Association of HLA class I and II genes with cutaneous leishmaniasis: a case control study from Sri Lanka and a systematic review.
The outcome of leishmaniasis is an interplay between Leishamania and the host. Identifying contributory host genetic factors is complicated by the variability in phenotype, ethnicity and parasite species. Leishmaniasis is caused exclusively by L. donovani in Sri Lanka with localized cutaneous leishmaniasis (LCL) being the predominant form. We report here an association study of human leucocyte antigen (HLA) class I and II genes with LCL in Sri Lanka, the first on HLA associations in cutaneous leishmaniasis in a South Asian population.



An existing DNA repository of 200 each of patients and controls was typed for HLA-DQ by PCR-SSP. Next generation sequencing-based typing for HLA-A, HLA-B and HLA-DRB1 alleles was done in a subset of 280 samples. Association tests were performed on 28,489 genotyped and imputed SNPs spanning a region of 1.4 Mb across the HLA genes. To compare our results with similar studies, we carried out a systematic review to document all HLA associations reported to-date for cutaneous and muco-cutaneous leishmaniasis.



DRB1*04 DQB1*02 (P = 0.03; Pc = 0.09), DRB1*07 DQB1*02 (P = 0.03; Pc = 0.09) haplotypes were absent in patients. B*07 (P = 0.007; Pc = 0.13; OR = 0.36; 95 % CI = 0.17-0.77) allele and DRB1*15 DQB1*06 (P = 0.00; Pc < 0.01; OR = 0.3; 95 % CI = 0.2-.0.6) haplotype were over represented in controls and DRB1*15 (P = 0.002; Pc = 0.01) allele was over represented in patients. Two SNPs (rs281864595/rs1050517) in the antigen recognition region of HLA-B, comprised a haplotype more frequent in controls (P = 0.04). The alleles identified by the systematic review to predispose or to protect from cutaneous/mucocutaneous leishmaniasis remained highly heterogeneous in different populations studied.



Our preliminary findings suggest a role for some class I and class II HLA genes in determining predisposition to LCL in this population which should be corroborated with further studies. The systematic review reiterates this need, as the purported susceptibility or protection gained by certain HLA alleles or haplotypes has rarely been independently verified.
Department of Parasitology, Faculty of Medicine, University of Colombo, 271, Kynsey Road, Colombo, 008, Sri Lanka.
Nilakshi
N
Samaranayake
Department of Parasitology, Faculty of Medicine, University of Colombo, 271, Kynsey Road, Colombo, 008, Sri Lanka. ferndeep@gmail.com.
Sumadhya D
SD
Fernando
Human Genetics Unit, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka.
Nilaksha F
NF
Neththikumara
Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka.
Chaturaka
C
Rodrigo
Department of Parasitology, Faculty of Medicine, University of Colombo, 271, Kynsey Road, Colombo, 008, Sri Lanka.
Nadira D
ND
Karunaweera
Human Genetics Unit, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka.
Vajira H W
VH
Dissanayake
D000293:Adolescent; D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005006:Ethnicity; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016773:Leishmaniasis, Cutaneous / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D013188:Sri Lanka; D055815:Young Adult
D015234:HLA-A Antigens; D015235:HLA-B Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains
Asia; Genetic polymorphism; Genetic predisposition; Host-parasite interactions; Immune response genes; Leishmania donovani; Neglected diseases