A C-T SNP at position -31 from the transcription start site (rs1143627) involves the TATA sequence in the IL1B promoter. Using electrophoretic mobility shift analysis to assess DNA binding in vitro, El-Omar et al. (2000) found that the IL1B -31T allele was associated with a 5-fold increase in DNA binding after lipopolysaccharide stimulation. Individuals carrying the IL1B -31T allele were at higher risk of hypochlorhydria and of gastric cancer after H. pylori infection (see 613659).
Hamajima et al. (2001) observed the near complete linkage of the -31C/-511T and -31T/-511C IL1B alleles in 241 Japanese non-cancer outpatients participating in an H. pylori eradication program. They determined that the C-to-T transition at position -31, creating a TATA box, is associated with vulnerability to persistent H. pylori infection, and that the susceptibility is modified by smoking. They noted that this linkage was opposite to that reported in Caucasian subjects (El-Omar et al., 2000). Prompted by the report of Hamajima et al. (2001), El-Omar et al. (2000) reviewed and corrected their own data. In an erratum, El-Omar et al. (2000) stated that consistent with the observation of Hamajima et al. (2001), -511T/-31C is the correct linkage in Caucasians.
Among 310 individuals from eastern India, Chakravorty et al. (2006) found that the frequency of the IL1B -31TT genotype was 0.071 compared to 0.37 as reported in Caucasians. Among the Indian population, they observed a significantly higher frequency of the IL1B -511TT genotype (OR of 4.22) and -31CC genotype (OR of 2.16) in H. pylori-infected persons with duodenal ulcer compared to infected persons with normal mucosa. The -511T/-31C haplotype was present at a higher frequency in H. pylori-infected duodenal ulcer patients than in infected controls (OR of 2.47). Carriers of the -31CC genotype had significantly lower IL1B mRNA levels in gastric mucosa compared to other genotypes, and IL1B promoter assay showed that the -31T promoter had a 10-fold increase in activity compared to -31C. Chakravorty et al. (2006) suggested that H. pylori-infected individuals with the -31CC genotype secrete less IL1B and are susceptible to duodenal ulcers.
Possible Association with Tuberculosis Susceptibility
Zhang et al. (2014) examined the genotype distribution of 4 IL1B SNPs with potential regulatory effects in 2 independent Chinese populations with tuberculosis (TB; see 607948) and 2 independent sets of healthy controls (1,799 total TB cases and 1,707 total controls). They found that only the frequency of the T allele of the -31C-T SNP in the IL1B promoter was significantly higher in patients with active TB, both pulmonary and extrapulmonary. High-resolution computer-assisted tomography analysis indicated that the -31T allele was associated with more severe pulmonary TB than the -31C allele. Stimulation of monocytes with Mycobacterium tuberculosis (Mtb) antigens resulted in higher amounts of IL1B protein and mRNA, but not of IL1R antagonist (IL1RN; 147679), in healthy controls carrying -31TT or -31TC compared with those carrying -31CC. Stimulation of PBMCs with Mtb antigens resulted in no significant differences in IFNG (147570) or IL17 (603149) production in controls; however, stimulation was associated with higher IFNG production in TB patients carrying -31TT. Analysis of bronchoalveolar lavage fluid from patients with active TB showed that higher IL1B production was associated with higher neutrophil recruitment. EMSA supershift analysis detected higher binding of CEBPA (116897) and PU.1 (SPI1; 165170) to the -31T oligonucleotide compared with the -31C oligonucleotide. Zhang et al. (2014) concluded that the higher IL1B production and neutrophil recruitment associated with -31T lead to increased tuberculosis susceptibility, tissue-damaging inflammatory responses, and accelerated disease progression.
