UGT1A1
            promoter polymorphism associated with serum bilirubin level in Saudi patients with sickle cell disease

Abstract The chronic hemolysis of sickle cell anemia (SCA) produces hyperbilirubinemia but serum bilirubin level varies considerably and the modulating factors have not been fully elucidated. One identified genetic factor is the uridine diphosphate glucuronosyl transferase 1A (UGT1A) gene promoter polymorphism in which homozygosity for the (AT)7 allele has been associated with increased bilirubin levels in children with SCA. The same association has been reported in apparently healthy individuals, in β-thalassemia, G6PD deficiency, neonatal jaundice and hereditary spherocytosis. In the present study, in addition to UGT1A promoter genotype, serum bilirubin level was related to other genetic modifiers - βS-globin gene haplotype, Hb F, co-inherited α-thal trait, age and gender. The patients were randomly selected from the sickle cell clinic, Medical College of Georgia. UGT1A promoter genotypes were determined using automated sequencing and spreadex gel electrophoresis. Other investigations were with standard techniques. There were 67 SCA patients (41 males, 26 females), aged 2 to 44 years (mean of 20.6±10.7). Ten (14.9%) patients were homozygous for the (AT)6 UGT1A allele, 22 (32.8%) were homozygous for the (AT)7, while 35 (52.2%) were heterozygous for the two. Serum bilirubin was significantly higher in the homozygous (AT)7 group (3.7±1.5, 5.6±2.4 and 3.8±2.3 mg/dl respectively). It was also significantly higher in males than females (4.9±2.7 vs 3.7±1.7 mg/dl) and highest in patients aged >10 years. Co-inherited α-thal trait did not significantly affect the levels. There was a significant negative linear correlation (r = −0.304, p=0.016) of serum bilirubin with Hb F. Hb F was also significantly higher among females than males and when the different age groups were compared, it was highest in those <10 years old. Apart from UGT1A (AT)7 homozygosity, Hb F significantly influences serum bilirubin level in steady-state SCA. This is probably mediated via its hemolysis-sparing effect. Our (AT)7 homozygotes, including both children and adults, had significantly higher mean serum bilirubin level as previously reported by others. Indeed, when only the adults were analyzed, there was a distinct trimodal distribution among the 6/6, 6/7 and 7/7 UGT1A genotypes with serum bilirubin levels of 3.9 ± 0.9, 4.9 ± 2.2 and 5.8 ± 2.5 mg/dl respectively. Among children (<10 years), this trimodal distribution is lost, which supports the premise that a high Hb F is probably more important in modulating serum bilirubin levels in this age group. Serum Bilirubin and Other Parameters Grouped According to UGT1A1 Genotype UGT1A1 Genotype Age (yrs) Hb (g/dl) Retics (%) Hb F (%) Bilirubin (mg/dl) 6/6 (n=10) 18.1±8.7 7.9±1.2 11.3±4.7 8.4±6.4 3.7±1.5 6/7 (n=35) 17.9±10.9 8.7±1.3 11.4±4.2 10.9±8.6 3.8±2.3 7/7 (n=22) 26.1±9.3 8.3±2.1 10.9±4.8 6.6±5.4 5.6±2.4

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Genetic diversity of CD14, CD28, CTLA-4 and ICOS gene promoter polymorphism in African and American sickle cell disease

Human Immunology ◽

10.1016/j.humimm.2019.08.005 ◽

2019 ◽

Vol 80 (11) ◽

pp. 930-936

Author(s):

Brooke N. Seamans ◽

Summer L. Pellechio ◽

Anna L. Capria ◽

Smith E. Agyingi ◽

Olanrewaju B. Morenikeji ◽

...

Keyword(s):

Genetic Diversity ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Gene Promoter ◽

Promoter Polymorphism ◽

Cell Disease ◽

Gene Promoter Polymorphism

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Renal Involvement in Saudi Patients with Sickle Cell Disease. A Single Institution Experience.

Blood ◽

10.1182/blood.v104.11.3734.3734 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3734-3734

Author(s):

Hikmat N. Abdel-Razeq ◽

Ali Bajouda ◽

Manar Khalil ◽

Muneera Al-Shareef ◽

Nauman Siddiqi

Keyword(s):

Sickle Cell Disease ◽

Serum Creatinine ◽

Sickle Cell ◽

Urine Analysis ◽

Renal Involvement ◽

Urine Volume ◽

Cell Disease ◽

Study Results ◽

Renal Tubular ◽

Saudi Patients

Abstract Background: Renal involvement in patients with sickle cell disease has been reported to be as high as 20%. This can take the form of proteinuria, decreased GFR, isothenuria or hematuria. Our own clinical observation of patients attending our sickle cell clinic or admitted to the medical ward at our institution suggests lower rates of renal involvement than previously reported. In this report, we evaluate Saudi patients with sickle cell disease (SS) at our institution for renal involvement. Patients and Methods: Consecutive afebrile patients attending sickle cell clinic or admitted to inpatient wards were screened. Serum creatinine, urine analysis and 24 hr urine collection for creatinine clearance (GFR) and proteinuria were performed. Data on demographics and co-morbidities (DM, HTN, hepatitis B and C) and medications were obtained. Analysis was performed using SPSS 10.0®. Results: 62 patients were available for study; results are summarized in tables. Seven of 48 patients (15%) had proteinuria >300mg/d while two (4.2%) had proteinuria of more than 1.0 gram/24 hrs. Nearly 20% had GFR < 60ml/min. None of the patients had renal tubular acidosis. Serum creatinine was normal in all patients including those with low GFR and proteinuria. Conclusions: Contrary to our initial believes, significant percentage of Saudi sickle cell patients, like others, have renal involvement with low GFR and proteinuria. Serum Creatinine alone doesn’t indicate this decline in renal function. We recommend annual evaluation for proteinuria and GFR determination in all sickle cell patients, and those at risk should be aggressively managed with nephroprotective agents like angiotensin converting enzyme (ACE) inhibitors. Age (yrs) M:F BMI Hepatitis C Hydroxyurea NSAID 22.1+/−8.1 23:39 19.3+/−5.1 9 (17.3%) 29 (58%) 33 (66%) Urine Volume (ml/24 hrs) Specific Gravity Serum Creatinine (u mol/L) GFR Proteinuria (mg/24hrs) 1927 +/− 780 1.011 +/− 0.005 40.6 +/− 12.9 113.7 +/− 47.7 256 +/− 371 (20–2390)

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Interethnic diversity of the CD209 (rs4804803) gene promoter polymorphism in African but not American sickle cell disease

PeerJ ◽

10.7717/peerj.799 ◽

2015 ◽

Vol 3 ◽

pp. e799 ◽

Cited By ~ 10

Author(s):

Jenelle A. Noble ◽

Kimberley C. Duru ◽

Aldiouma Guindo ◽

Li Yi ◽

Ikhide G. Imumorin ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Gene Promoter ◽

Promoter Polymorphism ◽

Cell Disease ◽

Gene Promoter Polymorphism

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IMPACT OF MANNOSE-BINDING PROTEIN GENE POLYMORPHISMS IN OMANI SICKLE CELL DISEASE PATIENTS

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2016.013 ◽

2016 ◽

Vol 8 ◽

pp. 2016013 ◽

Cited By ~ 2

Author(s):

Mathew Zachariah ◽

Anil Pathare

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Promoter Region ◽

Binding Protein ◽

Gene Mutations ◽

Promoter Polymorphism ◽

Cell Disease ◽

Heterozygous Genotype ◽

Mannose Binding Protein ◽

Mannose Binding

Objectives: Our objective was to study mannose binding protein (MBP) polymorphisms in exonic and promoter region and correlate associated infections and vasoocculsive (VOC) episodes, since MBP plays an important role in innate immunity by activating the complement system.Methods: We studied the genetic polymorphisms in the Exon 1 (alleles A/O) and promoter region (alleles Y/X; H/L, P/Q) of the MBL2 gene, in sickle cell disease (SCD) patients as increased incidence of infections is seen in these patients. A PCR-based, targeted genomic DNA sequencing of MBL2 was used to study 68 SCD Omani patients and 44 controls (voluntary blood donors).Results: The observed frequencies of MBL2 promoter polymorphism (-221, Y/X) were 44.4% and 20.5% for the heterozygous genotype Y/X and 3.2% and 2.2% for the homozygous (X/X) respectively between SCD patients and controls. MBL2 Exon1 gene mutations were 29.4% and 50% for the heterozygous genotype A/O and 5.9% and 6.8% respectively for the homozygous (O/O) genotype between SCD patients and controls. The distribution of variant MBL2 polymorphisms did not show any correlation in SCD patients with or without vasoocculsive crisis (VOC) attacks (p=0.162; OR-0.486; CI=0.177 -1.33), however, it was correlated with infections (p=0.0162; OR-3.55; CI 1.25-10.04).Conclusions: Although the frequency of the genotypes and haplotypes of MBL2 in SCD patients did not differ from controls, overall in the SCD patient cohort the increased representation of variant alleles was significantly correlated with infections (p<0.05). However, these variant MBL2 polymorphisms did not seem to play a significant role in the VOC episodes in this SCD cohort.Keywords: Mannose-binding lectin, polymorphism, promoter, Sickle cell disease, MBL2, MBP

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The Role of Pro-Inflammatory Cytokines in Sickle Cell Disease Saudi Patients

Bioscience Biotechnology Research Communications ◽

10.21786/bbrc/14.3.15 ◽

2021 ◽

Vol 14 (3) ◽

pp. 1002-1007

Author(s):

Nesrin. I. Tarbiah

Keyword(s):

Sickle Cell Disease ◽

Inflammatory Cytokines ◽

Sickle Cell ◽

Cell Disease ◽

Saudi Patients ◽

Pro Inflammatory Cytokines

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The Interaction of UGT1A, HO1 and α-Thalassemia Variants with Bilirubin Levels and Gallstones in Sickle Cell Disease.

Blood ◽

10.1182/blood.v108.11.1202.1202 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1202-1202

Author(s):

Nisha Vasavda ◽

Stephan Menzel ◽

Sheila Kondaveeti ◽

Emma Maytham ◽

Moji Awogbade ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Genetic Variants ◽

Serum Bilirubin ◽

Repeat Length ◽

Major Influence ◽

Cell Disease ◽

First Time ◽

The Relationship ◽

Rate Limiting

Abstract Chronic hyperbilirubinemia is common in patients with sickle cell disease (SCD), frequently resulting in the formation of gallstones. This hyperbilirubinemia (predominantly unconjugated) is attributed to hemolysis that exceeds the conjugating capacity of the hepatic UDP-glucuronosyltransferase (UGT1A) enzyme. Previous studies have shown that genetic variants ([TA]n repeats) in the promoter region of the UGT1A gene have a major influence on the levels of bilirubin and gallstones. Alpha-thalassemia, which is associated with reduced hemolysis, has also been shown to affect bilirubin levels. Another potential modulating factor is heme-oxygenase, a rate-limiting enzyme in the heme catabolic pathway that results in the production of bilirubin. While the severity of jaundice and cholelithiasis in patients with SCD is predisposed by the inheritance of certain variants of the UGT1A gene, inconsistencies have been observed. We propose that some of these inconsistencies may be explained by the modulating effects of genetic variants of HO1 and α-thalassemia. A total of 263 patients with SCD attending specialist clinics in two hospitals were studied: King’s 116 SS, 5 Sβ0 and 59 SC; St Thomas’ 83 SS. 81 ethnically matched subjects were recruited as controls (HbAA). Groups were age and sex matched. Cholelithiasis data, ascertained by liver ultrasound, was available for a subset of SCD patients (76 SS, 4 SC). Samples were genotyped for variants of UGT1A, HO1 and α-thalassemia. The different genetic allele distributions were statistically similar between groups. Data was analysed according to the sum of [TA] repeats on both alleles of UGT1A. A range of 10–15 [TA] repeats was observed. For HO1, the median sum of repeats on both alleles was 63, so samples were grouped as <63 or ≥ 63. α-thalassemia genotypes were as follows: SS, 127 αα/αα, 55 αα/α-, 11 α-/α-; SC, 37 αα/αα, 20 αα/α-; controls 51 αα/αα, 22 αα/α-, 4 α-/α-. Median bilirubin levels varied as expected between groups according to β-globin genotype and were as follows: King’s SS 42 (15–269.5); St Thomas’ SS 52.5 (15.5–696.5); King’s SC 22 (10–81.8); AA Controls 10 (5–24), median (range) mmol/L. Regression analysis showed that serum bilirubin levels were strongly associated with UGT1A repeat length in all subjects (p<0.0001). Furthermore, the increase in serum bilirubin (21.3% mean for SS/Sβ0, 20.5% for SC) and cholelithiasis risk odds (86.5% mean for SS/Sβ0, 67.6% for SC) could be quantified per [TA] repeat. HO1 genotype did not affect serum bilirubin in SCD patients or the control cohort. The presence of α- thalassemia correlated (negatively) with serum bilirubin in SCD patients (p<0.0001) but not controls. This is the first time the relationship between UGT1A [TA] repeat length, serum bilirubin and cholelithiasis has been shown quantitatively. Additionally, co-existing α-thalassemia appears to moderate bilirubin levels but HO1 variants do not.

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Sonographic Assessment of Spleen Size in Saudi Patients with Sickle Cell Disease

Annals of Saudi Medicine ◽

10.5144/0256-4947.1998.217 ◽

1998 ◽

Vol 18 (3) ◽

pp. 217-220 ◽

Cited By ~ 9

Author(s):

Ahmed H. Al-Salem ◽

Soror Al-Aithan ◽

Prabhakar Bhamidipati ◽

Ali Al Jam'a ◽

Ibrahim Al Dabbous

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Spleen Size ◽

Cell Disease ◽

Sonographic Assessment ◽

Saudi Patients

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Heme oxygenase-1 gene promoter polymorphism is associated with reduced incidence of acute chest syndrome among children with sickle cell disease

Blood ◽

10.1182/blood-2011-06-361642 ◽

2012 ◽

Vol 120 (18) ◽

pp. 3822-3828 ◽

Cited By ~ 53

Author(s):

Christopher J. Bean ◽

Sheree L. Boulet ◽

Dorothy Ellingsen ◽

Meredith E. Pyle ◽

Emily A. Barron-Casella ◽

...

Keyword(s):

Sickle Cell Disease ◽

Heme Oxygenase ◽

Sickle Cell ◽

Globin Gene ◽

Fetal Hemoglobin ◽

Promoter Polymorphism ◽

Adverse Outcomes ◽

Acute Chest Syndrome ◽

Heme Oxygenase 1 ◽

Cell Disease

Abstract Sickle cell disease is a common hemolytic disorder with a broad range of complications, including vaso-occlusive episodes, acute chest syndrome (ACS), pain, and stroke. Heme oxygenase-1 (gene HMOX1; protein HO-1) is the inducible, rate-limiting enzyme in the catabolism of heme and might attenuate the severity of outcomes from vaso-occlusive and hemolytic crises. A (GT)n dinucleotide repeat located in the promoter region of the HMOX1 gene is highly polymorphic, with long repeat lengths linked to decreased activity and inducibility. We examined this polymorphism to test the hypothesis that short alleles are associated with a decreased risk of adverse outcomes (hospitalization for pain or ACS) among a cohort of 942 children with sickle cell disease. Allele lengths varied from 13 to 45 repeats and showed a trimodal distribution. Compared with children with longer allele lengths, children with 2 shorter alleles (4%; ≤ 25 repeats) had lower rates of hospitalization for ACS (incidence rate ratio 0.28, 95% confidence interval, 0.10-0.81), after adjusting for sex, age, asthma, percentage of fetal hemoglobin, and α-globin gene deletion. No relationship was identified between allele lengths and pain rate. We provide evidence that genetic variation in HMOX1 is associated with decreased rates of hospitalization for ACS, but not pain. This study is registered at www.clinicaltrials.gov as #NCT00072761.

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