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Olivo Miotto edited this page Sep 17, 2021 · 1 revision

pfdhps

Locus: PF3D7_0810800 (pfdhps)


Plasmodium falciparum dihyropteroate synthase (pfdhps) gene encodes an important protein in the folate biosynthesis pathway of the parasite. Polymorphisms of PfDHPS have been associated with reduced susceptibility to antifolate treatment, e.g. sulfadoxine and sulfadoxine/pyrimethamine.


Table 1 Frequent mutations in PfDHPS

Codon Wild-type Mutation
436 S A, C, F, H, Y
437 A G
540 K E, I, K, N, Y
581 A G
613 A S, T

Haplotype Distribution

The following table demonstrated the distribution of PfDHPS haplotypes in different geographical subcontinents. This table used the data from Version 6.0 of MalariaGEN Plasmodium falciparum Community Project .

Table 2 Haplotype distribution of PfDHPS among different geographical locations

Haplotypea SAM EAF CAF WAF SAS ESEA WSEA OCE TOTAL
AAKAA 0 13 9 384 0 16 0 0 422
AAKAS 0 0 0 2 0 0 0 0 2
AAKGS 0 0 0 1 0 0 0 0 1
AGEAA 0 1 0 0 71 342 283 0 697
AGEAT 0 0 0 0 0 2 0 0 2
AGEGA 0 0 0 0 0 1 0 0 1
AGIAA 0 0 0 0 0 0 1 0 1
AGKAA 0 0 24 367 0 135 0 0 526
AGKAS 0 0 1 63 0 0 0 0 64
AGKAT 0 0 0 0 0 3 0 0 3
AGKGS 0 0 4 43 0 0 0 0 47
AGNAA 0 0 0 0 0 0 18 0 18
CAKAA 0 0 0 5 0 1 0 3 9
FAKAA 0 0 0 0 0 3 0 0 3
FAKAS 0 1 0 8 0 1 0 0 10
FGEAS 0 0 0 0 0 37 0 0 37
FGEAT 0 0 0 0 0 2 4 0 6
FGKAS 1 2 0 0 0 1 0 0 4
FGKAT 0 3 0 0 0 0 0 0 3
HAKAA 0 1 0 0 0 0 0 0 1
HGEAA 0 7 0 0 0 0 0 8 15
SAKAA (wild-type) 45 57 14 120 13 143 3 79 474
SGEAA 0 634 25 12 15 85 21 96 888
SGEGA 4 68 9 1 13 49 752 0 896
SGKAA 42 12 398 755 3 113 2 11 1336
SGKAS 0 0 0 2 0 0 0 0 2
SGKGA 5 4 0 1 5 18 22 0 55
SGNGA 0 0 0 0 0 633 72 0 705
SGYAA 0 0 0 0 0 2 0 0 2
YAKAS 0 0 0 7 0 0 0 0 7
TOTAL 97 803 484 1771 120 1587 1178 197 6237

aRepresents amino acids, left-to-right, at codons 436, 437, 540, 581 and 613, respectively

SAM = South America; EAF = East Africa; CAF = Central Africa; WAF = West Africa;

SAS = South Asia; ESEA = East South-East Asia; WSEA = West South-East Asia; OCE = Oceania

Associations between alleles

To impute the missing codons in PfDHPS, the associations between amino acids at position 436, 437, 540, 581 and 613 were assessed to generate the imputation rules using the data from MalariaGEN Plasmodium falciparum Community Project version 6.0.


Codons 436 and 581

There is a significant association between PfDHPS codons 436 and 581 in the parasites from all regions (see Table 3). The results suggested the following imputation rules:

  1. 436F predicts A581
  2. 436H predicts A581

Table 3 Contingency table of co-occurrence between codons 436 and 581

All regions A581 581G Total
436A 1954 58 2012
436C 9 0 9
436F 63 0 63
436H 17 0 17
S436 3114 1716 4830
436Y 9 0 9
Total 5166 1774 6940

Fisher's exact test : P < 0.05


Codons 437 and 581

There is a significant association between PfDHPS codons 437 and 581 in the parasites from all regions (see Table 4). Co-occurrence between A437 and 581G occurred only in 1 sample (haplotype: AAKGS) from West Africa. This suggested the following imputation rules for all region:

  1. A437 predicts A581
  2. 581G predicts 437G

Table 4 Contingency table of co-occurrence between codons 437 and 581

All regions A581 581G Total
A437 1032 1 1033
437G 4370 1780 6150
Total 5402 1781 7183

Fisher's exact test : P < 0.01


Codons 613 and 581

There is no significant association between PfDHPS codons 613 and 581 in the parasites from all regions (see Table 5) However, the results from Table 6 suggested the following imputation rules for parasites in Asia (SubContinent: SAS, ESEA and WSEA):

  1. 613S predicts A581
  2. 613T predicts A581
  3. 581G predicts A613

Table 5 Contingency table of co-occurrence between codons 613 and 581

All regions A581 581G Total
A613 5682 1746 7428
613S 147 57 204
613T 14 0 14
Total 5843 1803 7646

Fisher's exact test : P = 0.051

Table 6 Contingency table of co-occurrence between codons 613 and 581 in Asia

Asia A581 581G Total
A613 1473 1646 3119
613S 40 0 40
613T 11 0 11
Total 1524 1646 3170

Fisher's exact test : P < 0.01


Codons 540 and 613

There is a significant association between 540N mutation and A613 (Fisher's exact test: P < 0.01) in parasites from all regions (See table 7). This result suggest a general imputation rule for parasites from all regions:

  1. 540N predicts A613

Table 7 Contingency table of co-occurrence between codons 540 and 613

All regions A613 613S 613T Total
540E 2739 40 8 2787
540I 1 0 0 1
K540 3809 169 6 3984
540N 751 0 0 751
540Y 2 0 0 2
Total 7302 209 14 7525

The African parasites data (subcontinent codes: WAF, CAF and EAF) also suggest these following additional imputation rules (see Table 8):

  1. 540E predicts A613
  2. 613S predicts K540
  3. 613T predicts K540

Table 8 Contingency table of co-occurrence between codons 540 and 613 in Africa

Africa A613 613S 613T Total
540E 835 0 0 835
K540 2789 140 3 2932
Total 3624 140 3 3767

Fisher's exact test : P < 0.01


Codons 436 and 613

The data showed significant association only when considering Asian parasites (see Table 9). The results suggested the following rules for Asia (Subcontinent codes: SAS, ESEA, WSEA).

  1. S436 predicts A613
  2. 613S predicts 436F

Table 9 Contingency table of co-occurrence between codons 436 and 613 in Asia

Asia A613 613S 613T Total
436A 920 0 5 925
436C 1 0 0 1
436F 3 42 6 51
S436 2114 0 0 2114
Total 3038 42 11 3091

Fisher's exact test : P < 0.01


Codons 436 and 540

There are significant associations between K540 and 436C mutation and between K540 and 436Y mutation in the parasites from all regions (Fisher's exact test : P < 0.01). The results from Table 10 suggested the following imputation rules:

  1. 436C predicts K540
  2. 436Y predicts K540

Table 10 Contingency table of co-occurrence between codons 436 and 540

All regions 540E 540I K540 540N 540Y Total
436A 717 1 1270 18 0 2006
436C 0 0 9 0 0 9
436F 45 0 20 0 0 65
436H 16 0 1 0 0 17
S436 1864 0 2155 720 2 4741
436Y 0 0 9 0 0 9
Total 2642 1 3464 738 2 6847

The African parasites data (subcontinent codes: WAF, CAF and EAF) also suggest these following additional imputation rules (see Table 11):

  1. 436F predicts K540

Table 11 Contingency table of co-occurrence between codons 436 and 540 in Africa

Africa 540E K540 Total
436A 1 1033 1034
436C 0 5 5
436F 0 14 14
436H 7 1 8
S436 802 1410 2212
436Y 0 9 9
Total 810 2472 3282

Fisher's exact test : P < 0.01


Codons 437 and 540

There is a significant association between codons 437 and 540 in parasites from all regions. The results in Table 12 suggested the following imputation rules:

  1. 540E predicts 437G
  2. 540N predicts 437G
  3. A437 predicts K540

Table 11 Contingency table of co-occurrence between codons 437 and 540

All regions 540E 540I K540 540N 540Y Total
A437 0 0 1024 0 0 1024
437G 2758 1 2686 742 2 6189
Total 2758 1 3710 742 2 7213

Fisher's exact test : P < 0.01


Codons 436 and 437

There is a significant association between codons 436 and 437 in parasites from all regions. The results in Table 12 suggested the following imputation rules:

  1. 436C predicts A437
  2. 436Y predicts A437

Table 12 Contingency table of co-occurrence between codons 436 and 437

All regions A437 437G Total
436A 454 1495 1949
436C 9 0 9
436F 13 53 66
436H 1 16 17
S436 491 4344 4835
436Y 9 0 9
Total 977 5908 6885

Fisher's exact test : P < 0.01


Imputation Rules

Summary of imputation rules generated from association among PfDHPS codons in MalariaGEN Plasmodium falciparum Community Project dataset.

Table 13 Imputation rules for predicting PfDHPS haplotype

Region Inputa Outputa Coding
Any F - - - - F - - A - if(dhps_436[S] == "F") {dhps_581[A] <- "A"}
Any H - - - - H - - A - if(dhps_436[S] == "H") {dhps_581[A] <- "A"}
Any C - - - - C A K A - if(dhps_436[S] == "C") {dhps_437[A] <- "A" &
dhps_540[K] <- "K" & dhps_581[A] <- "A"}
Any Y - - - - Y A K A - if(dhps_436[S] == "Y") {dhps_437[A] <- "A" &
dhps_540[K] <- "K" & dhps_581[A] <- "A"}
Any - A - - - - A K A - if(dhps_437[A] == "A") {dhps_540[K] <- "K" &
dhps_581[A] <- "A"}
Any - - N - - - G N - A if(dhps_540[K] == "N") {dhps_437[A] <- "G" &
dhps_613[A] <- "A"
Any - - E - - - G E - - if(dhps_540[K] == "E") {dhps_437[A] <- "G"}
Any - - - G - - G - G - if(dhps_581[A] == "G") {dhps_437[A] <- "G"}
EAF, CAF, WAF F - - - - F - K A - if(dhps_436[S] == "F") {dhps_540[K] <- "K" &
dhps_581[A] <- "A"}
EAF, CAF, WAF - - E - - - G E - A if(dhps_540[K] == "E") {dhps_437[A] <- "G" &
dhps_613[A] <- "A"}
EAF, CAF, WAF - - - - S - - K - S if(dhps_613[A] == "S") {dhps_540[K] <- "K"}
EAF, CAF, WAF - - - - T - - K - T if(dhps_613[A] == "T") {dhps_540[K] <- "K"}
SAS, WSEA, ESEA S - - - - S - - - A if(dhps_436[S] == "S") {dhps_613[A] <- "A"}
SAS, WSEA, ESEA - - - G - - G - G A if(dhps_581[A] == "G") {dhps_437[A] <- "G" &
dhps_613[A] <- "A"}
SAS, WSEA, ESEA - - - - S F - - A S if(dhps_613[A] == "S") {dhps_436[S] <- "F" &
dhps_581[A] <- "A"}
SAS, WSEA, ESEA - - - - T - - - A T if(dhps_613[A] == "T") {dhps_581[A] <- "A"}

aRepresents amino acids, left-to-right, at codons 51, 59, 108 and 164, respectively


See also

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