Khadija Al-Ola

The relation of C-reactive protein to vasoocclusive crisis in children with sickle cell disease

In view of evidence linking sickle cell anemia (SCA) with chronic inflammation, and given the role of high sensitivity C-reactive protein (hs-CRP) as inflammatory mediator, we hypothesized that SCA vasoocclusive crisis (VOC) is associated with heightened hs-CRP levels. Study subjects comprised 104 SCA patients who experienced VOC event during the study period (VOC group), and 40 SCA patients who did not develop VOC for at least 9 months prior to blood collection (Steady-state group). hs-CRP determination was done by latex-enhanced nephelometry. Higher hs-CRP levels were seen in VOC [median(range)=31.3(1.14-363.0)] than steady-state [median(range)=5(0.16-185.0)] groups (P<0.001), with enrichment in high hs-CRP percentiles in VOC cases, which translated into step-wise increased VOC risk. Receiver-operating characteristic (ROC) analysis was employed in assessing the usefulness of hs-CRP as predictor of the frequency and severity of VOC. Spearmans correlation coefficient between hs-CRP and VOC was 0.65 (P<0.001) among unselected patients (0.71 in males and 0.59 in females). hs-CRP area under ROC curves was 0.90 (95% CI=0.85-0.94) among unselected patients, 0.94 (95% CI=0.89-0.98) for males, and 0.85 (95% CI=0.77-0.93) for females. Logistic regression analysis confirmed the positive association of increased hs-CRP levels with VOC, which correlated positively with VOC frequency (P<0.001), type (P<0.001), pain (P<0.001), and need for hospitalization (P=0.024). These data support strong association of increased hs-CRP levels with VOC, which impacts VOC-related parameters, and support a role for hs-CRP in VOC follow-up.

Depression, anxiety, and stress comorbidities in sickle cell anemia patients with vaso-occlusive crisis.

We investigated the association of sickle cell anemia (SCA) vaso-occlusive crisis (VOC) with depression, anxiety, and stress disorders among Bahraini patients and controls. This was a cross-sectional study that involved administering Depression Anxiety Stress Scales (DASS-21) consisting of structured depression, anxiety, and stress scales to SCA patients with (n=138) and without (n=105) VOC. Multinomial regression and correlation analysis were used in assessing the association of VOC with depression and/or anxiety and/or stress, after adjusting for other covariates. Significantly higher proportion of VOC patients was found among the severe-extremely severe anxiety (P<0.002) and stress (P=0.001) groups; the frequency of depressed patients was comparable between the 2 groups. Adjusting for age, sex, income, number of affected individuals per family, and HbS levels, mild-moderate (P=0.042; odds ratio=2.00; 95% confidence interval=1.03-3.91) and severe-extremely severe (P=0.004; odds ratio=4.43; 95% confidence interval=1.59-12.34) anxiety were independently associated with VOC. Both depression and stress were not associated with VOC after adjusting for these covariates. These results suggest a positive contribution of VOC to the increased rates of anxiety disorders among SCA patients, thereby recommending counseling SCA patients with repeated VOC for these psychologic comorbidities, in particular anxiety.

Human platelet alloantigens (HPA) 1, HPA2, HPA3, HPA4, and HPA5 polymorphisms in sickle cell anemia patients with vaso-occlusive crisis

Objectives:  Vaso‐occlusive crisis (VOC) is a significant cause of morbidity and mortality in sickle cell anemia (SCA) patients. Insofar as polymorphism in human platelet alloantigen (HPA) exhibit a prothrombotic nature, we hypothesized that specific HPA polymorphic variants are associated with VOC. We investigated the distribution of HPA1, HPA2, HPA3, HPA4, and HPA5 alleles genotypes among VOC and non‐VOC control SCA patients.

Evidence for HLA class II susceptible and protective haplotypes for osteomyelitis in pediatric patients with sickle cell anemia

We investigated the association of human leukocyte antigen (HLA) class II alleles and haplotypes with the pathogenesis of sickle cell anemia (SCA) osteomyelitis. SCA patients comprised 42 patients with osteomyelitis and 150 patients without osteomyelitis; HLA-DRB1* and HLA-DQB1* genotyping was performed by polymerase chain reaction-sequence-specific priming (SSP). DRB1*100101 (P value corrected for the number of different alleles tested, Pc=0.003) was positively associated with osteomyelitis. At the haplotype level, DRB1*100101-DQB1*050101 (Pc=0.001) was more prevalent among patients, while DRB1*030101-DQB1*0201 (Pc=0.020) and DRB1*040101-DQB1*0302 (Pc=0.039) were more prevalent among SCA controls, thereby conferring disease susceptibility or protection to these haplotypes, respectively. These results show that specific HLA haplotypes influence SCA osteomyelitis risk and that specific HLA types may serve as markers for identifying SCA patients at high risk for osteomyelitis.

Modulation of Type 1 Diabetes Susceptibility by Tumor Necrosis Factor Alpha −308 G/A and Lymphotoxin Alpha +249 A/G Haplotypes and Lack of Linkage Disequilibrium with Predisposing DQB1-DRB1 Haplotypes in Bahraini Patients

ABSTRACT Tumor necrosis factor alpha (TNF-α) −308 G/A and lymphotoxin alpha (LTα) +249 A/G single-nucleotide polymorphisms were investigated in 228 type 1 diabetes mellitus (T1DM) patients and 240 controls. Only LTα +249G allele and +249G/+249G genotype frequencies were higher among patients, and no linkage disequilibrium was found between TNF-α/LTα alleles and susceptible/protective DRB1-DQB1 haplotypes. TNF-α/LTα T1DM-susceptible (−308G/+249G) and protective (−308G/+249A) haplotypes were identified.

HLA DRB1*130101-DQB1*060101 haplotype is associated with acute chest syndrome in sickle cell anemia patients.

We investigated the association of human leukocyte antigens (HLA) class II alleles and haplotypes with the pathogenesis of acute chest syndrome (ACS) in 186 sickle cell anemia (SCA) patients, of whom 58 had documented ACS (new pulmonary infiltrate, fever, and other associated clinical events) and 128 with a negative history of ACS, serving as controls. HLA DRB1* and -DQB1* genotyping was performed by polymerase chain reaction-sequence-specific priming. Of the DRB1* and DQB1* alleles analyzed, only DRB1*130101 (Pc < 0.001) was positively associated with ACS. DRB1*130101-DQB1*060101 haplotype was more prevalent among ACS patients (P = 0.018), thus conferring disease susceptibility. Specific HLA alleles and haplotypes may influence ACS risk in SCA patients, and specific HLA genotypes may be useful markers for identifying high-risk SCA ACS patients.

Protein Z polymorphisms associated with vaso-occlusive crisis in young sickle cell disease patients

We investigated the association of protein Z (PZ) promoter (rs3024718, rs3024719, and rs3024731) and intron (rs3024735; G79A) SNPs with sickle cell disease (SCD) vaso-occlusive crisis (VOC). Study subjects included 239 SCD patients with VOC and 138 pain-free SCD control patients. PZ genotyping was done by allelic discrimination (real-time PCR) assays. The minor allele frequency of rs3024718 (P = 0.03), rs3024719 (P = 0.02), rs3024731 (P < 0.001), and rs3024735 (P < 0.001) were higher in VOC patients than control SCD patients. Significant differences in the distribution of rs3024731 (P = 0.028) and rs3024735 (P = 0.045) genotypes were seen between VOC and steady-state SCD patients. This association remained significant after adjusting for gender, HbS, and HbF. Four-locus (rs3024718/rs3024719/rs3024731/rs3024735) PZ haplotypes analysis demonstrated increased frequency of GAAA (P = 0.024), AGAA (P = 0.011), and GGTG (P = 0.002), and reduced frequency of AGTG haplotype (P = 0.001) in VOC than in steady-state control patients, thereby conferring disease susceptibility and protective nature to these haplotypes, respectively. Of these, only AGTG (Pc = 0.001) and GGTG (Pc = 0.018) remained significant after applying the Bonferroni correction. In conclusion, specific PZ variants and haplotypes are significantly associated with SCD VOC.

Anti-annexin V IgG and IgM antibodies in sickle cell disease patients with vaso-occlusive crisis.

Vaso-occlusive crisis (VOC) is a significant cause of morbidity and mortality in sickle cell anemia (SCA) patients; however, its mechanisms are poorly understood. In view of their prothrombotic nature, we hypothesized that SCA-associated VOC may be due to the presence of anti-annexin V antibodies. Anti-annexin V antibodies were measured with ELISA in 177 VOC and 81 steady-state SCA patients. Anti-annexin V IgM and IgG concentrations were significantly higher in VOC patients than in steady-state patients and were associated with elevated VOC risk. After categorizing anti-annexin V antibodies, the adjusted odds ratio increased as the percentile value increased. Monovariate logistic regression analysis demonstrated a positive dose–effect relationship for anti-annexin V IgM with VOC, with increased VOC risk seen with increased antibody titers. Multivariate logistic regression analyses confirmed the association of anti-annexin V IgM, more so than IgG, as an independent VOC risk factor. Anti-annexin V IgG antibodies correlated positively with VOC type and negatively with HbF and age of VOC onset, while anti-annexin V IgM correlated positively with VOC type, duration, frequency, site, pain severity, hospitalization, and medication, and negatively with age of VOC onset and HbS levels. High levels of anti-annexin V IgM antibodies constitute a risk factor for VOC in SCA patients.

HLA Class II Haplotypes Distinctly Associated with Vaso-Occlusion in Children with Sickle Cell Disease

ABSTRACT We investigated the association of HLA class II alleles and haplotypes with sickle cell anemia vaso-occlusive crisis (VOC). DRB1*100101 was positively associated, while DRB1*140101, DRB1*150101, and DQB1*060101 were negatively associated, with VOC. Both susceptible (DRB1*100101-DQB1*050101) and protective (DRB1*110101-DQB1*030101 and DRB1*150101-DQB1*060101) haplotypes were identified, indicating that HLA class II haplotypes influence VOC risk.