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Influence of interleukin-12 receptor beta1 polymorphisms on tuberculosis
Mitsuteru Akahoshi1, Hitoshi Nakashima, Katsuhisa Miyake
1Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Human Genetics
|February 22, 2003
Summary
Genetic variations in the interleukin-12 receptor beta 1 gene (IL12RB1) are linked to increased tuberculosis susceptibility in the Japanese population. Specific IL12RB1 alleles reduce cellular responses to IL-12, potentially impairing immunity.
Area of Science:
- Immunogenetics
- Tuberculosis Research
- Cytokine Signaling
Background:
- Host genetic factors significantly influence tuberculosis (TB) susceptibility.
- Deficiencies in the type-1 cytokine pathway highlight the role of specific genes.
- Polymorphisms in cytokine receptor genes may contribute to TB risk in the general population.
Purpose of the Study:
- To investigate the association between polymorphisms in the interleukin-12 receptor (IL-12R) gene and predisposition to tuberculosis.
- To identify specific genetic variants within the IL-12R beta 1 (IL12RB1) gene associated with TB risk.
Main Methods:
- Single-strand conformational polymorphism analysis and direct sequencing to identify polymorphisms in IL-12R beta 2 (IL12RB2) and IL-12R beta 1 (IL12RB1) genes.
- Polymerase chain reaction/restriction fragment length polymorphism and sequence analyses to genotype IL12RB1 polymorphisms in Japanese TB patients and healthy controls.
- Case-control association study to evaluate the link between IL12RB1 variants and TB.
- Assessment of cellular responses to IL-12 in healthy subjects with different IL12RB1 haplotypes.
Main Results:
- Four single nucleotide polymorphisms (SNPs) were identified in the IL12RB1 gene, forming two common haplotypes: allele 1 (Q214-M365-G378) and allele 2 (R214-T365-R378).
- The R214-T365-R378 allele (allele 2) was significantly over-represented in patients with tuberculosis.
- Homozygosity for the R214-T365-R378 genotype (2/2) was strongly associated with an increased risk of tuberculosis (odds ratio: 2.45, P=0.013).
- Homozygotes for the R214-T365-R378 genotype exhibited reduced IL-12-induced signaling in cellular assays.
Conclusions:
- The R214-T365-R378 allele in the IL12RB1 gene is associated with increased susceptibility to tuberculosis in the Japanese population.
- This genetic variation may predispose individuals to TB by diminishing IL-12 and IL-23 receptor responsiveness.
- Reduced receptor responsiveness can lead to partial dysfunction of interferon-gamma-mediated immunity, increasing TB risk.