Miscarriage in Saudi Arabia.

BACKGROUND: An insertion/deletion (I/D) polymorphism in the angiotensin converting enzyme (ACE) gene has been associated with recurrent miscarriage (RM) in several populations. We initiated this study to determine the association, if any, between the I/D polymorphism of ACE gene and RM in Saudi females. METHOD: This study was conducted on 61 Saudi females suffering from RM (mean age: 34.1±6.2 years; range 15-45) attending clinics at King Khalid University Hospital, and 59 age matched females who had at least 2 children, as controls. Blood samples were drawn in EDTA tubes by venipuncture. DNA was extracted using the Puregene DNA purification kits. Insertion/Deletion (I/D) polymorphism of ACE gene was investigated by amplifying the genomic DNA by PCR using gene-specific primers. A single 190 bp or 490 bp band was obtained in the homozygous cases for the D allele or I allele, respectively, while the presence of both 190 and 490 bp bands indicated heterozygosity (ID). STATISTICAL ANALYSIS: Deviation from Hardy-Weinberg equilibrium was determined (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). A standard chi-square (χ2) test was used for comparing the genotype and allele frequencies in the two groups and Students't' test and χ2 test were employed to compare values between the two groups. P<0.05 was considered statistically significant. RESULTS: The frequencies of DD, ID, and II genotypes were 56.7%, 29.5% and 4.9%, respectively, in females with RM and 54.2%, 42.3% and 3.3% respectively in the control group, but the difference was not statistically significant. CONCLUSION: In some populations, meta-analyses showed an association between I/D polymorphism and RM risk, and the D allele was implicated as an increased risk factor for RM. However, this association was not apparent in the Saudi females.

Leptin concentration during different trimesters of pregnancy and its relation to other pregnancy hormones.

OBJECTIVE: To determine the levels of leptin and other pregnancy hormones (progesterone, estradiol, folliculi stimulating hormone, luteinizing hormone and beta human chorionic gonadotropin) in pregnant females during different stages of pregnancy and to correlate these levels to maternal weight, body mass index (BMI), babies weight and babies BMI. METHODS: Leptin level and other pregnancy hormones were measured in 36 pregnant females and 30 non-pregnant females followed at King Khaled University Hospital, Riyadh, Kingdom of Saudi Arabia in the year 2001 in a prospective study. Blood samples were collected at the first, 2nd and 3rd trimester and after delivery. Correlation analysis between leptin level and pregnancy hormones, in addition to maternal weight, BMI, babies weight and BMI. RESULTS: The mean leptin levels during pregnancy and postnatally were significantly higher in pregnant females compared to the non-pregnant controls. Serum concentration of leptin increased significantly (p=0.01) in the pregnant females from 21.24 +/- 9 ng/ml during the first trimester to 26.3 +/- 8.69 ng/ml during the 2nd trimester, but insignificantly decreased to 23.29 +/- 8.62 ng/ml during the 3rd trimester (p=0.073). After delivery leptin concentration significantly decreased to 17.36 +/- 7.95 ng/ml (p=0.0025). The changes in levels of leptin during pregnancy were independent to other pregnancy hormones which showed a different pattern of variation. CONCLUSION: The changes in levels of leptin during pregnancy were independent to other pregnancy hormones which showed a different pattern of variation.

Leptin level in pregnant mothers at term and cord blood and the effect of newborns gender.

OBJECTIVE: To evaluate the leptin level in healthy pregnant mothers at term and in their newborns and its relationship to their body mass index (BMI) and gender of the newborn. METHODS: The leptin level was measured in serum of 187 pregnant women at term delivering at the King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia in July 2001 and their newborns. Correlation studies were made between leptin level and their growth parameters, and gender of the newborns. RESULTS: Leptin level of the mothers was significantly higher compared to their newborns. There was a significant correlation between leptin level in the pregnant women and their weight, BMI, and the newborns leptin level and weight, but not their height or BMI. A statistically significant difference was found between male and female newborns plasma leptin level. A significant correlation was found between male newborns leptin level and all their growth parameters, while in the female newborns there was no correlation between their leptin level and BMI. CONCLUSION: Leptin plays an important role in providing a growth promoting signal during pregnancy, but the fat mass does not seem to be the most important predictor of cord leptin level.

The prevalence of obesity and overweight in 1-18-year-old Saudi children.

OBJECTIVES: The aim of this study was to review the prevalence of overweight and obesity in Saudi children with ages ranging up to 18 years. SUBJECTS AND METHODS: The study was a cross-sectional national epidemiological household survey, and the study group included 12071 children (boys 6281; girls 6420), with ages ranging from 1-18 years. Their height and weight were measured and body mass index (BMI) was calculated. The study group was classified as obese or overweight, using age- and sex-specific cut-off points for BMI for determining overweight and obesity in children. RESULTS: The overall prevalence of overweight was 10.7% and 12.7% in the boys and girls, respectively, and obesity was 6.0% and 6.74% in the two groups, respectively. The children were grouped according to the province to which they belonged, and prevalence of obesity and overweight were calculated for each province. The highest frequency was in the Eastern Province, while the lowest was in the Southern Province. The children were further grouped into 1-6, 6-12 and 12-18-year-olds and prevalence of obesity and overweight was calculated. In addition, at yearly intervals, the prevalence of obesity and overweight was calculated. Among the boys and girls, the maximum prevalence of obesity was in the 2-3 year-olds. A decrease in prevalence was found in both males and females up to the age group of 8-13 years, and then the prevalence increased again up to the 18 years age. CONCLUSION: This epidemiological household survey shows the overweight and obesity trends in Saudi children based on the international sex-specific cut-off points for BMI. It also shows a variable prevalence in different age groups until after 13 years, when the prevalence rate increases.

Increased frequency of angiotensin-converting enzyme DD genotype in Saudi overweight and obese patients.

BACKGROUND: Several studies have been carried out to investigate the insertion/deletion (I/D) polymorphism of angiotensin-converting enzyme (ACE) in obese and normal weight individuals, often with contradictory results in different populatios. In some studies, the DD genotype occurs at a high frequency in obesity, while in others no association has been demonstrated. Since obesity and overweight are of frequent occurrence in the Saudi population, we initiated this study to investigate the I/D polymorphism of ACE in obese, overweight and normal weight Saudis. PATIENTS AND METHODS: The study group included 457 Saudi males and females. The height and weight were measured and body mass index (BMI) was calculated. Based on the BMI value, the total study population was classified as normal, overweight and obese. A total of 117 obese (BMI >30 (kg/m(2))), 185 overweight (BMI=25-29.9 (kg/m(2))) and 155 normal weight individuals (BMI< (kg/m (2)) were enrolled. Polymerase chain reaction (PCR) and agarose gel electrophoresis were used to study the ACE polymorphism. For the deletion (D) form, a 190 bp and for the insertion (I) form, 490 bp DNA fragment were obtained on 2% agarose gel electrophoresis. RESULTS: The frequency of DD genotype was 76.9% in the obese, and 73.5% in the overweight individuals, compared to 19.66% and 24.86% of the ID genotype in the obese and overweight, respectively. Among the normal weight individuals, the frequency was significantly lower for DD and higher for the ID genotype, i.e., 58.7% for DD and 40% for ID. The allele frequencies in the obese were 0.867 and 0.133 for the D and I alleles, respectively. While in the overweight, the frequencies were 0.859 and 0.141 for these alleles, respectively, compared to 0.787 and 0.213 in the normal weight individuals. CONCLUSIONS: The DD genotype and D allele occur at a high frequency in Saudi overweight and obese individuals, and may have some role in fat accumulation by affecting metabolic pathways of fat, thus leading to the development of overweight and obesity.

In silico analysis of single nucleotide polymorphism (SNPs) in human ß-globin gene.

Single amino acid substitutions in the globin chain are the most common forms of genetic variations that produce hemoglobinopathies--the most widespread inherited disorders worldwide. Several hemoglobinopathies result from homozygosity or compound heterozygosity to beta-globin (HBB) gene mutations, such as that producing sickle cell hemoglobin (HbS), HbC, HbD and HbE. Several of these mutations are deleterious and result in moderate to severe hemolytic anemia, with associated complications, requiring lifelong care and management. Even though many hemoglobinopathies result from single amino acid changes producing similar structural abnormalities, there are functional differences in the generated variants. Using in silico methods, we examined the genetic variations that can alter the expression and function of the HBB gene. Using a sequence homology-based Sorting Intolerant from Tolerant (SIFT) server we have searched for the SNPs, which showed that 200 (80%) non-synonymous polymorphism were found to be deleterious. The structure-based method via PolyPhen server indicated that 135 (40%) non-synonymous polymorphism may modify protein function and structure. The Pupa Suite software showed that the SNPs will have a phenotypic consequence on the structure and function of the altered protein. Structure analysis was performed on the key mutations that occur in the native protein coded by the HBB gene that causes hemoglobinopathies such as: HbC (E→K), HbD (E→Q), HbE (E→K) and HbS (E→V). Atomic Non-Local Environment Assessment (ANOLEA), Yet Another Scientific Artificial Reality Application (YASARA), CHARMM-GUI webserver for macromolecular dynamics and mechanics, and Normal Mode Analysis, Deformation and Refinement (NOMAD-Ref) of Gromacs server were used to perform molecular dynamics simulations and energy minimization calculations on ß-Chain residue of the HBB gene before and after mutation. Furthermore, in the native and altered protein models, amino acid residues were determined and secondary structures were observed for solvent accessibility to confirm the protein stability. The functional study in this investigation may be a good model for additional future studies.

A comparative study of prevalence of overweight and obesity in children in different provinces of Saudi Arabia.

The aim of this study was to determine the prevalence of overweight and obesity in Saudi children from different provinces of the country and in different age groups. A total of 12,701 children (6,281 boys and 6,420 girls) with ages ranging from 1 to 18 years were enrolled during a household screening programme in different provinces of Saudi Arabia and height and weight were recorded. Body Mass Index (BMI) was calculated and applying age and sex specific cut-off points for BMI the children were grouped into overweight and obese. The overall prevalence of overweight was 10.68 and 12.7 per cent and that of obesity was 5.98 and 6.74 per cent in the boys and girls, respectively. In the different provinces the prevalence of overweight ranged from 8.8 to 27.4 per cent and from 9.3 to 27.6 per cent and obesity ranged from 4.7 to 10.4 per cent and from 4.3 to 13.8 per cent in the boys and girls, respectively. Prevalence of overweight and obesity was also calculated after grouping the children into 17 groups according to age. It is concluded that overweight and obesity occur in all provinces of Saudi Arabia although at a variable prevalence. In general, girls have a higher prevalence of both overweight and obesity compared with boys. Eastern province children have the highest prevalence and the Southern province children have the lowest prevalence of overweight and obesity. When grouped according to age, overweight and obesity tend to increase with age. Suggestions are made to prevent overweight and obesity development in Saudi children.

Sickle cell gene as a multifaceted problem in Saudi Arabia.

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The inter-relationship hematological parameters between Saudi newborns and parents.

OBJECTIVE: To determine the relationship of the hematological parameters between Saudi newborns and their parents. METHODS: This study was carried out at King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia, over a one-year period. Venous blood samples were taken from 82 healthy Saudi pregnant women in labor at full term, their husbands, and umbilical cord blood after delivery. Estimation of the hematological indices, in addition to transferrin level were performed. RESULTS: A statistically significant correlation was found between parents and cord blood with regards to red blood count, mean corpuscular volume, mean corpuscular hemoglobulin, mean corpuscular hemoglobulin concentration and packed cell volume, while no correlation was found with hemoglobulin and transferrin. CONCLUSION: Some of the hematological indices could be mainly genetically determined including red blood count, mean corpuscular volume, mean corpuscular hemoglobulin concentration, and packed cell volume as significant correlation was found between parents and their newborns while hemoglobulin and transferrin levels were not as these variables are mainly affected by environmental factors.

Blood groups in Saudi obstetrics patients.

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Prevalence of hypertension in adult Saudi population.

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