Genome-wide association study identifies two risk loci for tuberculosis in Han Chinese

Zheng, Ruijuan; Li, Zhiqiang; He, Fusheng; Liu, Haipeng; Chen, Jianhua; Chen, Jiayu; Xie, Xuefeng; Zhou, Juan; Chen, Hao; Wu, Xiangyang; Wu, Juehui; Chen, Boyu; Liu, Yahui; Cui, Haiyan; Fan, Lin; Wang, Sha; Liu, Yin; Wang, Jiqiang; Huang, Xiaochen; Zhang, Linfeng; Xu, Fei; Wang, Jie; Feng, Yonghong; Qin, Lianhua; Yang, Hua; Z, Liu; Cui, Zhenglin; Feng, Lei; Chen, Xinchun; Gao, Shaorong; Sun, Silong; Shi, Yongyong; Ge, Baoxue

doi:10.1038/s41467-018-06539-w

Cited by 56 publications

(72 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is more likely to be >10, as shown by the data for the infected control simulation, corresponding to a lifetime risk of TB between 40 and 80%. This OR is higher than those reported for the few SNPs identified by genome-wide association studies (GWAS) in TB (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). These 12 GWAS did not detect the effect of P1104A, as they did not report testing a recessive model.…”

Section: Discussioncontrasting

confidence: 56%

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

Kerner

Ramírez-Alejo

Seeleuthner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common TYK2 P1104A variant in a heterogeneous cohort of patients with TB from non-European countries in which TB is endemic. This variant is homozygous in ∼1/600 Europeans and ∼1/5,000 people from other countries outside East Asia and sub-Saharan Africa. We report a study of this variant in the UK Biobank cohort. The frequency of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of 5.0 [95% confidence interval (CI): 1.96-10.31, P = 2 × 10 −3 ]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for TYK2 I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with Mycobacterium tuberculosis, as 97% were of European genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom. Had all of them been infected, the OR for developing TB upon infection would be higher. These findings suggest that homozygosity for TYK2 P1104A may account for ∼1% of TB cases in Europeans.T uberculosis (TB) remains a major global public health problem. About a quarter of the world's population is infected with Mycobacterium tuberculosis (1, 2), resulting in ∼10 million new cases and 1.6 million deaths worldwide in 2017 (3). Nevertheless, only ∼5% of infected individuals develop active TB in their lifetime (1,4). Abundant evidence for the existence of a genetic component of TB in humans has accumulated from classic genetics studies performed from the turn of the 20th century onward, but its molecular architecture has long remained elusive (5-9). From 1996 onward, single-gene inborn errors of IFN-γ immunity have been found to underlie Mendelian susceptibility to mycobacterial disease (MSMD), which is characterized by severe disease caused by poorly virulent mycobacteria (bacillus Calmette-Guérin vaccines and environmental mycobacteria) (10-15). The clinical penetrance for MSMD depends on the genetic etiology and is inversely correlated with the levels of residual IFN-γ immunity (16). From 2001 onward, autosomal recessive interleukin-12 receptor β1 (IL-12Rβ1) and tyrosine kinase 2 (TYK2) deficiencies have also been identified in children with severe TB and without MSMD (17-23). These two deficiencies impair both the IL-12-and IL-23-dependent production of IFN-γ. They are caused by very rare (minor allele frequency, MAF <5 × 10 −5 worldwide) or private loss-of-function alleles.We recently discovered a strong enrichment in homozygosity for the common TYK2 missense variant P1104A in a genetically heterogeneous cohort of patients with TB from countries outside of Europe in which this disease is endemic, relative to ancestryadjusted controls, with an odds ratio (OR) of 89.3 (95% CI, 14.7-1,725, P = 8.37 × 10 −8 ) (24). Homozygosity for P1104A is also a genetic etiology of MSMD, albeit with much lower estimate...

show abstract

Section: Discussioncontrasting

confidence: 56%

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

Kerner

Ramírez-Alejo

Seeleuthner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…These results indicate that ERAP2 may play a significant role in TB resistance. However, in a previous GWAS study in China, no association was identified between TB and ERAP genes (Chen et al, 2016a;Zheng et al, 2018). The race, sample size, characteristics of the patients and controls, and the genotyping methods used, are some of the factors that may affect the association study results.…”

Section: Discussionmentioning

confidence: 96%

“…The genes involved in antigen presentation, induction and function of cytokines/chemokines, and associated receptors have been suggested to play important roles in controlling an M. tb infection (Fol et al, 2015;Mao et al, 2015). In recent genome-wide association studies (GWAS) of TB risk in the Han Chinese population, new risk loci in ASAP1, ESRRB, and TGM6 genes have been identified (Chen et al, 2016a;Zheng et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in ERAP1 and ERAP2 Genes Are Associated With Tuberculosis in the Han Chinese

Zhang

Liu

et al. 2020

Front. Genet.

View full text Add to dashboard Cite

Single nucleotide polymorphisms (SNPs) in the endoplasmic reticulum aminopeptidase (ERAP1 and ERAP2) genes are associated with the pathogenesis of bacterial and viral infections. To search for the variations in the ERAP1 and ERAP2 genes associated with tuberculosis (TB), 449 TB cases and 435 healthy individuals of the Han population in the Yunnan province of China were included in the present study. Eleven SNPs of ERAPs were genotyped using the SNaPshot SNP assay. Allelic, genotypic, and haplotypic association analyses were performed between the TB and control groups. Furthermore, stratification analyses among pulmonary TB (PTB), extrapulmonary TB (EPTB), and healthy controls; and initial treatment TB (ITTB), retreatment TB (RTB), and healthy controls were also performed. The TT genotype of rs26618 in ERAP1 exhibited a protective factor for TB, compared with the role of the CC/CT genotype (P = 0.003; OR = 1.490, 95% CI: 1.140-1.940). In ERAP2, the frequency of the G allele of rs2549782 was higher in the case group than in the control group (0.491 vs. 0.417, P = 0.002, OR = 1.350, 95% CI: 1.118-1.631), and the TT genotype exhibited a protective factor for TB, compared with the role of the GG/GT genotype (P = 0.001; OR = 1.650, 95% CI: 1.230-2.220). The frequency of the C allele of rs1056893 was higher in the case group than in the control group (0.468 vs. 0.394, P = 0.002, OR = 1.350, 95% CI: 1.118-1.631), and the genotype exhibited a difference in the log-additive model (P = 0.002; OR = 1.350, 95% CI: 1.120-1.630). The frequencies of the haplotype rs27037-rs27044-s30187-rs26618-rs26653-rs3734016-GCCCGC in ERAP1 (0.290 vs. 0.240, P-adj = 0.028, OR = 1.320, 95% CI: 1.063-1.638) and the haplotypes rs2549782-rs2248374-rs2287988-rs1056893-GTAGC in ERAP2 (0.446 vs. 0.348, P-adj = 4.80E-05, OR = 1.510, 95% CI: 1.246-1.829) was higher in the TB groups, while the frequencies of the haplotypes rs2549782-rs2248374-rs2287988-rs1056893-TAGAT (0.478 vs. 0.539, P-adj = 0.020, OR = 0.782, 95% CI: 0.649-0.943) were lower in the TB groups. The allelic and genotypic associations were also investigated in the subsequent stratification between the PTB, EPTB and control groups as well as between the ITTB, RTB, and control groups. In conclusion, variations in ERAP1 and ERAP2 genes were identified to be associated with TB in the Han Chinese population.

show abstract

“…GWAS may provide insights into the genetic factors driving population susceptibility to viral infections [67,68]. This information can be utilized to identify populations within geographic regions at higher or lower risk of being infected with a new pathogen.…”

Section: Host-based Diagnostics and Genomics Approachesmentioning

confidence: 99%

Emerging viral infections

Colón-López

Stefan

Koehler

2019

Genomic and Precision Medicine

View full text Add to dashboard Cite

Genome-wide association study identifies two risk loci for tuberculosis in Han Chinese

Cited by 56 publications

References 55 publications

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

Polymorphisms in ERAP1 and ERAP2 Genes Are Associated With Tuberculosis in the Han Chinese

Emerging viral infections

Contact Info

Product

Resources

About