An exploratory genome-wide association study of leprosy susceptibility genes in a Thai cohort

Sukanya Wattanapokayakit; Ekawat Pasomsub; Punna Kunhapan; Suphannee Phatsadon; Punnarai Veeraseatakul; Krisada Mahotarn; Taisei Mushiroda

Authors

Sukanya Wattanapokayakit 1 Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health, Nonthaburi
Ekawat Pasomsub Faculty of Medicine Ramathibodi Hospital, Mahidol University
Punna Kunhapan Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health, Nonthaburi
Suphannee Phatsadon Sirinthorn Hospital, Ministry of Public Health, Nonthaburi
Punnarai Veeraseatakul Regional Medical Sciences Center 1 Chiang Mai, Department of Medical Sciences, Ministry of Public Health, Chiang Mai
Krisada Mahotarn Rajprachasamasai Institute, Department of Disease Control, Ministry of Public Health, Samut Prakan
Taisei Mushiroda Center for Genomic Medicine, RIKEN Yokohama Campus, Yokohama City, Kanagawa

Keywords:

Leprosy, Genome-wide association studies, GWAS

Abstract

Leprosy is a chronic granulomatous infectious disease caused by Mycobacterium leprae. Although candidate gene studies have explored genetic susceptibility to leprosy, only a limited number of genomic loci have been independently replicated. In contrast, genome-wide association studies (GWAS) have provided clear evidence that host genetic factors—varying across different ethnic populations—play a critical role in determining human susceptibility to infection and in influencing the progression of infectious diseases. We performed genome-wide association study involving 344 individuals with leprosy - 103 with paucibacillary form and 241 multibacillary form - and 200 control individuals, using the Illumina Ommi express platform. This study highlights a potential genome-wide association signal for leprosy on chromosome 18 (18q21.33–18q22.1) supported by suggestive evidence (P-values<1×10^-5). Within this region, the lead variant rs9949621 demonstrated the strongest association (P-values<4.75×10^-6, Odds Ratio [OR] = 0.53, 95% Confidence Interval [CI] = 0.40-0.70) and is located near the HMSD gene. The association peak extended across a broader region encompassing several SERPIN family genes (SERPINB2, SERPINB10, HMSD, and SERPINB8), where multiple single nucleotide polymorphisms (SNPs) consistently showed P-values below 5.0×10⁻⁵. Collectively, this suggests that variants within this gene cluster may influence genetic susceptibility to leprosy. Importantly, all associated SNPs appeared to confer a protective effect, as the minor alleles were more frequent in controls than in cases, indicating reduced disease risk in carriers. Our genome-wide association study (GWAS) suggests a potential novel link between HMSD and several genes within the SERPIN family and susceptibility to leprosy in the Thai population. While these results highlight a promising genetic association, they will need to be confirmed through independent replication studies and supported by functional investigations. Additional high-resolution genotyping or sequencing analyses will also be necessary to refine these findings and clarify their biological significance.

References

Hastings RC, editor. Leprosy. Edinburgh: Churchill Livingstone; 1985. p. 31-36, 189-194, 322-323.

McDougall AC, Jopling WH. Handbook of leprosy. 5th ed. Oxford: Heinemann Professional Publishing; 1988.

World Health Organization. Global leprosy (Hansen disease) update, 2024: Beyond zero cases – what elimination of leprosy really means. Wkly Epidemiol Rec. 2025;100(37):365-384.

Department of Disease Control, Ministry of Public Health. สถานการณ์โรคเรื้อนในประเทศไทย ปี พ.ศ. 2567 [Internet]. Nonthaburi: Department of Disease Control; 2024 [cited 2025 Aug 28]. Available from: https://rajpracha.ddc.moph.go.th/Rpsi_pages/Nonthaburi/satus_lep.html.

Siddiqui MR, Meisner S, Tosh K, Balakrishnan K, Ghei S, Fisher SE, et al. A major susceptibility locus for leprosy in India maps to chromosome 10p13. Nat Genet. 2001;27(4):439-41.

Tosh K, Meisner S, Siddiqui MR, Balakrishnan K, Ghei S, Golding M, et al. A region of chromosome 20 is linked to leprosy susceptibility in a South Indian population. J Infect Dis. 2002;186(8):1190-3.

Mira MT, Alcaïs A, Van Thuc N, Thai VH, Huong NT, Ba NN, et al. Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nat Genet. 2003;33(3):412-5.

Zhang FR, Huang W, Chen SM, Sun LD, Liu H, Li Y, et al. Genomewide association study of leprosy. N Engl J Med. 2009;361(27):2609-18.

Fava VM, Dallmann-Sauer M, Orlova M, Correa-Macedo W, Van Thuc N, Thai VH, et al. Deep resequencing identifies candidate functional genes in leprosy GWAS loci. PLoS Negl Trop Dis. 2021;15(12):e0010029.

Gilchrist JJ, Auckland K, Parks T, Mentzer AJ, Goldblatt L, Naranbhai V, et al. Genome-wide association study of leprosy in Malawi and Mali. PLoS Pathog. 2022;18(9):e1010312.

Chaichoompu K, Abegaz F, Tongsima S, Shaw PJ, Sakuntabhai A, Pereira L, et al. IPCAPS: an R package for iterative pruning to capture population structure. Source Code Biol Med. 2019;14:2.

Lippert C, Listgarten J, Liu Y, Kadie CM, Davidson RI, Heckerman D. FaST linear mixed models for genome-wide association studies. Nature Methods. 2011;8(10):833-5.

Boughton AP, Welch RP, Flickinger M, VandeHaar P, Taliun D, Abecasis GR, et al. LocusZoom.js: interactive and embeddable visualization of genetic association study results. Bioinformatics. 2021 Sep;37(18):3017-3018.

Leblond J, Laprise MH, Gaudreau S, Grondin F, Kisiel W, Dubois CM. The serpin proteinase inhibitor 8: an endogenous furin inhibitor released from human platelets. Thromb Haemost. 2006;95(2):243-52.

Pigors M, Sarig O, Heinz L, Plagnol V, Fischer J, Mohamad J, et al. Loss-of-Function Mutations in SERPINB8 Linked to Exfoliative Ichthyosis with Impaired Mechanical Stability of Intercellular Adhesions. Am J Hum Genet. 2016;99(2):430-6.

Przygodzka P, Ramstedt B, Tengel T, Larsson G, Wilczynska M. Bomapin is a redox-sensitive nuclear serpin that affects responsiveness of myeloid progenitor cells to growth environment. BMC Cell Biol. 2010;11:30.

Kawase T, Akatsuka Y, Torikai H, Morishima S, Oka A, Tsujimura A, et al. Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen. Blood. 2007;110(3):1055-63.

Medcalf RL, Stasinopoulos SJ. The undecided serpin. The ins and outs of plasminogen activator inhibitor type 2. Febs j. 2005;272(19):4858-67.

Kruithof EK, Baker MS, Bunn CL. Biological and clinical aspects of plasminogen activator inhibitor type 2. Blood. 1995;86(11):4007-24.

Perazzoli S, Fiuza MF, De Moraes PC, Heck R, Vianna FS, Bonamigo RR. Prevalence of genetic variants in SERPINB2 and PKNOX1 genes in erythema nodosum leprosum patients from southern Brazil. J Infect Dev Ctries. 2025;19(7):1083-8.