RESUMO
BACKGROUND: Sickle cell disease (SCD) is a Mendelian disease characterized by multigenic phenotypes. Previous reports indicated a higher rate of thromboembolic events (TEEs) in SCD patients. A number of candidate polymorphisms in certain genes (e.g., FVL, PRT, and MTHFR) were previously reported as risk factors for TEEs in different clinical conditions. This study aimed to genotype these genes and other loci predicted to underlie TEEs in SCD patients. METHODOLOGY: A multi-center genome-wide association study (GWAS) involving Saudi SCD adult patients with a history of TEEs (n = 65) and control patients without TEE history (n = 285) was performed. Genotyping used the 10× Affymetrix Axiom array, which includes 683,030 markers. Fisher's exact test was used to generate p-values of TEE associations with each single-nucleotide polymorphism (SNP). The haplotype analysis software tool version 1.05, designed by the University of Göttingen, Germany, was used to identify the common inherited haplotypes. RESULTS: No association was identified between the targeted single-nucleotide polymorphism rs1801133 in MTHFR and TEEs in SCD (p = 0.79). The allele frequency of rs6025 in FVL and rs1799963 in PRT in our cohort was extremely low (<0.01); thus, both variants were excluded from the analysis as no meaningful comparison was possible. In contrast, the GWAS analysis showed novel genome-wide associations (p < 5 × 10-8) with seven signals; five of them were located on Chr 11 (rs35390334, rs331532, rs317777, rs147062602, and rs372091), one SNP on Chr 20 (rs139341092), and another on Chr 9 (rs76076035). The other 34 SNPs located on known genes were also detected at a signal threshold of p < 5 × 10-6. Seven of the identified variants are located in olfactory receptor family 51 genes (OR51B5, OR51V1, OR51A1P, and OR51E2), and five variants were related to family 52 genes (OR52A5, OR52K1, OR52K2, and OR52T1P). The previously reported association between rs5006884-A in OR51B5 and fetal hemoglobin (HbF) levels was confirmed in our study, which showed significantly lower levels of HbF (p = 0.002) and less allele frequency (p = 0.003) in the TEE cases than in the controls. The assessment of the haplotype inheritance pattern involved the top ten significant markers with no LD (rs353988334, rs317777, rs14788626882, rs49188823, rs139349992, rs76076035, rs73395847, rs1368823, rs8888834548, and rs1455957). A haplotype analysis revealed significant associations between two haplotypes (a risk, TT-AA-del-AA-ins-CT-TT-CC-CC-AA, and a reverse protective, CC-GG-ins-GG-del-TT-CC-TT-GG-GG) and TEEs in SCD (p = 0.024, OR = 6.16, CI = 1.34-28.24, and p = 0.019, OR = 0.33, CI = 0.13-0.85, respectively). CONCLUSIONS: Seven markers showed novel genome-wide associations; two of them were exonic variants (rs317777 in OLFM5P and rs147062602 in OR51B5), and less significant associations (p < 5 × 10-6) were identified for 34 other variants in known genes with TEEs in SCD. Moreover, two 10-SNP common haplotypes were determined with contradictory effects. Further replication of these findings is needed.
Assuntos
Anemia Falciforme , Receptores Odorantes , Adulto , Humanos , Estudo de Associação Genômica Ampla , Genótipo , Anemia Falciforme/complicações , Anemia Falciforme/genética , Haplótipos , Polimorfismo de Nucleotídeo Único , Proteínas de Neoplasias/genética , Receptores Odorantes/genéticaRESUMO
Sickle cell anemia (SCA) is one of the commonly inherited hemoglobinopathies in the Kingdom of Saudi Arabia. It is characterized by periods of remissions and exacerbations called crises as well as certain pathological phenomenon such as acute chest syndrome, priapism, hepatopathy, and cerebrovascular stroke. Blood transfusion (BT) as therapy and prophylaxis in SCA, although was advocated as early as the 1940's, there are still debates regarding its benefits and risks. This is a review of the value of BT in patients with SCA with emphasis on the risks and benefits as well as guidelines towards safe BT.
Assuntos
Anemia Falciforme/terapia , Transfusão de Sangue , Humanos , Medição de RiscoRESUMO
Thalassemia major is a hereditary disorder of hemoglobin synthesis resulting in severe anemia. Treatment consists of multiple blood transfusions, a complication of which is iron overload. Excessive iron is then deposited in almost all tissues but primarily in the liver, heart and the endocrine glands. Lately, desferrioxamine has been used as a chelating agent in an attempt to prevent the complications of tissue damage by iron deposition. Early introduction of the chelating agent to combat iron overload in vulnerable organs leads to improved life expectancy. However, these patients often present with multiple endocrine dysfunction such as growth failure, hypogonadism, abnormalities in glucose metabolism, hypothyroidism, hypoparathyroidism and less frequently hypoadrenalism. We briefly review the current status of endocrine gland abnormalities in patients with thalassemia major.
Assuntos
Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/epidemiologia , Talassemia beta/diagnóstico , Talassemia beta/epidemiologia , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/epidemiologia , Glicemia/metabolismo , Comorbidade , Feminino , Humanos , Hipogonadismo/diagnóstico , Hipogonadismo/epidemiologia , Hipoparatireoidismo/diagnóstico , Hipoparatireoidismo/epidemiologia , Hipotireoidismo/diagnóstico , Hipotireoidismo/epidemiologia , Masculino , Prevalência , Prognóstico , Medição de Risco , Arábia Saudita/epidemiologia , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: Patients with sickle cell disease (SCD) often present with abdominal pain, usually attributed to vaso-occlusive crisis, but not rarely, it may be caused by other surgical conditions. Acute appendicitis although common in patients with SCD, it is rare and has a rapid course with a high incidence of perforation. METHODS: Over a period of 7 years from 1995 to 2001, only 8 patients with SCD out of 1563 (0.5%) patients with acute appendicitis underwent operation at Qatif Central Hospital, Qatif, Kingdom of Saudi Arabia. Their histological slides were reviewed and the findings were compared to those with sickle cell trait (9 patients) and control group (28 patients). RESULTS: All patients with SCD and in spite of a short duration of symptoms had a moderate to severe inflammation and the vessels were packed with sickle red blood cells (RBCs) except one who had an intact mucosa, extensive transmural hemorrhage and congested blood vessels with sickled RBCs without inflammatory cell infiltrate. The mucosa was intact in only one patient with SCD when compared to 5 (55.6%) in those with sickle cell trait and 6 (21.4%) in the control group and in the majority (87.5%) of those with SCD there were moderate to severe mucosal ulcerations when compared to those with sickle cell trait (44.4%) or controls (64.3%). CONCLUSION: In patients with SCD, acute appendicitis is rare, and these appendicular changes were a sequelae of blockage of appendiceal vessels by sickled RBCs leading to congestion, edema, and ischemia with subsequent mucosal ulceration and marked inflammatory cell infiltrate.
Assuntos
Anemia Falciforme/complicações , Apendicite/complicações , Apêndice/patologia , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Doença Aguda , Apendicite/cirurgia , Apêndice/cirurgia , Humanos , Mucosa Intestinal/patologia , Arábia SauditaRESUMO
OBJECTIVE: Kukuchi-Fujimito disease is a rare, benign and self limiting condition, which usually presents with lymphadenopathy or fever of an unknown etiology, or both. Its rarity, as well as the similarity of its clinical features to other more common conditions, contribute to overlooking it in the differential diagnosis of patients presenting with lymphadenopathy or fever of an unknown etiology. METHODS: The study was carried out at Qatif Central Hospital, Qatif, Kingdom of Saudi Arabia. All lymph node excisional biopsies received in the histopathology laboratory between 1989 and 1999 were evaluated and those diagnosed as Kukuchi-Fujimito disease were reviewed for clinical data and histological findings. RESULTS: A total of 6 cases were diagnosed as Kukuchi-Fujimito disease out of 390 lymph node biopsies. All patients were young with an average age of 21.5 years and equal sex distribution. Enlarged cervical lymph nodes with or without fever were the most familiar presenting symptoms. Anemia and leukopenia were observed in 3 patients. There was no recurrence of the lymphadenopathy over a period of 1-12 years follow up. CONCLUSION: Kukuchi-Fujimito disease although rare should be included in the differential diagnosis of patients presenting with lymphadenopathy as well as fever of an unknown origin. To obviate unnecessary investigations and therapeutic trials, these patients should undergo early lymph node biopsy which must be interpreted by an experienced pathologist.
Assuntos
Linfadenite Histiocítica Necrosante/diagnóstico , Adolescente , Adulto , Diagnóstico Diferencial , Feminino , Linfadenite Histiocítica Necrosante/patologia , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Linfonodos/patologia , MasculinoRESUMO
Thalassemia syndrome has diverse clinical presentations and a global spread that has far exceeded the classical Mediterranean basin where the mutations arose. The mutations that give rise to either alpha or beta thalassemia are numerous, resulting in a wide spectrum of clinical severity ranging from carrier state to life-threatening, inherited hemolytic anemia that requires regular blood transfusion. Beta thalassemia major constitutes a remarkable challenge to health care providers. The complications arising due to the anemia, transfusional iron overload, as well as other therapy-related complications add to the complexity of this condition. To produce this consensus opinion manuscript, a PubMed search was performed to gather evidence-based original articles, review articles, as well as published work reflecting the experience of physicians and scientists in the Arabian Gulf region in an effort to standardize the management protocol.