Liver X receptor gene polymorphisms in tuberculosis: effect on susceptibility.
OBJECTIVE
The Liver X receptors (LXRs), Liver X receptor A (LXRA) and Liver X receptor B (LXRB), regulate lipid metabolism and antimicrobial response. LXRs have a crucial role in the control of Mycobacterium tuberculosis (M.tb). Lacking LXRs mice is more susceptibility to infection M.tb, developing higher bacterial burdens and an increase in the size and number of granulomatous lesions. We aimed to assess the associations between single nucleotide polymorphisms (SNPs) in LXRs and risk of tuberculosis.


METHODS
We sequenced the LXRs genes to detect SNPs and to examine genotypic frequencies in 600 patients and 620 healthy controls to investigate for associations with tuberculosis (TB) in the Chinese Han population. DNA re-sequencing revealed eight common variants in the LXRs genes.


RESULTS
The G allele of rs1449627 and the T allele of rs1405655 demonstrated an increased risk of developing TB (p<0.001, p = 0.002), and the T allele of rs3758673, the T allele of rs2279238, and the C allele of rs1449626 in LXRA and the C allele of rs17373080, the G allele of rs2248949, and the C allele of rs1052677 in LXRB were protective against TB patients compared to healthy controls (p = 0.0002, p = 0.006, p<0.001, p = 0.004, p = 0.008, p = 0.003, respectively). All SNP genotypes were significantly associated with TB. An estimation of the frequencies of haplotypes revealed two potential risk haplotypes,GGCG in LXRB (p = 0.004,) and TTCG in LXRA (p<0.001, p = 0.004). Moreover, three protective haplotypes, TTAT and CCAT in LXRA and CATC in LXRB, were significantly "protective" (p = 0.008, p<0.001, p = 0.031) for TB. Furthermore, we determined that the LXRs SNPs were nominally associated with the clinical pattern of disease.


CONCLUSIONS
Our study data supported that LXRs play a fundamental role in the genetic susceptibility to TB and to different clinical patterns of disease. Thus, further investigation is required in larger populations and in additional areas.
Shanghai Key Laboratory of Mycobacterium Tuberculosis, Shanghai Pulmonary Hospital Affiliated to Tongji University School of Medicine, Shanghai, P.R. China.
Min
M
Han
Shanghai Key Laboratory of Mycobacterium Tuberculosis, Shanghai Pulmonary Hospital Affiliated to Tongji University School of Medicine, Shanghai, P.R. China.
Li
L
Liang
Shanghai Key Laboratory of Mycobacterium Tuberculosis, Shanghai Pulmonary Hospital Affiliated to Tongji University School of Medicine, Shanghai, P.R. China.
Li-Rong
LR
Liu
Shanghai Key Laboratory of Mycobacterium Tuberculosis, Shanghai Pulmonary Hospital Affiliated to Tongji University School of Medicine, Shanghai, P.R. China.
Jun
J
Yue
National Center for Tuberculosis Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, P.R. China.
Yan-Lin
YL
Zhao
Shanghai Key Laboratory of Mycobacterium Tuberculosis, Shanghai Pulmonary Hospital Affiliated to Tongji University School of Medicine, Shanghai, P.R. China.
He-Ping
HP
Xiao
D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D000071518:Liver X Receptors; D008297:Male; D008875:Middle Aged; D057093:Orphan Nuclear Receptors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014376:Tuberculosis / Q000175:diagnosis / Q000235:genetics*; D014397:Tuberculosis, Pulmonary / Q000235:genetics
D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors