Table 2.
Polymorphisms with significant signals of association in different severe malaria phenotypes
| Frequency (%) of derived allele in controls (normal/het/hom [n]) | Frequency (%) of derived allele in cases (normal/het/hom [n]) | Model* |
Unadjusted |
Adjusted† |
|||
|---|---|---|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | ||||
| ATP2B4 (rs1541255, chromosome 1; A→G) | |||||||
| Severe malaria | 33% (1741/1774/418) | 31% (1010/1016/185) | R | 0·74 (0·62–0·89) | 0·001 | 0·76 (0·63–0·92) | 0·001 |
| Cerebral malaria | 33% (1741/1774/418) | 30% (581/549/96) | R | 0·68 (0·54–0·86) | 0·001 | 0·69 (0·54–0·89) | 0·001 |
| Severe malarial anaemia | 33% (1741/1774/418) | 29% (323/293/49) | R | 0·63 (0·46–0·87) | 0·003 | 0·60 (0·43–0·84) | 0·003 |
| Respiratory distress | 33% (1741/1774/418) | 30% (322/313/49) | R | 0·62 (0·46–0·85) | 0·001 | 0·64 (0·46–0·88) | 0·002 |
| Death | 33% (1741/1774/418) | 31% (119/117/23) | R | 0·80 (0·51–1·25) | 0·31 | 0·74 (0·46–1·29) | 0·25 |
| IL10 (rs1800890, chromosome 1; A→T) | |||||||
| Severe malaria | 24% (2270/1418/257) | 23% (1313/821/199) | R | 0·69 (0·55–0·88) | 0·002 | 0·72 (0·56–0·93) | 0·002 |
| Cerebral malaria | 24% (2270/1418/257) | 23% (725/443/57) | R | 0·74 (0·55–0·99) | 0·03 | 0·76 (0·55–0·99) | 0·04 |
| Severe malarial anaemia | 24% (2270/1418/257) | 24% (394/256/37) | R | 0·83 (0·58–1·19) | 0·3 | 0·89 (0·62–1·30) | 0·33 |
| Respiratory distress | 24% (2270/1418/257) | 23% (400/252/33) | R | 0·75 (0·51–1·09) | 0·12 | 0·75 (0·51–1·11) | 0·12 |
| Death | 24% (2270/1418/257) | 23% (156/86/16) | R | 0·96 (0·57–1·63) | 0·9 | 0·98 (0·72–1·72) | 0·97 |
| LPHN2 (also known as ADGRL2; rs72933304, chromosome 1, C→A) | |||||||
| Severe malaria | 8% (3297/619/26) | 7% (1912/296/8) | A | 0·80 (0·69–0·92) | 0·001 | 0·83 (0·72–0·96) | 0·002 |
| Cerebral malaria | 8% (3297/619/26) | 7% (1057/168/5) | A | 0·82 (0·69–0·98) | 0·02 | 0·86 (0·71–0·99) | 0·03 |
| Severe malarial anaemia | 8% (3297/619/26) | 7% (570/93/3) | A | 0·85 (0·68–1·06) | 0·15 | 0·88 (0·70–1·11) | 0·17 |
| Respiratory distress | 8% (3297/619/26) | 7% (587/93/3) | A | 0·83 (0·66–1·03) | 0·09 | 0·85 (0·68–1·07) | 0·11 |
| Death | 8% (3297/619/26) | 6% (228/34/0) | A | 0·74 (0·51–1·05) | 0·08 | 0·77 (0·53–1·11) | 0·12 |
| LOC727982 (rs1371478, chromosome 2; C→T) | |||||||
| Severe malaria | 26% (2123/1466/320) | 29% (1088/958/163) | H | 1·30 (1·17–1·45) | 1·90 × 10−6 | 1·35 (1·20–1·51) | 2·31 × 10−6 |
| Cerebral malaria | 26% (2123/1466/320) | 29% (606/536/84) | H | 1·31 (1·15–1·50) | 4·61 × 10−5 | 1·37 (1·19–1·57) | 7·19 × 10−5 |
| Severe malarial anaemia | 26% (2123/1466/320) | 30% (318/291/154) | H | 1·31 (1·11–1·55) | 0·001 | 1·45 (1·22–1·74) | 0·001 |
| Respiratory distress | 26% (2123/1466/320) | 29% (331/308/43) | H | 1·38 (1·17–1·63) | 0·0001 | 1·47 (1·23–1·74) | 0·0001 |
| Death | 26% (2123/1466/320) | 29% (126/116/21) | H | 1·34 (1·04–1·73) | 0·02 | 1·42 (1·09–1·86) | 0·02 |
| ARL14 (rs75731597, chromosome 3, A→C) | |||||||
| Severe malaria | 8% (2957/500/34) | 10% (1754/401/18) | H | 1·27 (1·10–1·47) | 0·001 | 1·25 (1·07–1·46) | 0·001 |
| Cerebral malaria | 8% (2957/500/34) | 10% (975/222/9) | H | 1·25 (1·05–1·49) | 0·01 | 1·25 (1·04–1·51) | 0·01 |
| Severe malarial anaemia | 8% (2957/500/34) | 10% (520/119/7) | H | 1·27 (1·02–1·59) | 0·03 | 1·30 (1·07–1·59) | 0·04 |
| Respiratory distress | 8% (2957/500/34) | 12% (546/119/5) | H | 1·23 (0·98–1·53) | 0·06 | 1·28 (0·99–1·59) | 0·08 |
| Death | 8% (2957/500/34) | 10% (1754/401/18) | H | 1·45 (1·03–2·04) | 0·01 | 1·55 (1·13–2·13) | 0·01 |
| FREM3 (rs186873296, chromosome 4, A→G) | |||||||
| Severe malaria | 10% (3216/670/40) | 6% (1967/233/6) | A | 0·57 (0·49–0·66) | 4·23 × 10−14 | 0·64 (0·53–0·79) | 3·18 × 10−14 |
| Cerebral malaria | 10% (3216/670/40) | 6% (1087/136/2) | A | 0·59 (0·49–0·71) | 7·16 × 10−9 | 0·63 (0·49–0·79) | 1·12 × 10−8 |
| Severe malarial anaemia | 10% (3216/670/40) | 5% (593/69/1) | A | 0·55 (0·43–0·70) | 4·56 × 10−7 | 0·67 (0·45–0·81) | 8·20 × 10−7 |
| Respiratory distress | 10% (3216/670/40) | 5% (611/68/3) | A | 0·53 (0·41–0·69) | 4·67 × 10−7 | 0·61 (0·44–0·83) | 2·70 × 10−7 |
| Death | 10% (3216/670/40) | 6% (228/29/1) | A | 0·59 (0·40–0·85) | 0·003 | 0·60 (0·31–0·82) | 0·004 |
| INPP4B (rs77389579, chromosome 4, G→T) | |||||||
| Severe malaria | 6% (3407/516/14) | 4% (2019/188/2) | A | 0·61 (0·51–0·72) | 4·48 × 10−9 | 0·64 (0·53–0·77) | 4·79 × 10−9 |
| Cerebral malaria | 6% (3407/516/14) | 5% (1113/109/1) | A | 0·63 (0·51–0·78) | 1·48 × 10−5 | 0·66 (0·52–0·83) | 1·64 × 10−5 |
| Severe malarial anaemia | 6% (3407/516/14) | 4% (613/52/1) | A | 0·56 (0·42–0·75) | 3·57 × 10−5 | 0·60 (0·43–0·82) | 5·35 × 10−5 |
| Respiratory distress | 6% (3407/516/14) | 4% (625/58/0) | A | 0·58 (0·44–0·78) | 8·53 × 10−5 | 0·62 (0·46–0·83) | 9·54 × 10−5 |
| Death | 6% (3407/516/14) | 4% (241/19/0) | A | 0·50 (0·31–0·80) | 0·001 | 0·48 (0·28–0·80) | 0·001 |
| ABO (rs8176719, chromosome 9; blood group O vs non-blood group O)‡ | |||||||
| Severe malaria | 26% (256/3632) | 31% (198/2032) | R | 0·73 (0·65–0·81) | 3·99 × 10−9 | 0·74 (0·66–0·82) | 6·26 × 10−8 |
| Cerebral malaria | 26% (256/3632) | 30% (198/2032) | R | 0·77 (0·68–0·88) | 9·36 × 10−5 | 0·78 (0·69–0·92) | 0·0004 |
| Severe malarial anaemia | 26% (256/3632) | 32% (198/2032) | R | 0·66 (0·56–0·78) | 8·45 × 10−7 | 0·67 (0·78–0·79) | 3·68 × 10−6 |
| Respiratory distress | 26% (256/3632) | 31% (198/2032) | R | 0·70 (0·59–0·83) | 2·74 × 10−5 | 0·71 (0·60–0·84) | 6·45 × 10−5 |
| Death | 26% (256/3632) | 32% (198/2032) | R | 0·67 (0·52–0·87) | 0·002 | 0·67 (0·52–0·87) | 0·002 |
| ABO (rs8176746, chromosome 9; C→A)§ | |||||||
| Severe malaria | 13% (2970/878/76) | 17% (1529/622/76) | A | 1·37 (1·22–1·55) | 9·60 × 10−9 | 1·38 (1·22–1·50) | 2·38 × 10−7 |
| Cerebral malaria | 13% (2970/878/76) | 16% (870/317/36) | A | 1·23 (1·06–1·43) | 0·005 | 1·22 (1·04–1·42) | 0·01 |
| Severe malarial anaemia | 13% (2970/878/76) | 18% (459/196/27) | A | 1·44 (1·20–1·73) | 8·50 × 10−5 | 1·44 (1·19–1·74) | 0·0001 |
| Respiratory distress | 13% (2970/878/76) | 18% (474/178/31) | A | 2·55 (1·66–3·92) | 1·79 × 10−5 | 2·42 (1·56–3·76) | 8·04 × 10−5 |
| Death | 13% (2970/878/76) | 17% (2181/169/8) | A | 1·28 (0·96–1·71) | 0·08 | 1·29 (0·96–1·72) | 0·08 |
| HBB (rs334; chromosome 11; A→T) | |||||||
| Severe malaria | 8% (3320/596/33) | 1% (2159/57/11) | H | 0·14 (0·12–0·21) | 6·81 × 10−59 | 0·15 (0·11–0·20) | 2·61 × 10−58 |
| Cerebral malaria | 8% (3320/596/33) | 2% (1185/29/8) | H | 0·14 (0·09–0·21) | 8·64 × 10−39 | 0·14 (0·09–0·20) | 1·67 × 10−38 |
| Severe malarial anaemia | 8% (3320/596/33) | 2% (666/9/8) | H | 0·07 (0·04–0·15) | 2·11 × 10−31 | 0·07 (0·03–0·17) | 2·61 × 10−31 |
| Respiratory distress | 8% (3320/596/33) | 2% (664/13/7) | H | 0·11 (0·06–0·19) | 8·41 × 10−28 | 0·11 (0·06–0·20) | 1·62 × 10−27 |
| Death | 8% (3320/596/33) | 3% (242/11/3) | H | 0·26 (0·14–0·48) | 1·96 × 10−7 | 0·26 (0·14–0·49) | 2·41 × 10−7 |
| RPS6KL1 (rs3742785, chromosome 14; C→A) | |||||||
| Severe malaria | 29% (1935/1422/357) | 30% (1032/896/187) | H | 1·20 (1·08–1·34) | 0·001 | 1·18 (1·05–1·33) | 0·001 |
| Cerebral malaria | 29% (1935/1422/357) | 29% (584/491/95) | H | 1·18 (1·03–1·35) | 0·01 | 1·19 (1·03–1·37) | 0·01 |
| Severe malarial anaemia | 29% (1935/1422/357) | 32% (293/292/65) | H | 1·33 (1·12–1·57) | 0·001 | 1·37 (1·15–1·64) | 0·001 |
| Respiratory distress | 29% (1935/1422/357) | 28% (341/260/55) | H | 1·06 (0·89–1·26) | 0·45 | 1·06 (0·89–1·27) | 0·5 |
| Death | 29% (1935/1422/357) | 26% (140/95/18) | H | 0·98 (0·75–1·28) | 0·91 | 0·99 (0·76–1·29) | 0·96 |
| HBA (−α3·7-thalassaemia, chromosome 16; insertion/deletion) | |||||||
| Severe malaria | 40% (1356/1953/637) | 36% (853/1026/264) | A | 0·82 (0·76–0·89) | 6·59 × 10−7 | 0·83 (0·76–0·90) | 2·06 × 10−6 |
| Cerebral malaria | 40% (1356/1953/637) | 37% (458/590/141) | A | 0·83 (0·75–0·91) | 0·0001 | 0·83 (0·76–0·92) | 0·0001 |
| Severe malarial anaemia | 40% (1356/1953/637) | 34% (275/299/65) | A | 0·72 (0·64–0·82) | 1·55 × 10−6 | 0·72 (0·65–0·84) | 5·45 × 10−6 |
| Respiratory distress | 40% (1356/1953/637) | 35% (272/311/79) | A | 0·78 (0·69–0·89) | 0·0001 | 0·79 (0·70–0·90) | 0·0002 |
| Death | 40% (1356/1953/637) | 33% (108/117/24) | A | 0·70 (0·57–0·85) | 0·0003 | 0·72 (0·59–0·88) | 0·0004 |
When more than one SNP was genotyped at a locus, we show ORs for the SNP with the lowest p value for severe malaria or any one of its phenotypes. Individuals with multiple phenotypes are included in each of those phenotype groups for analysis. het=heterozygous. hom=homozygous. OR=odds ratio. SNP=single nucleotide polymorphism.
*
Statistical models were additive (A), heterozygous (H), or recessive (R).
†
Adjusted for ethnic group, gender, and rs334.
‡
The recessive model for rs8176719 is presented and represents blood group O.
§
The derived allele of rs8176746 identifies blood group B.