Genetic differences in CD36 and SR-B1 shape tuberculosis risk

Tuberculosis remains a major global health problem, and not everyone exposed to Mycobacterium tuberculosis (Mtb) develops active disease. Many people carry a latent tuberculosis infection (LTBI) without symptoms, while others progress to active TB. Scientists are increasingly looking at host genetics to explain these different outcomes. In a study led by corresponding author Sidra Younis, researchers focused on two scavenger receptor genes, CD36 and SR-B1, which help immune cells recognize microbes and handle lipids — processes important to how Mtb enters cells and alters immune responses. The team set out to see whether specific single nucleotide polymorphisms (SNPs) in these genes are linked to either LTBI or active TB. They genotyped three variants that had not previously been examined together in one population — rs1761667 and rs3211938 in CD36 and rs4238001 in SR-B1 — and compared their frequencies between people with LTBI, people with active TB, and controls. The study also used computational tools to predict whether these variants might change protein function or gene regulation, and compared allele frequencies with international population data.

The researchers used a case-control design and genotyped polymorphisms with ARMS-PCR, comparing genotype frequencies using Fisher’s exact chi-square test. Functional and regulatory effects were predicted with PolyPhen-2 and RegulomeDB, and population comparisons used the 1000 Genomes database. Key results showed distinct patterns for SR-B1 and CD36. For SR-B1 rs4238001, the homozygous AA genotype was strongly associated with active TB (p = 0.00), while the heterozygous GA genotype was linked to protection against LTBI (p = 0.00). In CD36, the homozygous GG genotype of rs3211938 was associated with protection against active TB (p = 0.02) but showed the opposite pattern in LTBI (p < 0.00). The heterozygous GA genotype of rs1761667 was significantly associated with increased risk of LTBI (p = 0.00). In silico prediction classified rs4238001 as a missense variant and rs3211938 as a nonsense variant. Regulatory analysis suggested that rs4238001 and rs1761667 affect transcription in TB-relevant tissues, and allele frequencies varied across populations in the 1000 Genomes comparison.

Taken together, these findings indicate that polymorphisms in SR-B1 and CD36 have different relationships with the two major stages of tuberculosis: infection establishment (LTBI) and disease onset (active TB). The contrasting association patterns — for example, the same CD36 variant showing protection in active disease but an opposite pattern in latent infection — suggest that genetic influences on initial infection and on progression to symptomatic disease can be separate and even opposing. The computational results add biological plausibility by identifying a missense change in SR-B1 and a nonsense change in CD36, and by flagging regulatory effects in tissues relevant to TB. The authors conclude that these polymorphisms reveal a novel host genetic component of TB pathogenesis and emphasize that the results should be validated in larger, multiethnic cohorts. If confirmed, the work could help scientists better understand who is most likely to harbor latent infection versus who may progress to active disease, guiding future research into risk stratification and host-directed strategies.