Association of rs4331426 and rs2057178 with Risk of Tuberculosis: Evidence from a Meta-Analysis.
Xue Yun,Bai Xuefei,Hu Zhigang,Zhao Zhanqin,Zuo Yanjun,Xia Yuehong,Gao Weina,Chen Fan
Genetic testing and molecular biomarkers
AIMS:A growing number of genome-wide association studies (GWAS) have revealed associations between single-nucleotide polymorphisms (SNPs) and susceptibility to tuberculosis (TB). However, the results of these studies have been inconclusive. This study evaluated whether the SNPs rs4331426 and rs2057178, identified by GWAS, are associated with TB susceptibility. METHODS:We performed meta-analyses for rs4331426, based on eight case-control studies which included a total of 4988 TB cases and 9041 controls; and rs2057178, based on five case-control studies, including a total of 9400 TB cases and 14,459 controls. RESULTS:Our meta-analyses indicated that both rs4331426 and rs2057178 were associated with increased risk of TB (G vs. A: odds ratio [OR] = 1.15, 95% confidence interval [CI]: 1.08-1.22 and A vs. G: OR = 0.84, 95% CI: 0.80-0.88, respectively), especially in an African subgroup. However, no significant TB association was found with rs4331426 in an Asian subgroup. CONCLUSIONS:These meta-analyses indicate that rs4331426 and rs2057178 might play a role in the risk of developing TB, especially in Africans; however, rs4331426 might not play a significant role in the risk of developing TB in Asians.
10.1089/gtmb.2015.0210
Genetic variants at 18q11.2 and 8q24 identified by genome-wide association studies were not associated with pulmonary tuberculosis risk in Chinese population.
Miao Ruifen,Ge Haibo,Xu Lin,Sun Zhaoping,Li Chen,Wang Rong,Ding Songning,Yang Chen,Xu Fei
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases
OBJECTIVE:Genome-wide association study (GWAS) recently identified several susceptibility loci in ASAP1 gene on chromosome 8q24 for tuberculosis (TB) in a Russian population, but no relevant studies have been performed to validate these findings. In addition, previous GWAS in Ghana and Gambia found that the variant rs4331426 at 18q11.2 was a susceptibility locus for TB. However, the follow-up studies reported conflicting results. Herein, we investigated the contribution of genetic variants at 8q24 and 18q11.2 to TB in Chinese population. METHODS:We genotyped four genetic variants at 8q24 (rs10956514 and rs11774633) and 18q11.2 (rs4331426 and rs6507226) in a case-control study with 355 newly bacteriologically confirmed pulmonary TB cases and 395 healthy controls using TaqMan allelic discrimination assay. Subsequently, we conducted a meta-analysis including 4 reported studies in Chinese populations and our case-control study with a total of 3118 cases and 3226 controls to further evaluate the relationship between rs4331426 at 18q11.2 and TB risk. RESULTS:We did not find significant association between genetic variants at 8q24 and risk of TB (rs10956514: OR=0.89, 95%CI: 0.72-1.09, P=0.253; rs11774633: OR=0.86, 95%CI: 0.69-1.08, P=0.206). We did not observe significant association for genetic variants at 18q11.2 (rs4331426: OR=0.62, 95%CI: 0.34-1.14, P=0.122; and rs6507226: OR=0.98, 95%CI: 0.80-1.20, P=0.853). Moreover, the pooled results from the Meta-analysis further supported that rs4331426 at 18q11.2 was not associated with TB risk in Chinese population (OR=0.90, 95% CI: 0.63-1.29). CONCLUSIONS:Our findings indicate that TB risk-associated loci at 8q24 and 18q11.2 identified by GWAS from the other populations may not contribute to TB susceptibility in Chinese population.
10.1016/j.meegid.2016.03.005
A genome-wide association study of pulmonary tuberculosis in Morocco.
Grant A V,Sabri A,Abid A,Abderrahmani Rhorfi I,Benkirane M,Souhi H,Naji Amrani H,Alaoui-Tahiri K,Gharbaoui Y,Lazrak F,Sentissi I,Manessouri M,Belkheiri S,Zaid S,Bouraqadi A,El Amraoui N,Hakam M,Belkadi A,Orlova M,Boland A,Deswarte C,Amar L,Bustamante J,Boisson-Dupuis S,Casanova J L,Schurr E,El Baghdadi J,Abel L
Human genetics
Although epidemiological evidence suggests a human genetic basis of pulmonary tuberculosis (PTB) susceptibility, the identification of specific genes and alleles influencing PTB risk has proven to be difficult. Previous genome-wide association (GWA) studies have identified only three novel loci with modest effect sizes in sub-Saharan African and Russian populations. We performed a GWA study of 550,352 autosomal SNPs in a family-based discovery Moroccan sample (on the full population and on the subset with PTB diagnosis at <25 years), which identified 143 SNPs with p < 1 × 10(-4). The replication study in an independent case/control sample identified four SNPs displaying a p < 0.01 implicating the same risk allele. In the combined sample including 556 PTB subjects and 650 controls these four SNPs showed suggestive association (2 × 10(-6) < p < 4 × 10(-5)): rs358793 and rs17590261 were intergenic, while rs6786408 and rs916943 were located in introns of FOXP1 and AGMO, respectively. Both genes are involved in the function of macrophages, which are the site of latency and reactivation of Mycobacterium tuberculosis. The most significant finding (p = 2 × 10(-6)) was obtained for the AGMO SNP in an early (<25 years) age-at-onset subset, confirming the importance of considering age-at-onset to decipher the genetic basis of PTB. Although only suggestive, these findings highlight several avenues for future research in the human genetics of PTB.
10.1007/s00439-016-1633-2
Discovery of susceptibility loci associated with tuberculosis in Han Chinese.
Qi Hui,Zhang Yong-Biao,Sun Lin,Chen Cheng,Xu Biao,Xu Fang,Liu Jia-Wen,Liu Jin-Cheng,Chen Chen,Jiao Wei-Wei,Shen Chen,Xiao Jing,Li Jie-Qiong,Guo Ya-Jie,Wang Yong-Hong,Li Qin-Jing,Yin Qing-Qin,Li Ying-Jia,Wang Ting,Wang Xing-Yun,Gu Ming-Liang,Yu Jun,Shen A-Dong
Human molecular genetics
Genome-wide association studies (GWASs) have revealed the worldwide heterogeneity of genetic factors in tuberculosis (TB) susceptibility. Despite having the third highest global TB burden, no TB-related GWAS has been performed in China. Here, we performed the first three-stage GWAS on TB in the Han Chinese population. In the stage 1 (discovery stage), after quality control, 691 388 SNPs present in 972 TB patients and 1537 controls were retained. After replication on an additional 3460 TB patients and 4862 controls (stages 2 and 3), we identified three significant loci associated with TB, the most significant of which was rs4240897 (logistic regression P = 1.41 × 10-11, odds ratio = 0.79). The aforementioned three SNPs were harbored by MFN2, RGS12 and human leukocyte antigen class II beta chain paralogue encoding genes, all of which are candidate immune genes associated with TB. Our findings provide new insight into the genetic background of TB in the Han Chinese population.
10.1093/hmg/ddx365
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,Sha Wei,Liu Yin,Wang Jiqiang,Huang Xiaochen,Zhang Linfeng,Xu Feifan,Wang Jie,Feng Yonghong,Qin Lianhua,Yang Hua,Liu Zhonghua,Cui Zhenglin,Liu Feng,Chen Xinchun,Gao Shaorong,Sun Silong,Shi Yongyong,Ge Baoxue
Nature communications
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), and remains a leading public health problem. Previous studies have identified host genetic factors that contribute to Mtb infection outcomes. However, much of the heritability in TB remains unaccounted for and additional susceptibility loci most likely exist. We perform a multistage genome-wide association study on 2949 pulmonary TB patients and 5090 healthy controls (833 cases and 1220 controls were genome-wide genotyped) from Han Chinese population. We discover two risk loci: 14q24.3 (rs12437118, P = 1.72 × 10, OR = 1.277, ESRRB) and 20p13 (rs6114027, P = 2.37 × 10, OR = 1.339, TGM6). Moreover, we determine that the rs6114027 risk allele is related to decreased TGM6 transcripts in PBMCs from pulmonary TB patients and severer pulmonary TB disease. Furthermore, we find that tgm6-deficient mice are more susceptible to Mtb infection. Our results provide new insights into the genetic etiology of TB.
10.1038/s41467-018-06539-w
Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family.
American journal of human genetics
An epidemic of tuberculosis occurred in a community of Aboriginal Canadians during the period 1987-89. Genetic and epidemiologic data were collected on an extended family from this community, and the evidence for linkage to NRAMP1, a candidate gene for susceptibility to mycobacterial diseases, was assessed. Individuals were grouped into risk (liability) classes based on vaccination, age, previous disease, and tuberculin skin-test results. Under the assumption of a dominant mode of inheritance and a relative risk of 10, which is associated with the high-risk genotypes, a maximum LOD score of 3.81 was observed for linkage between a tuberculosis-susceptibility locus and D2S424, which is located just distal to NRAMP1, in chromosome region 2q35. Significant linkage was also observed between a tuberculosis-susceptibility locus and a haplotype of 10 NRAMP1 intragenic variants. No linkage to the major histocompatibility-complex region on chromosome 6p was observed, despite distortion of transmission from one member of the oldest couple to their affected offspring. The ability to assign individuals to risk classes was crucial to the success of this study.
10.1086/303012
Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region.
Grant Audrey V,El Baghdadi Jamila,Sabri Ayoub,El Azbaoui Safa,Alaoui-Tahiri Kebir,Abderrahmani Rhorfi Ismail,Gharbaoui Yasser,Abid Ahmed,Benkirane Majid,Raharimanga Vaomalala,Richard Vincent,Orlova Marianna,Boland Anne,Migaud Mélanie,Okada Satoshi,Nolan Daniel K,Bustamante Jacinta,Barreiro Luis B,Schurr Erwin,Boisson-Dupuis Stephanie,Rasolofo Voahangy,Casanova Jean-Laurent,Abel Laurent
American journal of human genetics
Only a small fraction of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis (TB) in their lifetime. Genetic epidemiological evidence suggests a genetic determinism of pulmonary TB (PTB), but the molecular basis of genetic predisposition to PTB remains largely unknown. We used a positional-cloning approach to carry out ultrafine linkage-disequilibrium mapping of a previously identified susceptibility locus in chromosomal region 8q12-13 by genotyping 3,216 SNPs in a family-based Moroccan sample including 286 offspring with PTB. We observed 44 PTB-associated SNPs (p < 0.01), which were genotyped in an independent set of 317 cases and 650 controls from Morocco. A single signal, consisting of two correlated SNPs close to TOX, rs1568952 and rs2726600 (combined p = 1.1 × 10(-5) and 9.2 × 10(-5), respectively), was replicated. Stronger evidence of association was found in individuals who developed PTB before the age of 25 years (combined p for rs1568952 = 4.4 × 10(-8); odds ratio of PTB for AA versus AG/GG = 3.09 [1.99-4.78]). The association with rs2726600 (p = 0.04) was subsequently replicated in PTB-affected subjects under 25 years in a study of 243 nuclear families from Madagascar. Stronger evidence of replication in Madagascar was obtained for additional SNPs in strong linkage disequilibrium with the two initial SNPs (p = 0.003 for rs2726597), further confirming the signal. We thus identified around rs1568952 and rs2726600 a cluster of SNPs strongly associated with early-onset PTB in Morocco and Madagascar. SNP rs2726600 is located in a transcription-factor binding site in the 3' region of TOX, and further functional explorations will focus on CD4 T lymphocytes.
10.1016/j.ajhg.2013.01.013
A Locus at 5q33.3 Confers Resistance to Tuberculosis in Highly Susceptible Individuals.
American journal of human genetics
Immunosuppression resulting from HIV infection increases the risk of progression to active tuberculosis (TB) both in individuals newly exposed to Mycobacterium tuberculosis (MTB) and in those with latent infections. We hypothesized that HIV-positive individuals who do not develop TB, despite living in areas where it is hyperendemic, provide a model of natural resistance. We performed a genome-wide association study of TB resistance by using 581 HIV-positive Ugandans and Tanzanians enrolled in prospective cohort studies of TB; 267 of these individuals developed active TB, and 314 did not. A common variant, rs4921437 at 5q33.3, was significantly associated with TB (odds ratio = 0.37, p = 2.11 × 10(-8)). This variant lies within a genomic region that includes IL12B and is embedded in an H3K27Ac histone mark. The locus also displays consistent patterns of linkage disequilibrium across African populations and has signals of strong selection in populations from equatorial Africa. Along with prior studies demonstrating that therapy with IL-12 (the cytokine encoded in part by IL12B, associated with longer survival following MTB infection in mice deficient in CD4 T cells), our results suggest that this pathway might be an excellent target for the development of new modalities for treating TB, especially for HIV-positive individuals. Our results also indicate that studying extreme disease resistance in the face of extensive exposure can increase the power to detect associations in complex infectious disease.
10.1016/j.ajhg.2016.01.015
Early progression to active tuberculosis is a highly heritable trait driven by 3q23 in Peruvians.
Nature communications
Of the 1.8 billion people worldwide infected with Mycobacterium tuberculosis, 5-15% will develop active tuberculosis (TB). Approximately half will progress to active TB within the first 18 months after infection, presumably because they fail to mount an effective initial immune response. Here, in a genome-wide genetic study of early TB progression, we genotype 4002 active TB cases and their household contacts in Peru. We quantify genetic heritability ([Formula: see text]) of early TB progression to be 21.2% (standard error 0.08). This suggests TB progression has a strong genetic basis, and is comparable to traits with well-established genetic bases. We identify a novel association between early TB progression and variants located in a putative enhancer region on chromosome 3q23 (rs73226617, OR = 1.18; P = 3.93 × 10). With in silico and in vitro analyses we identify rs73226617 or rs148722713 as the likely functional variant and ATP1B3 as a potential causal target gene with monocyte specific function.
10.1038/s41467-019-11664-1
Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2.
Nature genetics
We combined two tuberculosis genome-wide association studies from Ghana and The Gambia with subsequent replication in a combined 11,425 individuals. rs4331426, located in a gene-poor region on chromosome 18q11.2, was associated with disease (combined P = 6.8 x 10(-9), odds ratio = 1.19, 95% CI = 1.13-1.27). Our study demonstrates that genome-wide association studies can identify new susceptibility loci for infectious diseases, even in African populations, in which levels of linkage disequilibrium are particularly low.
10.1038/ng.639
Genome-wide associations identify novel candidate loci associated with genetic susceptibility to tuberculosis in wild boar.
Queirós João,Alves Paulo Célio,Vicente Joaquín,Gortázar Christian,de la Fuente José
Scientific reports
Tuberculosis (TB) affects a wide range of host species worldwide. Understanding host-pathogen co-evolution remains a global challenge owing to complex interactions among host genetic factors, pathogen traits and environmental conditions. We used an endemic wild boar population that had undergone a huge increase in Mycobacterium bovis infection prevalence, from 45% in 2002/06 to 83% in 2009/12, to understand the effects of host genetics on host TB outcomes and disease dynamics. Host genomic variation was characterized using a high-density single nucleotide polymorphism (SNP) array, while host TB phenotype was assessed using both gross pathology and mycobacterial culture. Two complementary genome-wide association (GWAS) analyses were conducted: (i) infected-uninfected; and (ii) 2002/06-2009/12. The SNPs with the highest allelic frequency differences between time-periods and TB outcomes were identified and validated in a large dataset. In addition, we quantified the expression levels of some of their closest genes. These analyses highlighted various SNPs (i.e. rs81465339, rs81394585, rs81423166) and some of the closest genes (i.e. LOC102164072, BDNF/NT-3, NTRK2, CDH8, IGSF21) as candidates for host genetic susceptibility. In addition to TB-driven selection, our findings outline the putative role of demographic events in shaping genomic variation in natural populations and how population crashes and drift may impact host genetic susceptibility to TB over time.
10.1038/s41598-018-20158-x