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Table 1 Association between candidate molecular markers (mutations and copy number variation (CNV)) previously associated with piperaquine resistance and in vitro piperaquine survival assay (PSA) phenotypes of 32 culture-adapted isolates collected from patients treated with 3-day courses of dihydroartemisinin-piperaquine in 2012

From: Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations

Gene polymorphism

Piperaquine survival assay (PSA)

 

n

Survival rate (median, IQR)

P value*

PSA <10 % n = 8

PSA ≥10 % n = 21

P value **

P. falciparum chloroquine resistant transporter gene - Pfcrt (PF3D7_0709000)

      

Alleles

74I/75E/76 T/220S/271E/326S/343L/356 T/371I

7

61.5 (53.6–69.2)

0.005

0 (0 %)

7 (33 %)

0.03***

74I/75E/76 T/220S/271E/326S/356T/371I (Dd2 allele)

16

12.8 (0.6–43.7)

8 (100 %)

8 (38 %)

74I/75E/76 T/220S/271E/326S/353V/356 T/371I

2

49.2 (37–61.5)

0 (0 %)

2 (9.5 %)

74I/75E/76 T/97Y/220S/271E/326S/356T/371I

4

47.1 (40.9–61.2)

0 (0 %)

4 (19 %)

P. falciparum multidrug resistance 1 gene - Pfmdr-1 (PF3D7_0523000)

      

Alleles

643D

1

70.6

0.16

0 (0 %)

1 (5 %)

0.27

184 F

16

51.8 (3.5–61.5)

5 (63 %)

11 (52 %)

184 F/293D

3

19.3 (9.3–35.4)

1 (12 %)

2 (9.5 %)

184 F/1087 L

6

44 (40.1–49.6)

0 (0 %)

6 (29 %)

wild-type

3

0.8 (0.5–27.9)

2 (25 %)

1 (5 %)

CNV (957885 to 962144)

single copy

24

48.1 (38.2–60.1)

0.001

3 (38 %)

21 (100 %)

10−3***

multi-copy (184 F, n = 2 and wild-type, n = 3)

5

0.6 (0.4–2.1)

5 (62 %)

0 (0 %)

P. falciparum multidrug resistance-associated protein 1 - Pfmrp-1 (PF3D7_0112200)

      

Alleles

191Y/437A/785 N/876 V/1007 M

3

0.8 (0.5–83.1)

0.15

2 (25 %)

1 (5 %)

0.02***

191Y/437A/876 V

1

37

0 (0 %)

1 (5 %)

191Y/437A/876 V/1390 T

16

50.5 (39.7–60.1)

1 (13 %)

15 (72 %)

191Y/437A/876 V/1390 T/1669D

1

0.6

1 (12 %)

0 (0 %)

191Y/325S/437A

8

22.9 (0.6–47.1)

4 (50 %)

4 (19 %)

P. falciparum multidrug resistance-associated protein 2 - Pfmrp-2 (PF3D7_1229100)

      

Alleles

199 V/295R/593D/714I/1527 T/1531I

1

0.7

0.07

1 (12.5 %)

0 (0 %)

0.003***

199 V/622D/646D/714I/1188 N/1527 T/1531I

2

3.5 (0.6–6.4)

2 (25 %)

0 (0 %)

199 V/646D/714I/1176 N/1188 N/1527 T/1531I

1

0.8

1 (12.5 %)

0 (0 %)

199 V/646D/714I/1188 N/1527 T/1531I

10

58.7 (29.0–62.1)

2 (25 %)

8 (35 %)

199 V/646D/714I/1527 T/1531I

16

41.7 (38.2–51.6)

1 (12.5 %)

15 (65 %)

199 V/646D/714I/964D/970 N/1527 T/1531I

1

0.3

1 (12.5 %)

0 (0 %)

MAL10:688956 (Chr10)

       

Alleles

3D7 allele type (T)

10

22.9 (0.6–51.8)

0.20

5 (62.5 %)

5 (24 %)

0.08

V1/S mutant-type (A)

19

46.7 (31–58.2)

3 (37.5 %)

16 (76 %)

MAL13:1718319 (Chr13)

       

Alleles

3D7 allele type (A)

1

0.3

–

1 (12.5 %)

0 (0 %)

0.27

V1/S mutant-type (T)

28

41.6 (12.8–57.7)

7 (87.5 %)

21 (100 %)

PFE1010w (Chr5, 831614 to 834340)

      

CNV

single copy

29

–

–

8 (100 %)

21 (100 %)

–

multi-copy

0

–

0 (0 %)

0 (0 %)

–

PFE1085w (Chr5, 882373 to 884898)

      

CNV

single copy

29

–

–

8 (100 %)

21 (100 %)

–

multi-copy

0

–

0 (0 %)

0 (0 %)

–

  1. Pfcrt Dd2, MAL10:688956 and MAL13:1718319 allele types are defined based on sequences available at plasmoDB.org
  2. *Calculated by the Mann-Whitney U or Kruskal-Wallis (H-test) tests
  3. **Calculated by the Fisher exact or χ2 tests
  4. ***Significant P values are shown in bold font
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