Ghada M. Al-Khateeb

Association of comorbid depression, anxiety, and stress disorders with Type 2 diabetes in Bahrain, a country with a very high prevalence of Type 2 diabetes

This study examined the association of depression, anxiety, and stress with Type 2 diabetes (T2DM) in Bahrain, an island-country with a very high prevalence of T2DM. This was a cross-sectional study involving administering Depression Anxiety Stress Scales (DASS)- 21 structured depression, anxiety, and stress scale to 143 T2DM patients and 132 healthy controls. Higher proportion of T2DM patients were found in the mild-moderate and severe-extremely severe depression (p=0.002), anxiety (p<0.001), and stress (p<0.001) groups. Chronic disease and disease duration were significantly associated with the 3 disturbances, while employment status was associated with anxiety and depression. Logistic regression analysis showed that anxiety, depression, and stress were associated with T2DM after adjusting for all variables, while age was the only significant variable associated with stress. These results suggest a positive contribution of T2DM to increased depressive and/or anxiety and/or stress disorders among the patients examined, thereby recommending counseling for T2DM patients.

Contribution of VEGF polymorphisms to variation in VEGF serum levels in a healthy population

OBJECTIVE Vascular endothelial growth factor (VEGF) is a pro-angiogenic factor. Variability in VEGF expression, induced by specific VEGFA variants, are involved in angiogenesis-related disorders. This study examined the genotype distribution and functional role (VEGF expression) of rs699947, rs833061, rs1570360, rs2010963, rs833068, rs833070, rs3025020, and rs3025039 VEGFA variants and their haplotypes in 519 healthy Bahraini individuals of both genders. METHODS AND RESULTS The distribution of the eight VEGFA polymorphisms screened was in Hardy-Weinberg equilibrium. The minor allele frequencies of rs699947 (0.42), rs833061 (0.32), rs1570360 (0.31), rs2010963 (0.33), rs833068 (0.37), rs833070 (0.42), rs3025020 (0.33), and rs3025039 (0.13) were generally compared to those established for Caucasians. Of the variants tested, rs3025020 was associated with increased VEGF serum levels (p=0.019), while rs3025039 was associated with decreased levels (p=0.038). Linkage analysis identified two VEGFA blocks, the first, spanning 16 kb, was not associated with altered VEGF levels, while the second, spanning 3 kb containing rs3025020 and rs3025039, was linked with higher VEGF expression, of which the (-583)T/(+936)T haplotype (p=0.008) was linked with higher VEGF levels compared to the (-583)C/(+936)C (all wild-type) haplotype. CONCLUSION These results support the association of rs30250202 and rs3025039, and specific VEGF haplotypes, with altered VEGF serum levels, although the exact functional mechanisms remain to be elucidated.

Tumor necrosis factor-α polymorphisms in women with idiopathic recurrent miscarriage

We investigated the association of tumor necrosis factor-alpha (TNFalpha) gene polymorphisms with idiopathic recurrent miscarriage (RM). TNFalpha -1031T/C, -863C/A, -857C/T, -376G/A, -308G/A, -238G/A, and +488G/A single nucleotide polymorphisms (SNPs) were investigated in 204 RM women and 248 age-matched parous women by PCR-restriction fragment length polymorphism. Significantly higher frequencies of -1031C and -376A alleles were seen in RM patients; significant differences were also noted in the distribution of -1031T/C, -376G/A, and -238G/A genotypes between case and control subjects. Haploview analysis revealed high linkage disequilibrium between -857C/T and +488G/A SNPs, but was lower between the other polymorphisms. Of the possible 52 seven-locus haplotypes constructed, 10 were common, and were included in subsequent analysis. Increased frequency of CCCGGGG and CCCGGAA haplotypes, and reduced frequency of TCCGGGG and TCCGGGA haplotypes were seen in RM patients than in controls. When the Bonferroni correction was applied, differences were significant for the CCCGGAA haplotype, which was higher (OR=4.14; 95% CI=1.84-8.95), and the TCCGGGA haplotype, which were lower among RM cases (OR=0.09; 95% CI=0.02-0.68), thereby conferring RM susceptibility and protection to these haplotypes, respectively. Multivariate analysis confirmed the positive association of only CCCGGAA haplotype with RM (P=0.010; aOR=2.03; 95% CI=1.18-4.47), after controlling for a number of covariates. These results demonstrate that the TNFalpha polymorphisms, in particular the -1031T/C variant, are significantly associated with idiopathic RM. Additional replication studies on other racial groups are needed to confirm our findings.

Variants within the calpain-10 gene and relationships with type 2 diabetes (T2DM) and T2DM-related traits among Tunisian Arabs

BACKGROUND Common variations in the calpain 10 (CAPN10) gene variants UCSNP-43, UCSNP-19 and UCSNP-63, and the 112/121 diplotype, are associated with an increased risk of type 2 diabetes (T2DM) and T2DM-related traits. METHODS The association of UCSNP-43, -19 and -63 CAPN10 SNPs with T2DM was assessed in 917 Tunisian T2DM patients and 748 ethnically matched non-diabetic controls. CAPN10 genotyping was done by PCR-RFLP. RESULTS Significant differences in UCSNP-19 MAF, but not UCSNP-43 or -63, and genotype distribution were seen between patients and controls. Heterogeneity in UCSNP-19, but not UCSNP-43 and -63, genotype distribution was noted according to geographical origin. Obesity was associated with UCSNP-19, while raised fasting glucose was associated with UCSNP-63, and increased HDL was associated with UCSNP-43. Enrichment of homozygous UCSNP-19 2/2 was seen in overweight and obese compared with lean patients; logistic-regression analyses demonstrated a positive association of the 2/2 genotype with overweight [P=0.003; OR (95% CI)=2.07 (1.28-3.33)] and obese [P=0.021; OR (95% CI)=1.83 (1.10-3.07)] patients. Of the six CAPN10 haplotypes identified, significant enrichment of only haplotype 111 was seen in T2DM patients [Pc=0.034; OR (95% CI)=1.22 (1.06-1.41)], while the frequency of all identified CAPN10 diplotypes, including the high-risk 112/121, was comparable between patients and controls. CONCLUSION While CAPN10 UCSNP-19 SNP and haplotype 111 contribute to the risk of T2DM in Tunisian subjects, no significant association between CAPN10 diplotypes and T2DM was demonstrated.

Effect of the functional VEGFA −583C/T variant on vascular endothelial growth factor levels and the risk of recurrent spontaneous miscarriage

The association of vascular endothelial growth factor (VEGF) -583C/T variant with recurrent miscarriage (RSM) was investigated in 173 RSM cases and 248 control women. Increased minor allele and genotype frequencies of -583C/T, and reduced serum VEGF concentrations were associated with increased risk of RSM.

Anti-annexin V IgM and IgG autoantibodies and the risk of idiopathic recurrent spontaneous miscarriage

Anti-annexin V antibodies have been identified as risk factors for recurrent spontaneous miscarriage (RSM) in some, but not all previous studies. We investigated the association between anti-annexin IgM and IgG in RSM cases and control women. Blood samples from 244 women with idiopathic RSM, and 283 multi-parous control women were tested for anti-annexin V antibodies by ELISA. A significant elevation in anti-annexin V IgM and IgG was seen in the RSM cases. An increased prevalence of elevated anti-annexin V IgM and to a lesser extent anti-annexin V IgG was seen in RSM patients. Receiver operating characteristic analysis indicated that the area under the curve for anti-annexin V IgM was 0.916, and for anti-annexin V IgG was 0.725. A systematic shift in anti-annexin V IgM and IgG distributions toward higher values occurred in RSM women, which was confirmed by percentile analysis. For each of the anti-annexin V isotypes, the adjusted odds ratio increased as the percentile value increased; the strongest risk was for anti-annexin V IgM, in which the 99th percentile (P99) was associated with a 165-fold higher risk than P50, and for anti-annexin V IgG where P99 was associated with a 38-fold higher risk than P50. In addition, a higher prevalence of elevated anti-annexin V IgM and anti-annexin V IgG was seen in RSM cases than in control women. We conclude that anti-annexin V IgM and IgG antibody positivity are independent risk factors for RSM.

Analysis of interleukin-18 promoter polymorphisms and changes in interleukin-18 serum levels underscores the involvement of interleukin-18 in recurrent spontaneous miscarriage

OBJECTIVE To evaluate the association of interleukin-18 (IL-18) promoter single-nucleotide polymorphisms rs1946519 (-656C/A), rs187238 (-137G/C), rs360718 (-119A/C), and rs360717 (-105G/A) and changes in IL-18 serum levels with recurrent spontaneous miscarriage (RSM). DESIGN Case-control study. SETTING Outpatient obstetrics and gynecology clinics. PATIENT(S) Women with confirmed RSM (n = 282), and 283 age- and ethnically matched controls. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) IL-18 genotyping was accomplished by allelic discrimination assays; serum IL-18 levels were measured by ELISA. RESULT(S) The minor allele frequencies of rs360717 and rs1946519, but not rs360718 or rs187238, were higher in patients with RSM. Significant differences in the distribution of the rs360717 and rs1946519 genotypes were noted between patients and controls, and both rs360717 and rs1946519 IL-18 single-nucleotide polymorphisms showed significant association with RSM under additive, dominant, and recessive models. Lower serum IL-18 levels were seen between patients and controls and were more pronounced in rs360717 and rs1946519 heterozygous and homozygous genotypes. Four-locus (rs1946519/rs187238/rs360718/rs360717) IL-18 haplotype analysis identified that the AGAA (Pc<.001), CGAA (Pc<.001), and ACAG (Pc=.018) haplotypes were associated with a reduction in IL-18 secretion and with increased RSM risk, after adjustments for body mass index, menarche, and gravida. CONCLUSION(S) These results demonstrated that reduced IL-18 levels and rs360717 and rs1946519 IL-18 variants are significantly associated with RSM.

Genetic variations in the interleukin-21 gene and the risk of recurrent idiopathic spontaneous miscarriage

OBJECTIVES Insofar as recurrent spontaneous miscarriage (RSM) is linked with dysregulated immunity and inflammatory changes, and given the pro-inflammatory role of interleukin-21 (IL-21), we examined the association between IL-21 polymorphisms and RSM. METHODS AND RESULTS IL-21 rs2055979, rs13143866, rs9992580, and rs4833837 were genotyped in 235 cases of RSM and 235 controls. Regression analysis was employed in assessing the contribution of IL-21 variants to the overall RSM risk. Higher minor allele and genotype frequencies of rs2055979 and rs13143866, but not rs9992580 or rs4833837, were seen in RSM patients than in the controls. IL-21 haplotype [rs9992580/rs4833837/rs2055979/rs13143866] analysis revealed a lower frequency of the TGCG haplotype, and a higher frequency of the GGCG and GAAA haplotypes in patients, thus conferring protection from or a susceptibility to RSM by these haplotypes respectively. Regression analysis confirmed the association of TGCG [OR (95%CI)=0.09 (0.05-0.16)], and GGCG [OR (95%CI)=2.52 (1.34-4.54)] and GAAA [OR (95%CI)=4.02 (2.20-7.70)] haplotypes, after adjusting for age and BMI. CONCLUSIONS Our findings indicate that IL-21 is a novel susceptibility gene for RSM.