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Credit: Peter H. Seeberger
Investigators have identified 5 genes that appear to affect a person’s susceptibility to severe malaria.
The group’s analyses suggest that single-nucleotide polymorphisms (SNPs) in HBB, ABO, ATP2B4, G6PD, and CD40LG are associated with an increased or decreased risk of severe malaria, cerebral malaria, and severe malarial anemia.
This knowledge could lead to new therapeutics or vaccines to target severe malaria.
“[This study] has allowed for investigation of genes that influence susceptibility to malaria on a scale that has previously not been achieved,” said Sarah Dunstan, PhD, of the Oxford University Clinical Research Unit at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam.
“It involved a large number of severe malaria patients from multiple countries, which allows us to identify genes that truly have an effect on whether or not you develop severe malaria.”
Dr Dunstan and her colleagues detailed this research in Nature Genetics.
The team collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 control subjects across 12 locations in countries of Africa, Asia, and Oceania.
The researchers tested 55 SNPs in 27 gene regions that were associated with severe malaria in previous research: ABO, ADORA2B, ATP2B4, C6, CD36, CD40LG, CR1, ACKR1 (DARC), G6PD, GNAS, HBB, ICAM1, IL1A, IL1B, IL4, IL10, IL13, IL22, IRF1, LTA, NOS2, SPTB, TLR1, TLR4, TLR6, TLR9, and TNF.
The team found evidence of associations with the HBB, ABO, ATP2B4, G6PD, and CD40LG loci, but no association for the other 22 loci.
HBB
The HBB gene encodes β-globin, which has 3 variants associated with resistance to malaria: hemoglobin S (HbS), hemoglobin C (HbC), and hemoglobin E (HbE). The SNP responsible for HbE, rs33950507, was rare or absent in most groups, so the sample was too small to estimate association with severe malaria.
However, for HbS (SNP rs334), heterozygotes had a reduced risk of severe malaria (odds ratio [OR]=0.14; P=1.6×10−225), cerebral malaria (OR=0.11; P=4.7×10−88), and severe malarial anemia (OR=0.11; P=9.3×10−65).
For HbC (SNP rs33930165), each copy of the derived allele reduced the risk of severe malaria by 29% (OR=0.71; P=6.9×10−9), cerebral malaria by 28% (OR=0.72; P=0.01), and severe malarial anemia by 26% (OR=0.74; P=2.1×10−3).
ABO
The ABO gene encodes the glycosyltransferase enzyme that determines ABO blood group. Blood group O was associated with a lower risk of severe malaria (OR=0.74; P=5.0×10−32), cerebral malaria (OR=0.73; P=8.9×10−16), and severe malarial anemia (OR=0.68; P=7.9×10−14).
The researchers also found that rs8176746, an SNP in ABO that determines the production of B antigens, was associated with an increased risk of severe malaria (OR=1.25; P=2.0×10−17).
G6PD
G6PD is an X-linked gene encoding glucose-6-phosphate dehydrogenase. The investigators found that deficiency in G6PD (rs1050828 [G6PD c.202C>T]) can reduce the risk of cerebral malaria but increase the risk of severe malarial anemia.
There was an increased risk of severe malarial anemia in male hemizygotes (OR=1.49; P=3.6×10−5) and in female homozygotes (OR=1.94; P=1.9×10−3), as well as a decreased risk of cerebral malaria in female heterozygotes (OR=0.87; P=0.06) and male hemizygotes (OR=0.81; P=0.01).
ATP2B4
ATP2B4 encodes a calcium transporter found in the plasma membrane of erythrocytes. The derived alleles of rs10900585 and rs55868763 were associated with an increased risk of severe malaria, and the derived alleles of rs4951074 and rs1541255 were associated with a decreased risk.
Subjects with at least one copy of the derived allele at rs10900585 had an OR of 1.32 for severe malaria (P=1.7×10−9), and those homozygous for the derived allele at rs4951074 had an OR of 0.77 (P=7.6×10−7). Findings were similar for cerebral malaria and severe malarial anemia.
CD40LG
CD40LG is a gene on the X chromosome that has previously been associated with severe malaria. Homozygotes for the derived allele of rs3092945 had a decreased risk of severe malaria (OR=0.85; P=1.1×10−6) when the researchers analyzed data from the study sites together.
However, the results differed when they analyzed sites individually. For instance, homozygotes had a reduced risk of severe malaria in The Gambia (OR=0.54; P=2.3×10−22) and an increased risk in Kenya (OR=1.42; P=7.8×10−6).
These findings suggest the role of common human genetic disorders in severe malaria is more complex than we thought, Dr Dunstan said. But the results should enable a better understanding of the mechanisms and processes at work during progression to severe disease. 
Credit: Peter H. Seeberger
Investigators have identified 5 genes that appear to affect a person’s susceptibility to severe malaria.
The group’s analyses suggest that single-nucleotide polymorphisms (SNPs) in HBB, ABO, ATP2B4, G6PD, and CD40LG are associated with an increased or decreased risk of severe malaria, cerebral malaria, and severe malarial anemia.
This knowledge could lead to new therapeutics or vaccines to target severe malaria.
“[This study] has allowed for investigation of genes that influence susceptibility to malaria on a scale that has previously not been achieved,” said Sarah Dunstan, PhD, of the Oxford University Clinical Research Unit at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam.
“It involved a large number of severe malaria patients from multiple countries, which allows us to identify genes that truly have an effect on whether or not you develop severe malaria.”
Dr Dunstan and her colleagues detailed this research in Nature Genetics.
The team collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 control subjects across 12 locations in countries of Africa, Asia, and Oceania.
The researchers tested 55 SNPs in 27 gene regions that were associated with severe malaria in previous research: ABO, ADORA2B, ATP2B4, C6, CD36, CD40LG, CR1, ACKR1 (DARC), G6PD, GNAS, HBB, ICAM1, IL1A, IL1B, IL4, IL10, IL13, IL22, IRF1, LTA, NOS2, SPTB, TLR1, TLR4, TLR6, TLR9, and TNF.
The team found evidence of associations with the HBB, ABO, ATP2B4, G6PD, and CD40LG loci, but no association for the other 22 loci.
HBB
The HBB gene encodes β-globin, which has 3 variants associated with resistance to malaria: hemoglobin S (HbS), hemoglobin C (HbC), and hemoglobin E (HbE). The SNP responsible for HbE, rs33950507, was rare or absent in most groups, so the sample was too small to estimate association with severe malaria.
However, for HbS (SNP rs334), heterozygotes had a reduced risk of severe malaria (odds ratio [OR]=0.14; P=1.6×10−225), cerebral malaria (OR=0.11; P=4.7×10−88), and severe malarial anemia (OR=0.11; P=9.3×10−65).
For HbC (SNP rs33930165), each copy of the derived allele reduced the risk of severe malaria by 29% (OR=0.71; P=6.9×10−9), cerebral malaria by 28% (OR=0.72; P=0.01), and severe malarial anemia by 26% (OR=0.74; P=2.1×10−3).
ABO
The ABO gene encodes the glycosyltransferase enzyme that determines ABO blood group. Blood group O was associated with a lower risk of severe malaria (OR=0.74; P=5.0×10−32), cerebral malaria (OR=0.73; P=8.9×10−16), and severe malarial anemia (OR=0.68; P=7.9×10−14).
The researchers also found that rs8176746, an SNP in ABO that determines the production of B antigens, was associated with an increased risk of severe malaria (OR=1.25; P=2.0×10−17).
G6PD
G6PD is an X-linked gene encoding glucose-6-phosphate dehydrogenase. The investigators found that deficiency in G6PD (rs1050828 [G6PD c.202C>T]) can reduce the risk of cerebral malaria but increase the risk of severe malarial anemia.
There was an increased risk of severe malarial anemia in male hemizygotes (OR=1.49; P=3.6×10−5) and in female homozygotes (OR=1.94; P=1.9×10−3), as well as a decreased risk of cerebral malaria in female heterozygotes (OR=0.87; P=0.06) and male hemizygotes (OR=0.81; P=0.01).
ATP2B4
ATP2B4 encodes a calcium transporter found in the plasma membrane of erythrocytes. The derived alleles of rs10900585 and rs55868763 were associated with an increased risk of severe malaria, and the derived alleles of rs4951074 and rs1541255 were associated with a decreased risk.
Subjects with at least one copy of the derived allele at rs10900585 had an OR of 1.32 for severe malaria (P=1.7×10−9), and those homozygous for the derived allele at rs4951074 had an OR of 0.77 (P=7.6×10−7). Findings were similar for cerebral malaria and severe malarial anemia.
CD40LG
CD40LG is a gene on the X chromosome that has previously been associated with severe malaria. Homozygotes for the derived allele of rs3092945 had a decreased risk of severe malaria (OR=0.85; P=1.1×10−6) when the researchers analyzed data from the study sites together.
However, the results differed when they analyzed sites individually. For instance, homozygotes had a reduced risk of severe malaria in The Gambia (OR=0.54; P=2.3×10−22) and an increased risk in Kenya (OR=1.42; P=7.8×10−6).
These findings suggest the role of common human genetic disorders in severe malaria is more complex than we thought, Dr Dunstan said. But the results should enable a better understanding of the mechanisms and processes at work during progression to severe disease.
Credit: Peter H. Seeberger
Investigators have identified 5 genes that appear to affect a person’s susceptibility to severe malaria.
The group’s analyses suggest that single-nucleotide polymorphisms (SNPs) in HBB, ABO, ATP2B4, G6PD, and CD40LG are associated with an increased or decreased risk of severe malaria, cerebral malaria, and severe malarial anemia.
This knowledge could lead to new therapeutics or vaccines to target severe malaria.
“[This study] has allowed for investigation of genes that influence susceptibility to malaria on a scale that has previously not been achieved,” said Sarah Dunstan, PhD, of the Oxford University Clinical Research Unit at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam.
“It involved a large number of severe malaria patients from multiple countries, which allows us to identify genes that truly have an effect on whether or not you develop severe malaria.”
Dr Dunstan and her colleagues detailed this research in Nature Genetics.
The team collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 control subjects across 12 locations in countries of Africa, Asia, and Oceania.
The researchers tested 55 SNPs in 27 gene regions that were associated with severe malaria in previous research: ABO, ADORA2B, ATP2B4, C6, CD36, CD40LG, CR1, ACKR1 (DARC), G6PD, GNAS, HBB, ICAM1, IL1A, IL1B, IL4, IL10, IL13, IL22, IRF1, LTA, NOS2, SPTB, TLR1, TLR4, TLR6, TLR9, and TNF.
The team found evidence of associations with the HBB, ABO, ATP2B4, G6PD, and CD40LG loci, but no association for the other 22 loci.
HBB
The HBB gene encodes β-globin, which has 3 variants associated with resistance to malaria: hemoglobin S (HbS), hemoglobin C (HbC), and hemoglobin E (HbE). The SNP responsible for HbE, rs33950507, was rare or absent in most groups, so the sample was too small to estimate association with severe malaria.
However, for HbS (SNP rs334), heterozygotes had a reduced risk of severe malaria (odds ratio [OR]=0.14; P=1.6×10−225), cerebral malaria (OR=0.11; P=4.7×10−88), and severe malarial anemia (OR=0.11; P=9.3×10−65).
For HbC (SNP rs33930165), each copy of the derived allele reduced the risk of severe malaria by 29% (OR=0.71; P=6.9×10−9), cerebral malaria by 28% (OR=0.72; P=0.01), and severe malarial anemia by 26% (OR=0.74; P=2.1×10−3).
ABO
The ABO gene encodes the glycosyltransferase enzyme that determines ABO blood group. Blood group O was associated with a lower risk of severe malaria (OR=0.74; P=5.0×10−32), cerebral malaria (OR=0.73; P=8.9×10−16), and severe malarial anemia (OR=0.68; P=7.9×10−14).
The researchers also found that rs8176746, an SNP in ABO that determines the production of B antigens, was associated with an increased risk of severe malaria (OR=1.25; P=2.0×10−17).
G6PD
G6PD is an X-linked gene encoding glucose-6-phosphate dehydrogenase. The investigators found that deficiency in G6PD (rs1050828 [G6PD c.202C>T]) can reduce the risk of cerebral malaria but increase the risk of severe malarial anemia.
There was an increased risk of severe malarial anemia in male hemizygotes (OR=1.49; P=3.6×10−5) and in female homozygotes (OR=1.94; P=1.9×10−3), as well as a decreased risk of cerebral malaria in female heterozygotes (OR=0.87; P=0.06) and male hemizygotes (OR=0.81; P=0.01).
ATP2B4
ATP2B4 encodes a calcium transporter found in the plasma membrane of erythrocytes. The derived alleles of rs10900585 and rs55868763 were associated with an increased risk of severe malaria, and the derived alleles of rs4951074 and rs1541255 were associated with a decreased risk.
Subjects with at least one copy of the derived allele at rs10900585 had an OR of 1.32 for severe malaria (P=1.7×10−9), and those homozygous for the derived allele at rs4951074 had an OR of 0.77 (P=7.6×10−7). Findings were similar for cerebral malaria and severe malarial anemia.
CD40LG
CD40LG is a gene on the X chromosome that has previously been associated with severe malaria. Homozygotes for the derived allele of rs3092945 had a decreased risk of severe malaria (OR=0.85; P=1.1×10−6) when the researchers analyzed data from the study sites together.
However, the results differed when they analyzed sites individually. For instance, homozygotes had a reduced risk of severe malaria in The Gambia (OR=0.54; P=2.3×10−22) and an increased risk in Kenya (OR=1.42; P=7.8×10−6).
These findings suggest the role of common human genetic disorders in severe malaria is more complex than we thought, Dr Dunstan said. But the results should enable a better understanding of the mechanisms and processes at work during progression to severe disease.