β-Thalassemia pathogenic variants in a cohort of children from the East African coast

BACKGROUND: β-Thalassemia is rare in sub-Saharan Africa. Previous studies have suggested that it is limited to specific parts of West Africa. Based on hemoglobin A2 (HbA2 ) concentrations measured by HPLC, we recently speculated that β-thalassemia might also be present on the East African coast of Kenya. Here, we follow this up using molecular methods. METHODS: We used raised hemoglobin A2 (HbA2 ) values (> 4.0% of total Hb) to target all HbAA members of a cohort study in Kilifi, Kenya, for HBB sequencing for β-thalassemia (n = 99) together with a sample of HbAA subjects with lower HbA2 levels. Because HbA2 values are artifactually raised in subjects carrying sickle hemoglobin (HbS) we sequenced all participants with an HPLC pattern showing HbS without HbA (n = 116) and a sample with a pattern showing both HbA and HbS. RESULTS: Overall, we identified 83 carriers of four separate β-thalassemia pathogenic variants: three β0 -thalassemia [CD22 (GAA→TAA), initiation codon (ATG→ACG), and IVS1-3' end del 25bp] and one β+ -thalassemia pathogenic variants (IVS-I-110 (G→A)). We estimated the minimum allele frequency of all variants combined within the study population at 0.3%. CONCLUSIONS: β-Thalassemia is present in Kilifi, Kenya, an observation that has implications for the diagnosis and clinical care of children from the East Africa region

The epidemiology of sickle cell disease in children recruited in infancy in Kilifi, Kenya: a prospective cohort study.

BACKGROUND: Sickle cell disease is the most common severe monogenic disorder in humans. In Africa, 50-90% of children born with sickle cell disease die before they reach their fifth birthday. In this study, we aimed to describe the comparative incidence of specific clinical outcomes among children aged between birth and 5 years with and without sickle cell disease, who were resident within the Kilifi area of Kenya. METHODS: This prospective cohort study was done on members of the Kilifi Genetic Birth Cohort Study (KGBCS) on the Indian Ocean coast of Kenya. Recruitment to the study was facilitated through the Kilifi Health and Demographic Surveillance System (KHDSS), which covers a resident population of 260 000 people, and was undertaken between Jan 1, 2006, and April 30, 2011. All children who were born within the KHDSS area and who were aged 3-12 months during the recruitment period were eligible for inclusion. Participants were tested for sickle cell disease and followed up for survival status and disease-specific admission to Kilifi County Hospital by passive surveillance until their fifth birthday. Children with sickle cell disease were offered confirmatory testing and care at a dedicated outpatient clinic. FINDINGS: 15 737 infants were recruited successfully to the KGBCS, and 128 (0·8%) of these infants had sickle cell disease, of whom 70 (54·7%) enrolled at the outpatient clinic within 12 months of recruitment. Mortality was higher in children with sickle cell disease (58 per 1000 person-years of observation, 95% CI 40-86) than in those without sickle cell disease (2·4 per 1000 person-years of observation, 2·0-2·8; adjusted incidence rate ratio [IRR] 23·1, 95% CI 15·1-35·3). Among children with sickle cell disease, mortality was lower in those who enrolled at the clinic (adjusted IRR 0·26, 95% CI 0·11-0·62) and in those with higher levels of haemoglobin F (HbF; adjusted IRR 0·40, 0·17-0·94). The incidence of admission to hospital was also higher in children with sickle cell disease than in children without sickle cell disease (210 per 1000 person-years of observation, 95% CI 174-253, vs 43 per 1000 person-years of observation, 42-45; adjusted IRR 4·80, 95% CI 3·84-6·15). The most common reason for admission to hospital among those with sickle cell disease was severe anaemia (incidence 48 per 1000 person-years of observation, 95% CI 32-71). Admission to hospital was lower in those with a recruitment HbF level above the median (IRR 0·43, 95% CI 0·24-0·78; p=0·005) and those who were homozygous for α-thalassaemia (0·07, 0·01-0·83; p=0·035). INTERPRETATION: Although morbidity and mortality were high in young children with sickle cell disease in this Kenyan cohort, both were reduced by early diagnosis and supportive care. The emphasis must now move towards early detection and prevention of long-term complications of sickle cell disease. FUNDING: Wellcome Trust

Epistasis between the haptoglobin common variant and α+thalassemia influences risk of severe malaria in Kenyan children

Haptoglobin (Hp) scavenges free hemoglobin following malaria-induced hemolysis. Few studies have investigated the relationship between the common Hp variants and the risk of severe malaria, and their results are inconclusive. We conducted a case-control study of 996 children with severe Plasmodium falciparum malaria and 1220 community controls and genotyped for Hp, hemoglobin (Hb) S heterozygotes, and α(+)thalassemia. Hb S heterozygotes and α(+)thalassemia homozygotes were protected from severe malaria (odds ratio [OR], 0.12; 95% confidence interval [CI], 0.07-0.18 and OR, 0.69; 95% CI, 0.53-0.91, respectively). The risk of severe malaria also varied by Hp genotype: Hp2-1 was associated with the greatest protection against severe malaria and Hp2-2 with the greatest risk. Meta-analysis of the current and published studies suggests that Hp2-2 is associated with increased risk of severe malaria compared with Hp2-1. We found a significant interaction between Hp genotype and α(+)thalassemia in predicting risk of severe malaria: Hp2-1 in combination with heterozygous or homozygous α(+)thalassemia was associated with protection from severe malaria (OR, 0.73; 95% CI, 0.54-0.99 and OR, 0.48; 95% CI, 0.32-0.73, respectively), but α(+)thalassemia in combination with Hp2-2 was not protective. This epistatic interaction together with varying frequencies of α(+)thalassemia across Africa may explain the inconsistent relationship between Hp genotype and malaria reported in previous studies

The population dynamics of haemoglobins A, A2, F and S in the context of the haemoglobinopathies HbS and α+thalassaemia in Kenyan infants

Few studies have described the dynamics of haemoglobin production in African populations with a high prevalence of haemoglobinopathies. We have used the BioRad Variant ClassicTM HPLC method to document the production patterns of the common haemoglobin variants HbA, HbA2, HbF and HbS, stratified by a+thalassaemia genotype, among 15,301 infants recruited to a study on the Coast of Kenya. Notably, we confirm that HbA2 measurements determined using this instrument are unreliable in HbAS and HbSS subjects. Further, we showed that HbA2 exceeded 4.0%, a level consistent with the presence of a-thalassaemia, in 0.8% of infants of HbAA phenotype who participated in our study. a-thalassaemia, has not been widely reported in the East Africa region and, as such, this finding merits further study

Biomarkers of post-discharge mortality among children with complicated severe acute malnutrition

High mortality after discharge from hospital following acute illness has been observed among children with Severe Acute Malnutrition (SAM). However, mechanisms that may be amenable to intervention to reduce risk are unknown. We performed a nested case-control study among HIV-uninfected children aged 2–59 months treated for complicated SAM according to WHO recommendations at four Kenyan hospitals. Blood was drawn from 1778 children when clinically judged stable before discharge from hospital. Cases were children who died within 60 days. Controls were randomly selected children who survived for one year without readmission to hospital. Untargeted proteomics, total protein, cytokines and chemokines, and leptin were assayed in plasma and corresponding biological processes determined. Among 121 cases and 120 controls, increased levels of calprotectin, von Willebrand factor, angiotensinogen, IL8, IL15, IP10, TNFα, and decreased levels of leptin, heparin cofactor 2, and serum paraoxonase were associated with mortality after adjusting for possible confounders. Acute phase responses, cellular responses to lipopolysaccharide, neutrophil responses to bacteria, and endothelial responses were enriched among cases. Among apparently clinically stable children with SAM, a sepsis-like profile is associated with subsequent death. This may be due to ongoing bacterial infection, translocated bacterial products or deranged immune response during nutritional recovery

The population dynamics of haemoglobins A, A2, F and S in the context of the haemoglobinopathies HbS and α+thalassaemia in Kenyan infants

Few studies have described the dynamics of haemoglobin production in African populations with a high prevalence of haemoglobinopathies. We have used the BioRad Variant ClassicTM HPLC method to document the production patterns of the common haemoglobin variants HbA, HbA2, HbF and HbS, stratified by a+thalassaemia genotype, among 15,301 infants recruited to a study on the Coast of Kenya. Notably, we confirm that HbA2 measurements determined using this instrument are unreliable in HbAS and HbSS subjects. Further, we showed that HbA2 exceeded 4.0%, a level consistent with the presence of a-thalassaemia, in 0.8% of infants of HbAA phenotype who participated in our study. a-thalassaemia, has not been widely reported in the East Africa region and, as such, this finding merits further study

Fotografia d'en Pere Calders, la Rosa Artís Gener i la Zina Roure a un parc no identificat

Al darrere, amb màquina de fotos: Pere Calders. Al davant, d'esquerra a dreta: Rosa Artís i Zina Roure

β-Thalassemia pathogenic variants in a cohort of children from the East African coast

Background β-Thalassemia is rare in sub-Saharan Africa. Previous studies have suggested that it is limited to specific parts of West Africa. Based on hemoglobin A2 (HbA2) concentrations measured by HPLC, we recently speculated that β-thalassemia might also be present on the East African coast of Kenya. Here, we follow this up using molecular methods. Methods We used raised hemoglobin A2 (HbA2) values (> 4.0% of total Hb) to target all HbAA members of a cohort study in Kilifi, Kenya, for HBB sequencing for β-thalassemia (n = 99) together with a sample of HbAA subjects with lower HbA2 levels. Because HbA2 values are artifactually raised in subjects carrying sickle hemoglobin (HbS) we sequenced all participants with an HPLC pattern showing HbS without HbA (n = 116) and a sample with a pattern showing both HbA and HbS. Results Overall, we identified 83 carriers of four separate β-thalassemia pathogenic variants: three β0-thalassemia [CD22 (GAA→TAA), initiation codon (ATG→ACG), and IVS1-3ʹ end del 25bp] and one β+-thalassemia pathogenic variants (IVS-I-110 (G→A)). We estimated the minimum allele frequency of all variants combined within the study population at 0.3%. Conclusions β-Thalassemia is present in Kilifi, Kenya, an observation that has implications for the diagnosis and clinical care of children from the East Africa region

ß-thalassemia pathogenic variants in a cohort of children from the East African coast.

BACKGROUND: β-Thalassemia is rare in sub-Saharan Africa. Previous studies have suggested that it is limited to specific parts of West Africa. Based on hemoglobin A2 (HbA2 ) concentrations measured by HPLC, we recently speculated that β-thalassemia might also be present on the East African coast of Kenya. Here, we follow this up using molecular methods. METHODS: We used raised hemoglobin A2 (HbA2 ) values (> 4.0% of total Hb) to target all HbAA members of a cohort study in Kilifi, Kenya, for HBB sequencing for β-thalassemia (n = 99) together with a sample of HbAA subjects with lower HbA2 levels. Because HbA2 values are artifactually raised in subjects carrying sickle hemoglobin (HbS) we sequenced all participants with an HPLC pattern showing HbS without HbA (n = 116) and a sample with a pattern showing both HbA and HbS. RESULTS: Overall, we identified 83 carriers of four separate β-thalassemia pathogenic variants: three β0 -thalassemia [CD22 (GAA→TAA), initiation codon (ATG→ACG), and IVS1-3' end del 25bp] and one β+ -thalassemia pathogenic variants (IVS-I-110 (G→A)). We estimated the minimum allele frequency of all variants combined within the study population at 0.3%. CONCLUSIONS: β-Thalassemia is present in Kilifi, Kenya, an observation that has implications for the diagnosis and clinical care of children from the East Africa region

Biomarkers of post-discharge mortality among children with complicated severe acute malnutrition

High mortality after discharge from hospital following acute illness has been observed among children with Severe Acute Malnutrition (SAM). However, mechanisms that may be amenable to intervention to reduce risk are unknown. We performed a nested case-control study among HIV-uninfected children aged 2–59 months treated for complicated SAM according to WHO recommendations at four Kenyan hospitals. Blood was drawn from 1778 children when clinically judged stable before discharge from hospital. Cases were children who died within 60 days. Controls were randomly selected children who survived for one year without readmission to hospital. Untargeted proteomics, total protein, cytokines and chemokines, and leptin were assayed in plasma and corresponding biological processes determined. Among 121 cases and 120 controls, increased levels of calprotectin, von Willebrand factor, angiotensinogen, IL8, IL15, IP10, TNFα, and decreased levels of leptin, heparin cofactor 2, and serum paraoxonase were associated with mortality after adjusting for possible confounders. Acute phase responses, cellular responses to lipopolysaccharide, neutrophil responses to bacteria, and endothelial responses were enriched among cases. Among apparently clinically stable children with SAM, a sepsis-like profile is associated with subsequent death. This may be due to ongoing bacterial infection, translocated bacterial products or deranged immune response during nutritional recovery