Negative Epistasis between Sickle and Foetal Haemoglobin Suggests a Reduction in Protection against Malaria

Background Haemoglobin variants, Sickle (HbS) and foetal (HbF) have been associated with malaria protection. This study explores epistatic interactions between HbS and HbF on malaria infection. Methods The study was conducted between March 2004 and December 2013 within the sickle cell disease (SCD) programme at Muhimbili National Hospital, Tanzania. SCD status was categorized into HbAA, HbAS and HbSS using hemoglobin electrophoresis and High Performance Liquid Chromatography (HPLC). HbF levels were determined by HPLC. Malaria was diagnosed using rapid diagnostic test and/or blood film. Logistic regression and generalized estimating equations models were used to evaluate associations between SCD status, HbF and malaria. Findings 2,049 individuals with age range 0-70 years, HbAA 311(15.2%), HbAS 241(11.8%) and HbSS 1,497(73.1%) were analysed. At enrolment, malaria prevalence was significantly higher in HbAA 13.2% compared to HbAS 1.24% and HbSS 1.34% (p<0.001). Mean HbF was lower in those with malaria compared to those without malaria in HbAA (0.43% vs 0.82%) but was the reverse in HbSS (8.10% vs 5.59%). An increase in HbF was associated with a decrease in risk of malaria OR=0.50 (95%CI: 0.28, 0.90; p=0.021) in HbAA, whereas for HbSS the risk of malaria increased OR=2.94 (1.44, 5.98; p=0.003). A similar pattern was seen during multiple visits; HbAA OR=0.52 (0.34, 0.80; p=0.003) vs HbSS OR=2.01 (1.27, 3.23; p=0.003). Conclusion Higher prevalence of malaria in HbAA compared to HbAS and HbSS confirmed the protective effect of HbS. Lower prevalence of malaria in HbAA with high HbF supports a protective effect of HbF. However, in HbSS, the higher prevalence of malaria with high levels of HbF suggests loss of malaria protection. This is the first epidemiological study to suggest a negative epistasis between HbF and HbS on malaria.

[1]  Jane-Jane Chen.  Stress-enhanced translation of γ-globin mRNA. , 2014, Blood.

[2]  D. Kwiatkowski,et al.  Epistasis between the haptoglobin common variant and α+thalassemia influences risk of severe malaria in Kenyan children. , 2014, Blood.

[3]  S. Hay,et al.  Global Burden of Sickle Cell Anaemia in Children under Five, 2010–2050: Modelling Based on Demographics, Excess Mortality, and Interventions , 2013, PLoS medicine.

[4]  Sunetra Gupta,et al.  NEGATIVE EPISTASIS BETWEEN α+ THALASSAEMIA AND SICKLE CELL TRAIT CAN EXPLAIN INTERPOPULATION VARIATION IN SOUTH ASIA , 2011, Evolution; international journal of organic evolution.

[5]  Tobago.  Population and Housing Census. , 2011 .

[6]  J. Keefer,et al.  A Role for Fetal Hemoglobin and Maternal Immune IgG in Infant Resistance to Plasmodium falciparum Malaria , 2011, PloS one.

[7]  F. Kirkham,et al.  Mortality in Sickle Cell Anemia in Africa: A Prospective Cohort Study in Tanzania , 2011, PloS one.

[8]  J. Haldane,et al.  THE RATE OF MUTATION OF HUMAN GENES , 2010 .

[9]  Stephen W. Hartley,et al.  Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5' olfactory receptor gene cluster. , 2010, Blood.

[10]  K. Marsh,et al.  Malaria in patients with sickle cell anemia: burden, risk factors, and outcome at the outpatient clinic and during hospitalization. , 2010, Blood.

[11]  O. Pybus,et al.  Epistatic interactions between genetic disorders of hemoglobin can explain why the sickle-cell gene is uncommon in the Mediterranean , 2009, Proceedings of the National Academy of Sciences.

[12]  Mario Recker,et al.  Negative epistasis between the malaria-protective effects of α+-thalassemia and the sickle cell trait , 2005, Nature Genetics.

[13]  Dianne J Terlouw,et al.  Protective effects of the sickle cell gene against malaria morbidity and mortality , 2002, The Lancet.

[14]  G. Stamatoyannopoulos,et al.  Transgenic mice expressing human fetal globin are protected from malaria by a novel mechanism. , 1998, Blood.

[15]  J. Craig,et al.  Genetics of Hb F/F cell variance in adults and heterocellular hereditary persistence of fetal hemoglobin. , 1998, Hemoglobin.

[16]  O. Platt,et al.  Mortality in sickle cell disease. Life expectancy and risk factors for early death. , 1994, The New England journal of medicine.

[17]  M. Friedman.  Oxidant damage mediates variant red cell resistance to malaria , 1979, Nature.

[18]  R. Wilson,et al.  Effects of foetal haemoglobin on susceptibility of red cells to Plasmodium falciparum , 1977, Nature.

[19]  A. Allison,et al.  Protection Afforded by Sickle-cell Trait Against Subtertian Malarial Infection , 1954, British medical journal.

[20]  G. Stamatoyannopoulos,et al.  Fetal hemoglobin in acute and chronic states of erythroid expansion. , 1993, Blood.

[21]  L. Luzzatto,et al.  Fetal haemoglobin and malaria. , 1976, Lancet.