gene pfmdr1

pfmdr1

Locus: PF3D7_0523000 (pfmdr1)

The Plasmodium falciparum multidrug resistance 1 transporter (PfMDR1) is encoded by pfmdr1 gene. This transporter is located at the digestive vacuole membrane of the parasite. Two types of alterations to this transporter have been considered to affect antimalarial drug sensitivity: (1) PfMDR1 polymorphisms, and (2) pfmdr1 amplification. Mutations at amino acid residues 86, 184 and 1246 have been associated with altered parasite susceptibility to chloroquine, amodiaquine and artemether/lumefantrine. In addition, increased pfmdr1 copy numbers have been associated with resistance to mefloquine and lumefantrine.

Table 1 Frequent mutations in PfMDR1

Codon	Wild-type	Mutation
86	N	Y
184	Y	F
1246	D	Y

Haplotype Distribution

The following table demonstrated the distribution of PfMDR1 haplotypes in different geographical subcontinents. This table used the data from Version 6.0 of MalariaGEN Plasmodium falciparum Community Project . Haplotypes NYY, YFD, YFY and YYY are common in Africa while they are rarely occurred in other regions.

Table 2 Haplotype distribution of PfMDR1 among different geographical locations

Haplotypea	SAM	EAF	CAF	WAF	SAS	ESEA	WSEA	OCE	TOTAL
NFD	65	238	119	942	19	990	214	78	2665
NFY	34	3	0	2	0	0	3	0	42
NYD (wild-type)	1	250	165	552	92	767	1003	25	2855
NYY	0	4	0	1	0	0	0	0	5
YFD	0	7	48	296	0	0	0	1	352
YFY	0	0	9	5	0	0	0	0	14
YYD	2	42	69	11	16	4	12	103	259
YYY	0	63	17	30	0	0	0	0	110
TOTAL	102	607	427	1839	127	1761	1232	207	6302

^aRepresents amino acids, left-to-right, at codons 86, 184 and 1246, 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 PfMDR1, the associations between amino acids at position 86, 184 and 1246 were assessed to generate the imputation rules using the data from MalariaGEN Plasmodium falciparum Community Project version 6.0.

Codons 86 and 184

There is no significant association between PfMDR1 codons 86 and 184 in parasites from all regions (see Table 3) . However, the results from Table 4 suggested the following imputation rules for parasites in Asia (SubContinent: SAS, ESEA and WSEA):

1. 86Y predicts Y184
2. 184F predicts N86

Table 3 Contingency table of co-occurrence between codons 86 and 184

All regions	N86	86Y	Total
184F	2852	399	3251
Y184	2961	392	3353
Total	5813	791	6604

Fisher's exact test : P = 0.47

Table 4 Contingency table of co-occurrence between codons 86 and 184 in Asia

Asia	N86	86Y	Total
184F	1231	0	1231
Y184	1877	32	1909
Total	3108	32	3140

Fisher's exact test : P < 0.01

Codons 86 and 1246

There is a significant association between PfMDR1 codons 86 and 1246 (see Table 5) but it is not sufficient to generate a imputation rule.

Table 5 Contingency table of co-occurrence between codons 86 and 1246

All regions	N86	86Y	Total
D1246	6636	662	7298
1246Y	49	131	180
Total	6685	793	7478

Fisher's exact test : P < 0.01

Codons 184 and 1246

There is a significant association between PfMDR1 codons 184 and 1246 (see Table 6) but it is not sufficient to generate a imputation rule.

Table 6 Contingency table of co-occurrence between codons 184 and 1246

All regions	184F	Y184	Total
D1246	3345	3296	6641
1246Y	59	122	181
Total	3404	3418	6822

Fisher's exact test : P < 0.01

Imputation Rules

Summary of imputation rules generated from association among PfMDR1 codons in MalariaGEN Plasmodium falciparum Community Project dataset.

Table 7 Imputation rules for predicting PfMDR1 haplotype

Region	Inputa	Outputa	Coding
SAS, ESEA, WSEA	Y - -	Y Y -	if(mdr1_86[N] == “Y”){mdr1_184[F] <- “Y”}
SAS, ESEA, WSEA	- F -	N F -	if(mdr1_184[Y] == “F”){mdr1_86[F] <- “N”}

^aRepresents amino acids, left-to-right, at codons 86, 164 and 1246, respectively

See also

• Amodiaquine
• Lumefantrine
• Mefloquine