Polymorphisms in MC3R promoter and CTSZ 3′UTR are associated with tuberculosis susceptibility

We have validated the association of two genes on chromosome 20q13.31-33 with tuberculosis susceptibility. A previous genome-wide linkage study performed by Cooke et al identified the genes melanocortin-3-receptor (MC3R) and cathepsin Z (CTSZ) as possible candidates in tuberculosis susceptibility. MC3R has been implicated in obesity studies and is known to play a role in many biological systems including the regulation of energy homeostasis and fat metabolism. CTSZ has been detected in immune cells, such as macrophages and monocytes, and it is hypothesized that the protein may play a role in the immune response. In our South African population a case-control study confirmed the previously reported association with a single-nucleotide polymorphism (SNP) in CTSZ and found an association in MC3R with a SNP not previously implicated in tuberculosis susceptibility. Six SNPs in MC3R and eight in CTSZ were genotyped and haplotypes were inferred. SNP rs6127698 in the promoter region of MC3R (cases 498; controls=506) and rs34069356 in the 3'UTR of CTSZ (cases=396; controls=298) both showed significant association with tuberculosis susceptibility (P=0.0004 and <0.0001, respectively), indicating that pathways involving these proteins, not previously researched in this disease, could yield novel therapies for tuberculosis. European Journal of Human Genetics (2011) 19, 676-681; doi:10.1038/ejhg.2011.1; published online 2 February 2011