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1.  BMI and the risk of colorectal adenoma in African Americans 
Obesity (Silver Spring, Md.)  2014;22(5):1387-1391.
Objectives
Obesity is associated with the activation of the molecular pathways that increase the risk of colorectal cancer. Increasing body mass index may accelerate the development of adenomatous polyps, the antecedent lesion of colorectal cancer. The aim of this study was to assess the BMI effect on the risk of colonic polyp and adenoma in African American.
Design and Methods
We examined the records of 923 patients who underwent colonoscopy. Demographic and clinical data were collected before colonoscopy. Polyp and adenoma diagnosis were confirmed by pathology examinations.
Results
Overall, 43% of the patients were male, median age was 57 years and 77% had BMI≥25.0 kg/m2. The frequency of colorectal polyps and adenomas were 61% and 35%, respectively. BMI≥25.0 (OR=1.61, 95%CI=1.14-2.26), smoking (OR=1.61, 95%CI=1.15-2.26) and history of colon polyps (OR=1.64, 95%CI=1.09-2.47) were associated with higher risk of colon polyp. BMI≥25.0 (OR=1.81, 95%CI=1.24-2.62), age (OR=1.04, 95%CI=1.02-2.05 for each year), male gender (OR=1.38, 95%CI=1.02-1.86), and smoking (OR=1.73, 95%CI=1.23-2.42) were associated with higher risk of colon adenoma.
Conclusion
Male and overweight African Americans are at higher risk of colorectal adenoma. The findings of this study could be applied for risk stratification and modifying the colorectal cancer prevention including screening guideline in African Americans.
doi:10.1002/oby.20702
PMCID: PMC4008675  PMID: 24519988
Obesity; Colorectal polyp; African American
2.  Genetic determinants of haemolysis in sickle cell anaemia 
British journal of haematology  2013;161(2):270-278.
Summary
Haemolytic anaemia is variable among patients with sickle cell anaemia and can be estimated by reticulocyte count, lactate dehydrogenase, aspartate aminotransferase and bilirubin levels. Using principal component analysis of these measurements we computed a haemolytic score that we used as a subphenotype in a genome-wide association study. We identified in one cohort and replicated in two additional cohorts the association of a single nucleotide polymorphism in NPRL3 (rs7203560; chr16p13·3) (P = 6·04 × 10−07). This association was validated by targeted genotyping in a fourth independent cohort. The HBA1/HBA2 regulatory elements, hypersensitive sites (HS)-33, HS-40 and HS-48 are located in introns of NPRL3. Rs7203560 was in perfect linkage disequilibrium (LD) with rs9926112 (r2 = 1) and in strong LD with rs7197554 (r2 = 0·75) and rs13336641 (r2 = 0·77); the latter is located between HS-33 and HS-40 sites and next to a CTCF binding site. The minor allele for rs7203560 was associated with the −∝3·7thalassaemia gene deletion. When adjusting for HbF and ∝ thalassaemia, the association of NPRL3 with the haemolytic score was significant (P = 0·00375) and remained significant when examining only cases without gene deletion∝ thalassaemia (P = 0·02463). Perhaps by independently down-regulating expression of the HBA1/HBA2 genes, variants of the HBA1/HBA2 gene regulatory loci, tagged by rs7203560, reduce haemolysis in sickle cell anaemia.
doi:10.1111/bjh.12245
PMCID: PMC4129543  PMID: 23406172
haemolysis; sickle cell anaemia; haemolytic anaemia; genetic analysis; thalassaemia
3.  Risk Factors for Death in 632 Patients with Sickle Cell Disease in the United States and United Kingdom 
PLoS ONE  2014;9(7):e99489.
Background
The role of pulmonary hypertension as a cause of mortality in sickle cell disease (SCD) is controversial.
Methods and Results
We evaluated the relationship between an elevated estimated pulmonary artery systolic pressure and mortality in patients with SCD. We followed patients from the walk-PHaSST screening cohort for a median of 29 months. A tricuspid regurgitation velocity (TRV)≥3.0 m/s cuttof, which has a 67–75% positive predictive value for mean pulmonary artery pressure ≥25 mm Hg was used. Among 572 subjects, 11.2% had TRV≥3.0 m/sec. Among 582 with a measured NT-proBNP, 24.1% had values ≥160 pg/mL. Of 22 deaths during follow-up, 50% had a TRV≥3.0 m/sec. At 24 months the cumulative survival was 83% with TRV≥3.0 m/sec and 98% with TRV<3.0 m/sec (p<0.0001). The hazard ratios for death were 11.1 (95% CI 4.1–30.1; p<0.0001) for TRV≥3.0 m/sec, 4.6 (1.8–11.3; p = 0.001) for NT-proBNP≥160 pg/mL, and 14.9 (5.5–39.9; p<0.0001) for both TRV≥3.0 m/sec and NT-proBNP≥160 pg/mL. Age >47 years, male gender, chronic transfusions, WHO class III–IV, increased hemolytic markers, ferritin and creatinine were also associated with increased risk of death.
Conclusions
A TRV≥3.0 m/sec occurs in approximately 10% of individuals and has the highest risk for death of any measured variable.
The study is registered in ClinicalTrials.gov with identifier
NCT00492531
doi:10.1371/journal.pone.0099489
PMCID: PMC4079316  PMID: 24988120
4.  Clinical correlates of acute pulmonary events in children and adolescents with sickle cell disease* 
Objectives
We aimed to identify risk factors for acute pulmonary events in children and adolescents in the Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH) study.
Methods
Patients with hemoglobin SS (n=376) and other sickle cell genotypes (n=127) aged 3-20 years were studied at four centers in a cross-sectional manner. A sub-group (n=293) was followed for a median of 21 months (range 9-35).
Results
A patient-reported history of one or more acute pulmonary events, either acute chest syndrome (ACS) or pneumonia, was obtained in 195 hemoglobin SS patients (52%) and 51 patients with other genotypes (40%). By logistic regression, history of acute pulmonary events was independently associated with patient-reported history of asthma (p<0.0001), older age (p=0.001), >3 severe pain episodes in the preceding 12 months (p=0.002), higher tricuspid regurgitation velocity (TRV) (p=0.028), and higher white blood cell (WBC) count (p=0.043) among hemoglobin SS patients. History of acute pulmonary events was associated with >3 severe pain episodes (p=0.009) among patients with other genotypes. During follow-up, 43 patients (15%) had at least one new ACS episode including 11 without a baseline history of acute pulmonary events. History of acute pulmonary events (odds ratio 5.4; p<0.0001) and younger age (odds ratio 0.9; p=0.010) were independently associated with developing a new episode during follow-up.
Conclusions
Asthma history, frequent pain and higher values for TRV and WBC count were independently associated with history of acute pulmonary events in hemoglobin SS patients and frequent pain was associated in those with other genotypes. Measures to reduce pain episodes and control asthma may help to decrease the incidence of acute pulmonary events in SCD.
doi:10.1111/ejh.12118
PMCID: PMC3689858  PMID: 23560516
sickle cell disease; acute chest syndrome; vaso-occlusive crisis; asthma; pain
5.  Gastric Helicobacter pylori infection associates with an increased risk of colorectal polyps in African Americans 
BMC Cancer  2014;14:296.
Background
Gastric Helicobacter pylori (H. pylori) infection and colorectal polyps are more prevalent in African Americans than in the general population. We aimed to investigate whether gastric H. pylori infection is associated with colorectal polyps in African Americans.
Methods
Medical records of African Americans, 40 years and older (n = 1256) who underwent bidirectional gastrointestinal endoscopy on the same day were reviewed. H. pylori status was assessed by immunohistochemistry on gastric specimens. Colorectal polyps were confirmed by histological examination of colorectal biopsies. A subset of serum samples from healthy and polyp-bearing patients (n = 163) were analyzed by ELISA for anti-H. pylori and anti-CagA antibodies. The crude and adjusted effect of H. pylori on the risk of colorectal adenoma and polyp were computed by logistic regression models.
Results
The prevalence of colorectal polyps and adenomas were 456 (36%) and 300 (24%) respectively. Colorectal polyps were more prevalent in gastric H. pylori infected than non-infected subjects [43% vs. 34%; Odds Ratio (OR) (95% CI): 1.5 (1.2-1.9), P = 0.001]. Patients with H. pylori-associated chronic active gastritis were at high risk to have adenomas [Unadjusted OR (95% CI): 1.3 (1.0-1.8); P = 0.04]. There was no difference in histopathology, size, or location of polyps with respect to H. pylori status. Gastric H. pylori infection, age, male gender and high risk clinical presentations were independent risk factors for colorectal polyps. Serological testing also revealed a higher prevalence of H. pylori and its toxin Cag-A in polyp patients vs. non polyp patients’ sera, although in a non-statistically significant manner.
Conclusions
This study showed that current gastric H. pylori infection is associated with an increased risk of colorectal polyps in African Americans. Patients with H. pylori induced gastritis may benefit from early screening colonoscopy as a preventative measure for colorectal cancer.
doi:10.1186/1471-2407-14-296
PMCID: PMC4022546  PMID: 24774100
African Americans; H. pylori infection; Colorectal neoplasm; Gastric lesion; Risk factors; Forty year and older
6.  An Integrative CGH, MSI and Candidate Genes Methylation Analysis of Colorectal Tumors 
PLoS ONE  2014;9(1):e82185.
Background
Different DNA aberrations processes can cause colorectal cancer (CRC). Herein, we conducted a comprehensive molecular characterization of 27 CRCs from Iranian patients.
Materials and Methods
Array CGH was performed. The MSI phenotype and the methylation status of 15 genes was established using MSP. The CGH data was compared to two established lists of 41 and 68 cancer genes, respectively, and to CGH data from African Americans. A maximum parsimony cladogram based on global aberrations was established.
Results
The number of aberrations seem to depend on the MSI status. MSI-H tumors displayed the lowest number of aberrations. MSP revealed that most markers were methylated, except RNF182 gene. P16 and MLH1 genes were primarily methylated in MSI-H tumors. Seven markers with moderate to high frequency of methylation (SYNE1, MMP2, CD109, EVL, RET, LGR and PTPRD) had very low levels of chromosomal aberrations. All chromosomes were targeted by aberrations with deletions more frequent than amplifications. The most amplified markers were CD248, ERCC6, ERGIC3, GNAS, MMP2, NF1, P2RX7, SFRS6, SLC29A1 and TBX22. Most deletions were noted for ADAM29, CHL1, CSMD3, FBXW7, GALNS, MMP2, NF1, PRKD1, SMAD4 and TP53. Aberrations targeting chromosome X were primarily amplifications in male patients and deletions in female patients. A finding similar to what we reported for African American CRC patients.
Conclusion
This first comprehensive analysis of CRC Iranian tumors reveals a high MSI rate. The MSI tumors displayed the lowest level of chromosomal aberrations but high frequency of methylation. The MSI-L were predominantly targeted with chromosomal instability in a way similar to the MSS tumors. The global chromosomal aberration profiles showed many similarities with other populations but also differences that might allow a better understanding of CRC's clinico-pathological specifics in this population.
doi:10.1371/journal.pone.0082185
PMCID: PMC3903472  PMID: 24475022
7.  Decreased serum glucose and glycosylated hemoglobin levels in patients with Chuvash polycythemia: a role for HIF in glucose metabolism 
In Chuvash polycythemia, a homozygous 598C>T mutation in the von Hippel-Lindau gene (VHL) leads to an R200W substitution in VHL protein, impaired degradation of α-subunits of hypoxia inducible factor (HIF)-1 and HIF-2, and augmented hypoxic responses during normoxia. Chronic hypoxia of high altitude is associated with decreased serum glucose and insulin concentrations. Other investigators reported that HIF-1 promotes cellular glucose uptake by increased expression of GLUT1 and increased glycolysis by increased expression of enzymes such as PDK. On the other hand, inactivation of Vhl in murine liver leads to hypoglycemia associated with a HIF-2-related decrease in the expression of the gluconeogenic enzymes genes Pepck, G6pc, and Glut2. We therefore hypothesized that glucose concentrations are decreased in individuals with Chuvash polycythemia. We found that 88 Chuvash VHLR200W homozygotes had lower random glucose and glycosylated hemoglobin A1c levels than 52 Chuvash subjects with wildtype VHL alleles. Serum metabolomics revealed higher glycerol and citrate levels in the VHLR200W homozygotes. We expanded these observations in VHLR200W homozygote mice and found that they had lower fasting glucose values and lower glucose excursions than wild-type control mice but no change in fasting insulin concentrations. Hepatic expression of Glut2 and G6pc but not Pdk2 was decreased and skeletal muscle expression of Glut1, Pdk1 and Pdk4 was increased. These results suggest that both decreased hepatic gluconeogenesis and increased skeletal uptake and glycolysis contribute to the decreased glucose concentrations. Further study is needed to determine whether pharmacologically manipulating HIF expression might be beneficial for treatment of diabetic patients.
doi:10.1007/s00109-012-0961-5
PMCID: PMC3537876  PMID: 23015148
VHL; hypoxia inducible factors; glucose; insulin; glycolysis; gluconeogenesis
8.  Sickle cell disease is associated with decreased HIV but higher HBV and HCV comorbidities in US hospital discharge records: a cross-sectional study 
Sexually transmitted infections  2012;88(7):528-533.
Objective
Some studies suggest that HIV infection progresses slowly in patients with sickle cell disease (SCD). The authors aimed to determine the relationships between SCD and HIV infection.
Methods
National Hospital Discharge Survey data from adult Africane–Americans in the period of 1997–2009 were analysed. The comorbidities of SCD with HIV infections in hospital discharges were analysed. Multiple logistic regression was used to test the association between SCD and HIV. For comparative purposes, the relationships of SCD with hepatitis B virus (HBV) and hepatitis C virus (HCV) were also assessed.
Results
423 431 records were divided into two time periods 1997–2003 (53% of records) and 2004–2009 (47% of records). The frequency of HIV diagnosis was lower in patients with SCD (1.5% vs 3.3% in patients without SCD). In logistic regression, SCD diagnosis was associated with an OR of 0.24 (95% CI 0.18 to 0.32) for HIV diagnosis in the first period and with an OR of 0.31 (95% CI 0.22 to 0.42) in the second period. In contrast, SCD was associated with higher risk of HCV (OR=2.01, 95% CI 1.56 to 2.59 in the first period and OR=2.12, 95% CI 1.71 to 2.63 in the second period). SCD was also associated with a higher risk of HBV (OR=1.15, 95% CI 0.72 to 1.83 in the first period and OR=1.82, 95% CI 1.24 to 2.68 in the second period).
Conclusions
The lower risk of HIV comorbidity, but not HCV and HBV, with SCD is consistent with the possibility that SCD has a unique effect in altering the risk of HIV infection or progression. Investigation of how the haemolytic and immunological changes of SCD influence HIV might lead to new therapeutic or preventive approaches.
doi:10.1136/sextrans-2011-050459
PMCID: PMC3456988  PMID: 22628662
9.  Helicobacter pylori Protection Against Reflux Esophagitis 
Digestive diseases and sciences  2012;57(11):2924-2928.
Background and Aim
Negative association has been reported between presence of Helicobacter pylori and developing gastroesophageal reflux disease (GERD) and its complications. The aim of this study was to determine whether H. pylori (HP) can be protective against GERD in an African American (AA) population.
Methods
From 2004 to 2007, we studied 2,020 cases; esophagitis (58), gastritis (1,558), both esophagitis and gastritis (363) and a normal control group (41). We collected their pathology and endoscopy unit reports. HP status was determined based on staining of gastric biopsy.
Results
HP data was available for 79 % (1,611) of the cases. The frequency of HP positivity in gastritis patients was 40 % (506), in esophagitis patients 4 % and in normal controls 34 % (11), while HP was positive in 34 % of the patients with both esophagitis and gastritis. After adjusting for effects of age and sex, odds ratio of HP was 0.06 (95 % CI 0.01–0.59; P value = 0.01) for the esophagitis group versus the normal group.
Conclusions
Our results show H. pylori has a significant negative association with esophagitis in AAs which may point to a protective role of H. pylori in the pathogenesis of esophagitis. In addition, H. pylori may be the reason for the low GERD complications in AAs.
doi:10.1007/s10620-012-2349-3
PMCID: PMC3673721  PMID: 23010740
H. pylori; Reflux esophagitis; African Americans
10.  Clinicopathological features colon polyps from African-Americans 
Digestive diseases and sciences  2010;55(5):1442-1449.
Background & Aims
Among the ethnic groups age standardized incidence rate of colorectal cancer (CRC) is highest among African-Americans. The majority of CRC arise from preexisting adenoma. It is shown that 30% of the US adult population has adenomas. The potential risk of malignant transformation in adenomas differs by specific pathologic and clinical characteristics that we aimed to study in AAs.
Material and Methods
All pathologic reports (150,000) in Howard University Hospital from 1959 to 2006 were reviewed manually. Those pathology reports compatible with the colorectal polyps were carefully reviewed and selected by a GI pathologist. All cases with cancer then excluded from the list. Data then were entered into excel and checked for missing data and duplications. Differences in right side and left side polyps for sex, histology, clinical symptoms were assessed by chi-2 test.
Results
A total number of 5013 colorectal polyps were diagnosed in this period that include 47% male, with mean age (SD) of 63 (12). Half of cases were diagnosed in 2001–2006. Tubular adenoma was the most frequent pathology (73%). The highest frequency of right sided polyps was observed in 1990’s (56%). Left sided polyps were younger (P<0.000), more hyperplasic (23% vs. 5%; P<0.000) and more frequent in female (56% vs. 52%; P=0.02) compared to right sided. The frequency of right sided adenoma significantly increases from 18% in 60’s to 51% in the period of 2001–2006 (P<0.000). The most frequent symptom in both sides was GI bleeding (21%).
Conclusion
There was a ratio of 9:1 for neoplastic to hyperplastic polyps in our study which is more than what has been reported in Caucasians (7:1). Our data shows a shift in polyps from the left side to the right side of the colon in recent years. This data is consistent with the lack of a reduction in the incidence of colon cancer in African Americans. Screening is thus very important in AA to reduce the incidence of colon cancer.
doi:10.1007/s10620-010-1133-5
PMCID: PMC3702046  PMID: 20225129
Colon; polyp; African American
11.  Role of life events in the presence of colon polyps among African Americans 
BMC Gastroenterology  2013;13:101.
Background
African Americans have disproportionately higher incidence and death rates of colorectal cancer among all ethnic groups in the United States. Several lifestyle factors (e.g. diet, physical activity and alcohol intake) have been suggested as risk factors for colorectal cancer. Stressful life events have also been identified as risk factors for colorectal cancer. The association between stressful life events and colon polyps, which are precursors of colorectal cancer, has yet to be determined.
We aimed to evaluate the relationship between stressful life events and the presence of colon polyps and adenomas in African American men and women.
Methods
In this cross-sectional study, 110 participants were recruited from a colon cancer screening program at Howard University Hospital. Participants completed an 82-item Life Events Questionnaire (Norbeck 1984), assessing major events that have occurred in the participants’ life within the past 12 months. Participants also reported whether the event had a positive or negative impact. Three scores were derived (total, positive, and negative).
Results
Total life events scores were higher (Median [M] = 29 and Interquartile range [IQR] = 18-43) in patients with one or more polyps compared to patients without polyps (M, IQR = 21,13-38; P = 0.029). Total, positive or negative Life Events scores did not differ significantly between normal and adenoma patients. Total, negative and positive Life Events scores did not differ between patients who underwent diagnostic colonoscopy (symptomatic) and patients who underwent colonoscopy for colon cancer screening (asymptomatic) and patients for surveillance colonoscopies due to a personal history of colon polyps. Linear regression analysis indicated that male gender is associated with 9.0 unit lower total Life Events score (P = 0.025).
Conclusion
This study suggests that patients who experienced total life events may be at higher risk of having colon polyps and adenomas which indicates an association between stress and the development of colorectal polyps.
doi:10.1186/1471-230X-13-101
PMCID: PMC3694451  PMID: 23758671
Stress; Life events; Colon adenoma; African Americans
12.  Plasma thrombospondin-1 is increased during acute sickle cell vaso-occlusive events and associated with acute chest syndrome, hydroxyurea therapy, and lower hemolytic rates 
American journal of hematology  2012;87(3):326-330.
Platelets are activated in sickle cell disease (SCD), and particularly during vaso-occlusive episodes (VOE). Thrombospondin-1 (TSP1), a major secretory product of activated platelets, is increased in the circulation in VOE and binds to sickle red blood cells (RBC) promoting vascular adhesion. Thus, we hypothesized that TSP1 may represent a plasma biomarker of disease severity in SCD. We tested the plasma collected from patients in steady state (n = 27) and VOE (n = 14), as well as healthy controls (n = 17) at the University of Pittsburgh Medical Center (UPMC), and from patients in steady state enrolled in the walk-PHaSST clinical trial (n = 483). We found that TSP1 levels were increased in VOE in the UPMC cohort. Among steady-state patients at UPMC, TSP1 values correlated positively with lifetime history of acute chest syndrome (r = 0.72, P < 0.0001) and hemoglobin concentration (r = 0.49, P = 0.01), and negatively with markers of hemolysis, such as LDH (r = −0.50, P = 0.009). Analysis of the walk-PHaSST cohort also showed a positive association between TSP1 levels and hydroxyurea use (r = 0.14, P = 0.003), and confirmed the negative associations with the severity of hemolysis. Our results suggest that TSP1 levels are associated with more VOE, hydroxyurea use and lower rates of hemolysis. High TSP1 concentrations may indicate higher risk of the viscosity/vaso-occlusion phenotype of SCD.
doi:10.1002/ajh.22274
PMCID: PMC3619659  PMID: 22318901
13.  Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia 
The Journal of Pediatrics  2011;160(2):286-290.
Objective
To identify factors associated with frequent severe vaso-occlusive pain crises in a contemporary pediatric cohort of sickle cell anemia (SCA)enrolled in a prospective study of pulmonary hypertension and the hypoxic response in sickle cell disease (SCD).
Study design
Clinical and laboratory characteristics of children with SCA who had ≥3 severe pain crises requiring health care in the preceding year were compared with subjects with <3 such episodes.
Results
Seventy-five children (20%) reported ≥3 severe pain episodes in the preceding year, and 232 (61%) had none. Frequent pain episodes were associated with older age (OR 1.2; 95% CI 1.1–1.3; P<0.0001), α-thalassemia trait (OR 3.5; 1.6–6.7; P=0.002), higher median hemoglobin (OR 1.7; 95% CI: 1.2–2.4; P<0.003) and lower lactate dehydrogenase (LDH) concentration (OR 1.82; 95% CI: 1.07–3.11; P = 0.027). Children with high pain frequency also had an increased iron burden (serum ferritin 480 vs. 198 μg/L; P=0.006) and higher median tricuspid regurgitation jet velocity (2.41 vs. 2.31 m/s; P=0.001). Neither hydroxy urea use nor fetal hemoglobin levels were significantly different according to severe pain history.
Conclusions
In our cohort of children with SCA increasing age was associated with higher frequency of severe pain episodes as were α-thalassemia, iron overload, higher hemoglobin and lower LDH concentration and higher tricuspid regurgitation velocity.
doi:10.1016/j.jpeds.2011.07.018
PMCID: PMC3258348  PMID: 21890147
Sickle cell anemia; vaso-occlusive crisis; pain
14.  Echocardiographic Markers of Elevated Pulmonary Pressure and Left Ventricular Diastolic Dysfunction are Associated with Exercise Intolerance in Adults and Adolescents with Homozygous Sickle Cell Anemia in the US and UK 
Circulation  2011;124(13):1452-1460.
Background
Non-invasively assessed pulmonary pressure elevations and left ventricular diastolic dysfunction (LVDD) are associated with increased mortality in adults with sickle cell disease (SCD), but their relationship to exercise intolerance has not been evaluated prospectively.
Methods and Results
Echocardiography, six-minute walk distance, hemolytic rate, and serum concentrations of ferritin and erythropoietin were evaluated in a cohort of 483 subjects with homozygous hemoglobin S in the US and UK Walk-PHaSST study. Tricuspid regurgitation velocity (TRV), which reflects systolic pulmonary artery pressure, was 2.7 to <3.0 m/sec (mean±SD 2.8±0.1) in 26% of the subjects and ≥3.0 m/sec (3.4±0.4) in 11%. LV lateral E/e′ ratio, which has been shown to reflect LV filling pressure in other conditions but has not been studied in SCD, was significantly higher in the groups with TRV ≥2.7 m/sec. Increased hemolysis (P<0.0001), LV lateral E/e′ ratio (P=0.0001), BUN (P=0.0002) and erythropoietin (P=0.002) were independently associated with an increased TRV. Further, female gender (P<0.0001), older age (P<0.0001), LV lateral E/e′ ratio (P=0.014), and TRV (P=0.019) were independent predictors of a shorter six-minute walk distance.
Conclusions
Echocardiography-estimated elevated pulmonary artery systolic pressure and LV lateral E/e′ ratio were independently associated with poor exercise capacity in a large cohort of patients with sickle cell anemia. Controlled trials investigating whether strategies to prevent or delay pulmonary hypertension and/or LVDD will improve exercise capacity and long-term outcomes in sickle cell anemia should be considered.
doi:10.1161/CIRCULATIONAHA.111.032920
PMCID: PMC3183314  PMID: 21900080
sickle cell anemia; pulmonary hypertension; left ventricular diastolic dysfunction; echocardiography; six-minute walk
15.  FERROPORTIN Q248H, DIETARY IRON AND SERUM FERRITIN IN COMMUNITY AFRICAN AMERICANS WITH LOW TO HIGH ALCOHOL CONSUMPTION 
Background
Alcohol consumption is associated with increased iron stores. In sub-Saharan Africa, high dietary ionic iron and the ferroportin Q248H allele have also been implicated in iron accumulation. We examined the associations of ferroportin Q248H, alcohol and dietary iron with serum ferritin, aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT) concentrations in African Americans.
Methods
Inner-city African Americans (103 men, 40 women) were recruited from the community according to reported ingestion of >4 alcoholic drinks per day or <2 per week. Typical daily heme iron, non-heme iron and alcohol were estimated using University of Hawaii’s multiethnic dietary questionnaire. Based on dietary questionnaire estimates we established categories of < versus ≥56 g alcohol per day, equivalent to 4 alcoholic drinks per day assuming 14 g alcohol per drink.
Results
Among 143 participants, 77% drank <56 g alcohol/day and 23% ≥56 g/d as estimated by the questionnaire. The prevalence of ferroportin Q248H was 23.3% with alcohol >56 g/d versus 7.5% with lower amounts (P=0.012). Among subjects with no history of HIV disease, serum ferritin concentration had positive relationships with male gender (P=0.041), alcohol consumption (P=0.021) and ALT concentration (P=0.0001) but not with dietary iron intake or ferroportin Q248H. Serum AST and ALT concentrations had significant positive associations with male gender and hepatitis C seropositivity but not with alcohol or dietary iron intake or ferroportin Q248H.
Conclusions
Our findings suggest a higher prevalence of ferroportin Q248H with greater alcohol consumption, and this higher prevalence raises the possibility that the allele might ameliorate the toxicity of alcohol. Our results suggest that alcohol but not dietary iron contributes to higher body iron stores in African Americans. Studies with larger numbers of participants are needed to further clarify the relationship of ferroportin Q248H with the toxicity of alcohol consumption.
doi:10.1111/j.1530-0277.2008.00782.x
PMCID: PMC3369540  PMID: 18782341
16.  Esophageal Carcinoma in African Americans: A Five-Decade Experience 
Digestive Diseases and Sciences  2011;56(12):3577-3582.
Background
Esophageal cancer accounts for a considerable proportion of carcinomas of the upper gastrointestinal tract in African Americans. Our aim was to describe the epidemiology of esophageal squamous cell cancer (ESCC) and esophageal adenocarcinoma (EA) among African Americans in the last five decades.
Methods
A total of 601 records of patients with documented esophageal cancer between 1959 and 2007 at Howard University Hospital were reviewed. Demographic characteristics, risk factors, clinical stage and histological findings were reviewed. The change in prevalence of the disease and the interaction between main risk factors with tumor stage of the patients were assessed over the years of this study.
Result
A total of 552 patients (91.8%) had ESCC while 49 patients (8.2%) had EA. The mean age at diagnosis was 60.1 and 60.6 years for ESCC and EA, respectively (P = 0.8). The peak incidence was in the 1980–1989 decade. Out of 136 ESCC patients with TNM staging information, 130 (95.6%) were diagnosed in stage 2 and above. The majority (73%) of the ESCC were in the mid- and upper third of the esophagus and associated with smoking and alcohol exposure. The majority (81%) of the EA were in the mid- and lower third. The most common presenting symptoms were dysphagia (77.7%), and weight loss (31.9%).
Conclusion
ESCC is the predominant esophageal cancer in African Americans and diagnosed in late stages, and its diagnosis in our institution has decreased since 1990. A combination of genetic factors, environmental influences (e.g., those related to diet), and the deleterious changes associated with smoking and alcohol consumption, and differences in tumor histology, are the obvious parameters that should be the focus of future studies, and early diagnosis at an earlier stage should be considered among blacks.
doi:10.1007/s10620-011-1853-1
PMCID: PMC3345949  PMID: 21847566
African American; Esophageal cancer; Esophageal squamous cell carcinoma; Esophageal adenocarcinoma
17.  SEL1L, an UPR Response Protein, a Potential Marker of Colonic Cell Transformation 
Digestive Diseases and Sciences  2012;57(4):905-912.
Background
SEL1L gene product is implicated in the endoplasmic reticulum (ER)-associated protein degradation and Unfolded Protein Response pathways. This gene and associated miRNAs have been indicated as predictive and prognostic markers of pancreatic cancer.
Aim
Explore the role of SEL1L in colorectal cancer (CRC) progression.
Methods
SEL1L expression was analysed immunohistochemically in 153 adenomas and 71 CRCs from African American and North Italian patients. The distribution of stained cells was determined by computing median and inter quartile range. The receiver operating characteristics plot was used as discriminate power of SEL1L expression, CRC diagnosis and the effects on patient survival.
Results
SEL1L was low in normal mucosa and confined to few scattered cells at the base crypt of the villi and in the foveolar glandular compartment. The highest levels were in Paneth cells within the lysosomes. The enterocytic progenitor cells and mature enterocytes showed less cytoplasmic staining. In CRCs, SEL1L expression significantly correlated with the progression from adenoma to carcinoma (P = 0.0001) being stronger in well-to-moderately differentiated cancers. No correlation was found with other clinicopathological characteristics or ethnicity.
Conclusions
SEL1L expression is a potential CRC tissue biomarker since its expression is significantly higher in adenoma cells with respect to normal mucosa. The levels of expression decrease sensibly in undifferentiated CRC cancers. Interestingly, Paneth cells contain high levels of SEL1L protein that could indicate pre-neoplastic mucosa undergoing neoplastic transformation. Since SEL1L’s major function lies within ER stress and active ERAD response, it may identify CRCs with differentiated secretory phenotype and acute cellular stress.
doi:10.1007/s10620-011-2026-y
PMCID: PMC3345950  PMID: 22350780
SEL1L expression; Colorectal cancers; Paneth’s cells
18.  Is Opium a Real Risk Factor for Esophageal Cancer or Just a Methodological Artifact? Hospital and Neighborhood Controls in Case-Control Studies 
PLoS ONE  2012;7(3):e32711.
Background
Control selection is a major challenge in epidemiologic case-control studies. The aim of our study was to evaluate using hospital versus neighborhood control groups in studying risk factors of esophageal squamous cell carcinoma (ESCC).
Methodology/Principal Findings
We compared the results of two different case-control studies of ESCC conducted in the same region by a single research group. Case definition and enrollment were the same in the two studies, but control selection differed. In the first study, we selected two age- and sex-matched controls from inpatient subjects in hospitals, while for the second we selected two age- and sex-matched controls from each subject's neighborhood of residence. We used the test of heterogeneity to compare the results of the two studies. We found no significant differences in exposure data for tobacco-related variables such as cigarette smoking, chewing Nass (a tobacco product) and hookah (water pipe) usage, but the frequency of opium usage was significantly different between hospital and neighborhood controls. Consequently, the inference drawn for the association between ESCC and tobacco use did not differ between the studies, but it did for opium use. In the study using neighborhood controls, opium use was associated with a significantly increased risk of ESCC (adjusted OR 1.77, 95% CI 1.17–2.68), while in the study using hospital controls, this was not the case (OR 1.09, 95% CI 0.63–1.87). Comparing the prevalence of opium consumption in the two control groups and a cohort enrolled from the same geographic area suggested that the neighborhood controls were more representative of the study base population for this exposure.
Conclusions/Significance
Hospital and neighborhood controls did not lead us to the same conclusion for a major hypothesized risk factor for ESCC in this population. Our results show that control group selection is critical in drawing appropriate conclusions in observational studies.
doi:10.1371/journal.pone.0032711
PMCID: PMC3291619  PMID: 22396792
19.  Distinct Clinical and Immunologic Profiles in Severe Malarial Anemia and Cerebral Malaria in Zambia 
The Journal of Infectious Diseases  2011;203(2):211-219.
Background. The mechanisms of severe malarial anemia and cerebral malaria, which are extreme manifestations of Plasmodium falciparum malaria, are not fully understood.
Methods. Children aged <6 years from southern Zambia presenting to the hospital with severe malarial anemia (n = 72), cerebral malaria (n = 28), or uncomplicated malaria (n = 66) were studied prospectively. Children with overlapping severe anemia and cerebral malaria were excluded.
Results. Low interleukin 10 concentrations had the strongest association with severe anemia (standard β = .61; P < .001) followed by high tumor necrosis factor α and sFas concentrations, low weight-for-age z scores, presence of stool parasites, and splenomegaly (standard β = .15–.25; P ≤ .031); most of these factors were also associated with lower reticulocytes. Greater parasitemia was associated with higher interleukin 10 and tumor necrosis factor α concentrations, whereas sulfadoxizole/pyrimethamine therapy and lower weight-for-age z scores were associated with lower interleukin 10 levels. Thrombocytopenia and elevated tissue plasminogen activator inhibitor 1 levels had the strongest associations with cerebral malaria (standard β = .37 or .36; P < .0001), followed by exposure to traditional herbal medicine and hemoglobinuria (standard β = .21–.31; P ≤ .006).
Conclusions. Predictors of severe malarial anemia (altered immune responses, poor nutrition, intestinal parasites, and impaired erythropoiesis) differed from those of cerebral malaria (thrombocytopenia, herbal medicine, and intravascular hemolysis). Improved preventive and therapeutic measures may need to consider these differences.
doi:10.1093/infdis/jiq041
PMCID: PMC3071068  PMID: 21288821
20.  Prospective Echocardiography Assessment of Pulmonary Hypertension And Its Potential Etiologies In Children With Sickle Cell Disease 
The American journal of cardiology  2009;104(5):713-720.
Pulmonary hypertension (PH) is associated with adverse outcomes in adults with sickle cell disease (SCD) but its importance in children is less clear. We define the incidence and etiologies of PH in pediatric patients with SCD. Children with SCD (n = 310) and matched controls (n = 54) were prospectively enrolled under basal conditions. Participants underwent echocardiography, pulse oximetry, 6-minute walk, and hematologic testing. Echocardiographic measures were compared between SCD and control subjects before and after adjusting for hemoglobin. Correlation of echocardiographic and clinical parameters was performed. Tricuspid regurgitation velocity (TRV) was elevated compared to controls (2.28 vs. 2.10 m/s, p <0.0001). Increased TRV was associated with left ventricular diastolic diameter, hemoglobin, and estimated left atrial pressure. TRV remained elevated when controlled for left ventricular diameter and left atrial pressure. An echocardiography-derived pulmonary resistance was not significantly different between SCD and control patients, although it was elevated in the SCD subgroup with elevated TRV. When controlled for hemoglobin, TRV was no longer statistically different, but pulmonary insufficiency velocity, septal wall thickness and estimated pulmonary resistance were statistically higher. TRV, pulmonary insufficiency end diastolic velocity, and markers of increased cardiac output correlated with indicators of adverse functional status including history of acute chest syndrome, stroke, transfusions, and 6-minute walk. In conclusion, children with SCD have mildly increased TRV that correlated with increased cardiac output and left ventricular filling pressures. Hemoglobin adjusted analysis also suggests contribution of primary vascular changes.
doi:10.1016/j.amjcard.2009.04.034
PMCID: PMC3197734  PMID: 19699350
Pulmonary hypertension; Tricuspid regurgitation; Pulmonary vascular resistance; Sickle cell
21.  Case-Control Study of Vitamin D, dickkopf homolog 1 (DKK1) Gene Methylation, VDR Gene Polymorphism and the Risk of Colon Adenoma in African Americans 
PLoS ONE  2011;6(10):e25314.
Background
There are sparse data on genetic, epigenetic and vitamin D exposure in African Americans (AA) with colon polyp. Consequently, we evaluated serum 25(OH) D levels, vitamin D receptor (VDR) polymorphisms and the methylation status of the tumor suppressor gene dickkopf homolog 1 (DKK1) as risk factors for colon polyp in this population.
Methods
The case-control study consisted of 93 patients with colon polyp (cases) and 187 healthy individuals (controls) at Howard University Hospital. Serum levels of 25(OH)D (including D3, D2, and total) were measured by liquid chromatography-mass spectrometry. DNA analysis focused on 49 single nucleotide polymorphisms (SNPs) in the VDR gene. Promoter methylation analysis of DKK1 was also performed. The resulting data were processed in unadjusted and multivariable logistic regression analyses.
Results
Cases and controls differed in vitamin D status (D3<50 nmol/L: Median of 35.5 in cases vs. 36.8 in controls nmol/L; P = 0.05). Low levels of 25(OH)D3 (<50 nmol/L) were observed in 86% of cases and 68% of controls and it was associated with higher risks of colon polyp (odds ratio of 2.7, 95% confidence interval 1.3–3.4). The SNP analysis showed no association between 46 VDR polymorphisms and colon polyp. The promoter of the DKK1 gene was unmethylated in 96% of the samples.
Conclusion
We found an inverse association between serum 25(OH)D3 and colon polyp in AAs. VDR SNPs and DKK1 methylation were not associated with colon polyp. Vitamin D levels may in part explain the higher incidence of polyp in AAs.
doi:10.1371/journal.pone.0025314
PMCID: PMC3192764  PMID: 22022386
22.  Association of G6PD202A,376G with lower haemoglobin concentration but not increased haemolysis in patients with sickle cell anaemia 
British journal of haematology  2010;150(2):218-225.
The genetic bases of the highly variable degrees of anaemia and haemolysis in persons with Hb SS are not fully known, but several studies have indicated that G6PD deficiency is not a factor. The G6PD202A and G6PD376G alleles and α-thalassaemia were determined by molecular genetic testing in 261 children and adolescents with Hb SS in a multicentre study. G6PD202A,376G (G6PD A-) was defined as hemizygosity for both alleles in males and homozygosity in females. Among the participants 41% were receiving hydroxycarbamide.
The prevalence of G6PD202A,376G was 13.6% in males and 3.3% in females with an overall prevalence of 8.7%. G6PD202A,376G was associated with a 10 g/l decrease in haemoglobin concentration (P=0.008) but not with increased haemolysis as measured by lactate dehydrogenase, bilirubin, aspartate-aminotransferase, reticulocyte count or a haemolytic component derived from these markers (P>0.09). Similar results were found within a sub-group of children who were not receiving hydroxycarbamide. By comparison, single and double α-globin deletions were associated with progressively higher haemoglobin concentrations (P=0.005 for trend), progressively lower values for haemolytic component (P=0.007), and increased severe pain episodes (P<0.001).
Conclusions
In conclusion, G6PD202A,376G may be associated with lower haemoglobin concentration in sickle cell anaemia by a mechanism other than increased haemolysis.
doi:10.1111/j.1365-2141.2010.08215.x
PMCID: PMC2906678  PMID: 20507315
sickle cell anaemia; G6PD; haemolysis; alpha-thalassaemia; haemoglobin concentration
23.  NT-PROBNP AS A MARKER OF CARDIOPULMONARY STATUS IN SICKLE CELL ANAEMIA IN AFRICA 
British journal of haematology  2010;150(1):102-107.
Summary
N-terminal (NT) pro-brain natriuretic peptide (proBNP) ≥160 ng/l has a 78% positive predictive value for pulmonary hypertension and is associated with increased mortality in US sickle cell disease patients, but the importance in sickle cell disease patients in Africa is not known. In a cross-sectional study at Ahmadu Bello University Teaching Hospital, Shika-Zaria, Nigeria, we studied 133 hydroxycarbamide-naïve Nigerian sickle cell anaemia patients aged 18-52 years at steady-state and 65 healthy controls. Twenty-six percent of patients versus 5% of controls had NT-proBNP ≥160 ng/l (P=0.0006). By logistic regression among the patients, human immunodeficiency virus seropositivity, higher serum ferritin and lower haemoglobin or higher lactate dehydrogenase independently predicted elevated NT-proBNP. After adjustment for haemoglobin concentration, elevated NT-proBNP concentration was associated with an estimated 7.8-fold increase in the odds of severe functional impairment, defined as an inability to walk more than 300 m in six min (95% confidence interval 1.5-32.6; P=0.005). Similarly, elevated tricuspid regurgitation velocity was associated with an estimated 5.6-fold increase in the odds of functional impairment (95% confidence interval 1.5-21.0; P=0.011). In conclusion, NT-proBNP elevation is common and is associated with markers of anaemia, inflammation and iron status and with severe functional impairment among sickle cell anaemia patients in Nigeria.
doi:10.1111/j.1365-2141.2010.08195.x
PMCID: PMC2907438  PMID: 20408845
sickle cell disease; N-terminal pro-brain natriuretic peptide; six-minute walk; haemolysis; Africa
24.  SLC5A8 Gene, A Transporter of Butyrate: A Gut Flora Metabolite, Is Frequently Methylated in African American Colon Adenomas 
PLoS ONE  2011;6(6):e20216.
Background
Colon cancer is one of the leading causes of cancer related deaths. Its impact on African Americans (AAs) is higher than in the general population both in the incidence and mortality from the disease. Colon cancer aggressiveness in AAs as well as non-frequent check-ups and follow up in this population have been proposed as ways to explain the observed discrepancies. These facts made the detection of early carcinogenesis markers in this population a priority.
Materials and Methods
Here, we analyzed 50 colon adenomas from AA patients for both microsatellite instability (MSI) and the methylation status of SLC5A8 gene. This gene's product is involved in the transport of butyrate that has anti-proliferative properties through its effects on histone acetylation and gene expression. A proteomic analysis to check the expressed histones in adenoma and normal tissues was also performed.
Results
The analyzed samples displayed 82% (n = 41) methylation level of SLC5A8 gene in adenomas. The MSI-H (high) adenoma were about 18% (n = 9) while the rest were mostly MSS (microsatellite stable) with few MSI-L (Low). No association was found between SLC5A8 methylation and the MSI status. Also, there was no association between SLC5A8 methylation and the sex and age of the patients. However, there were more right sided adenomas with SLC5A8 methylation than the left sided ones. The proteomic analysis revealed distinct histone expression profiles between normal and adenoma tissues.
Conclusion
SLC5A8 is highly methylated in AA colon adenomas which points to its potential use as a marker for early detection. The MSI rate is similar to that found in colon cancer tumors in AAs. These findings suggest that both processes stem from the same epigenetic and genetic events occurring at an early stage in colon carcinogenesis in AAs.
doi:10.1371/journal.pone.0020216
PMCID: PMC3110579  PMID: 21687703
25.  COMPLETE BLOOD COUNT, MEASURES OF IRON STATUS AND INFLAMMATORY MARKERS IN INNER-CITY AFRICAN AMERICANS WITH UNDIAGNOSED HEPATITIS C SEROPOSITIVITY 
Background
Hepatitis C virus (HCV) infection may be associated with thrombocytopenia and increased iron stores in patients receiving medical care. We aimed to determine how often changes in hematologic, iron metabolic and inflammatory markers occur in individuals with undiagnosed HCV in the community.
Methods
Inner-city African Americans (n=143) were recruited from the community according to reported ingestion of alcohol. They were divided broadly into those who drank more or less than 56 g alcohol/day as assessed by dietary questionnaire. HCV serology was determined and laboratory values were compared according to HCV seropositivity in analyses that adjusted for alcohol consumption.
Results
The prevalence of HCV seropositivity was 23% among men and 29% among women. Levels of hepatocellular enzymes were higher with HCV seropositivity (P <0.0001) but hemoglobin concentrations, white blood cell and platelet counts and serum ferritin concentrations did not differ. The globulin fraction of the serum protein concentration (P=0.002) was increased with HCV seropositivity as expected with chronic inflammation. However, erythrocyte sedimentation rate and serum iron and haptoglobin levels did not differ significantly according to HCV status. Furthermore, multivariate analysis revealed that C-reactive protein was decreased and transferrin concentration was increased with both HCV and alcohol consumption (P<0.014).
Conclusions
Previously undiagnosed HCV seropositivity has little effect on the complete blood count and body iron stores but appears to perturb the response to an inflammatory stimulus, causing reduced rather than increased circulating CRP concentrations and increased rather than decreased transferrin concentrations.
doi:10.1016/j.cca.2010.01.028
PMCID: PMC2847047  PMID: 20117104
HCV infection; African American; CRP; Iron metabolism

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