Southern East Asian origin and coexpansion of Mycobacterium tuberculosis Beijing family with Han Chinese.

The Beijing family is the most successful genotype of Mycobacterium tuberculosis and responsible for more than a quarter of the global tuberculosis epidemic. As the predominant genotype in East Asia, the Beijing family has been emerging in various areas of the world and is often associated with disease outbreaks and antibiotic resistance. Revealing the origin and historical dissemination of this strain family is important for understanding its current global success. Here we characterized the global diversity of this family based on whole-genome sequences of 358 Beijing strains. We show that the Beijing strains endemic in East Asia are genetically diverse, whereas the globally emerging strains mostly belong to a more homogenous subtype known as "modern" Beijing. Phylogeographic and coalescent analyses indicate that the Beijing family most likely emerged around 30,000 y ago in southern East Asia, and accompanied the early colonization by modern humans in this area. By combining the genomic data and genotyping result of 1,793 strains from across China, we found the "modern" Beijing sublineage experienced massive expansions in northern China during the Neolithic era and subsequently spread to other regions following the migration of Han Chinese. Our results support a parallel evolution of the Beijing family and modern humans in East Asia. The dominance of the "modern" Beijing sublineage in East Asia and its recent global emergence are most likely driven by its hypervirulence, which might reflect adaption to increased human population densities linked to the agricultural transition in northern China.

Transmission of Mycobacterium tuberculosis in China: a population-based molecular epidemiologic study.

BACKGROUND: Understanding the transmission of Mycobacterium tuberculosis is essential for the development of efficient tuberculosis control strategies. China has the second-largest tuberculosis burden in the world. Recent transmission and infection with M. tuberculosis, particularly drug-resistant strains, may account for many new tuberculosis cases. METHODS: We performed a population-based molecular epidemiologic study of pulmonary tuberculosis in China during 1 July 2009 to 30 June 2012. We defined clusters as cases with identical variable number tandem repeat genotype patterns and identified the risk factors associated with clustering, by logistic regression. Relative transmission rates were estimated by the sputum smear status and drug susceptibility status of tuberculosis patients. RESULTS: Among 2274 culture-positive tuberculosis patients with genotyped isolates, there were 705 (31.0%) tuberculosis patients in 287 clusters. Multidrug-resistant (MDR) tuberculosis (adjusted odds ratio [aOR], 1.86; 95% confidence interval [CI], 1.25-2.63) and infection with a Beijing family strain (aOR, 1.56; 95% CI, 1.23-2.96) were associated with clustering. Eighty-four of 280 (30.0%) clusters had a putative source case that was sputum smear negative, and 30.6% of their secondary cases were attributed to transmission by sputum smear-negative patients. The relative transmission rate for sputum smear negative compared with sputum smear-positive patients was 0.89 (95% CI, .68-1.10), and was 1.51 (95% CI, 1.00-2.24) for MDR tuberculosis vs drug-susceptible tuberculosis. CONCLUSIONS: Recent transmission of M. tuberculosis, including MDR strains, contributes substantially to tuberculosis disease in China. Sputum smear-negative cases were responsible for at least 30% of the secondary cases. Interventions to reduce the transmission of M. tuberculosis should be implemented in China.

Specific differences and novel key regulatory genes of sex in influencing exceptional longevity phenotypes.

BACKGROUND AND AIMS: Although the life expectancy of women systematically and robustly exceeds that of men, specific differences and molecular mechanisms of sex in influencing longevity phenotypes remain largely unknown. Therefore, we performed transcriptome sequencing of peripheral blood samples to explore regulatory mechanisms of healthy longevity by incorporating sex data. METHODS: We selected 34 exceptional longevity (age: 98.26 ± 2.45 years) and 16 controls (age: 52.81 ± 9.78) without advanced outcomes from 1363 longevity and 692 controls recruited from Nanning of Guangxi for RNA sequencing 1. The transcriptome sequencing 1 data of 50 samples were compared by longevity and sex to screen differentially expressed genes (DEGs). Then, 121 aging samples (40-110 years old) without advanced outcomes from 355 longevity and 294 controls recruited from Dongxing of Guangxi were selected for RNA sequencing 2. The genes associated with aging from the transcriptome sequencing 2 of 121 aging samples were filtered out. Finally, the gender-related longevity candidate genes and their possible metabolic pathways were verified by cell model of aging and a real-time polymerase chain reaction (RT-PCR). RESULTS: Metabolism differs between male and female and plays a key role in longevity. Moreover, the principal findings of this study revealed a novel key gene, UGT2B11, that plays an important role in regulating lipid metabolism through the peroxisome proliferator activated receptor gamma (PPARG) signalling pathway and ultimately improving lifespan, particularly in females. CONCLUSION: The findings suggest specific differences in metabolism affecting exceptional longevity phenotypes between the sexes and offer novel therapeutic targets to extend lifespan by regulating lipid homeostasis.

Whole Genomic Analysis Revealed High Genetic Diversity and Drug-Resistant Characteristics of Mycobacterium tuberculosis in Guangxi, China.

Background: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a major public health issue in China. Nevertheless, the prevalence and drug resistance characteristics of isolates vary in different regions and provinces. In this study, we investigated the population structure, transmission dynamics and drug-resistant profiles of Mtb in Guangxi, located on the border of China. Methods: From February 2016 to April 2017, 462 clinical M. tuberculosis isolates were selected from 5 locations in Guangxi. Drug-susceptibility testing was performed using 6 common anti-tuberculosis drugs. The genotypic drug resistance and transmission dynamics were analyzed by the whole genome sequence. Results: Our data showed that the Mtb in Guangxi has high genetic diversity including Lineage 1 to Lineage 4, and mostly belong to Lineage 2 and Lineage 4. Novelty, 9.6% of Lineage 2 isolates were proto-Beijing genotype (L2.1), which is rare in China. About 12.6% of isolates were phylogenetically clustered and formed into 28 transmission clusters. We observed that the isolates with the high resistant rate of isoniazid (INH, 21.2%), followed by rifampicin (RIF, 13.2%), and 6.7%, 12.1%, 6.7% and 1.9% isolates were resistant to ethambutol (EMB), streptomycin (SM), ofloxacin (OFL) and kanamycin (KAN), respectively. Among these, 6.5% and 3.3% of isolates belong to MDR-TB and Pre-XDR, respectively, with a high drug-resistant burden. Genetic analysis identified the most frequently encountered mutations of INH, RIF, EMB, SM, OFL and KAN were katG_Ser315Thr (62.2%), rpoB_Ser450Leu (42.6%), embB_Met306Vol (45.2%), rpsL_Lys43Arg (53.6%), gyrA_Asp94Gly (29.0%) and rrs_A1401G (66.7%), respectively. Additionally, we discovered that isolates from border cities are more likely to be drug-resistant than isolates from non-border cities. Conclusion: Our findings provide a deep analysis of the genomic population characteristics and drug-resistant of M. tuberculosis in Guangxi, which could contribute to developing effective TB prevention and control strategies.

Identification and replication of novel genetic variants of ABO gene to reduce the incidence of diseases and promote longevity by modulating lipid homeostasis.

Genes related to human longevity have not been studied so far, and need to be investigated thoroughly. This study aims to explore the relationship among ABO gene variants, lipid levels, and longevity phenotype in individuals (≥90yrs old) without adverse outcomes. A genotype-phenotype study was performed based on 5803 longevity subjects and 7026 younger controls from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Four ABO gene variants associated with healthy longevity (rs8176719 C, rs687621 G, rs643434 A, and rs505922 C) were identified and replicated in the CLHLS GWAS data analysis and found significantly higher in longevity individuals than controls. The Bonferroni adjusted p-value and OR range were 0.013-0.020 and 1.126-1.151, respectively. According to the results of linkage disequilibrium (LD) analysis, the above four variants formed a block on the ABO gene (D'=1, r2range = 0.585-0.995). The carriers with genotypes rs687621 GG, rs643434 AX, or rs505922 CX (prange = 2.728 x 10-107-5.940 x 10-14; ORrange = 1.004-4.354) and haplotype CGAC/XGXX (p = 2.557 x 10-27; OR = 2.255) had a substantial connection with longevity, according to the results of genetic model analysis. Following the genotype and metabolic phenotype analysis, it has been shown that the longevity individuals with rs687621 GG, rs643434 AX, and rs505922 CX had a positive association with HDL-c, LDL-c, TC, TG (prange = 2.200 x 10-5-0.036, ORrange = 1.546-1.709), and BMI normal level (prange = 2.690 x 10-4-0.026, ORrange = 1.530-1.997). Finally, two pathways involving vWF/ADAMTS13 and the inflammatory markers (sE-selectin/ICAM1) that co-regulated lipid levels by glycosylation and effects on each other were speculated. In conclusion, the association between the identified longevity-associated ABO variants and better health lipid profile was elucidated, thus the findings can help in maintaining normal lipid metabolic phenotypes in the longevity population.

Adolescent tuberculosis associated with tuberculosis exposure in classrooms and dorm rooms in Guangxi, China.

OBJECTIVE: Quantify tuberculosis (TB) risk attributable to dorm room exposure in addition to classroom exposure. METHODS: Adolescent school contact investigations were conducted for every reported index TB case, and similar contact investigations were conducted in selected community-control classes from November 2016 to October 2017 in Guangxi, China. RESULTS: A total of 6263 contacts of 112 index TB cases and 6130 classmates of 112 controls were investigated. There were 14, 12, and 2 new active TB cases detected among classmates/non-roommates of index cases, classmates/roommates of index cases, and control classmates, respectively. Compared with control contacts, the adjusted relative risk (95% confidence interval (CI)) and population attributable fraction (PAF) for being a classmate/non-roommate of the index case increased the risk of active TB diagnosis to 8.44 (95% CI: 1.31-54.48) and 44.1%. The adjusted RR and PAF for being a classmate/roommate of the index case was 29.37 (95% CI: 3.80, 227.11) and 41.4%. Being classmates/roommates significantly increased the risk of TB compared to a classmate/non-roommate of the index case (RR=3.48, 95% CI: 1.64, 7.40). CONCLUSION: The additional risk of TB due to exposure in the dorm room should be taken into account in planning of TB prevention and control in boarding schools.

Infectivity of Mycobacterium tuberculosis Genotypes and Outcome of Contact Investigation in Classroom in Guangxi, China.

OBJECTIVE: To evaluate the infectivity of Mycobacterium tuberculosis (M.tb) genotypes of index cases in the classroom of adolescent schools in Guangxi, China. METHODS: Adolescent school tuberculosis (TB) contact investigations were conducted for all reported index TB cases from November 2016 to December 2017 in Guangxi, China. Genotypes of index cases and contact cases were identified by 15-loci mycobacterial interspersed repetitive units-variable number tandem repeat and spoligotyping. Outcome variable was 5 levels' order of tuberculin skin test (TST) results to new active TB [0-5 mm, 6-9 mm, 10-14 mm, ≥ 15 mm (without TB), and ≥15 mm (with TB)]. Multivariate ordered logistic regression analysis was performed to evaluate the independent effect of genotypes of index case on contact screening outcome. RESULTS: Beijing genotype occurred more commonly in female index patients. One genotypic cluster of two index cases and one cluster of two contact cases were detected. The association between infectivity of Beijing genotype of index cases and outcome of contact investigation was statistically significant in univariate analysis but no so after adjustment for characteristics of contacts and sex of index cases (P value=0.057). Female index cases increased the chance for TB infection/being active TB among contacts (ordinal odds ratio = 1.39, 95% confidence interval: 1.21, 1.60). Contacts who studied in the middle school, who with non-Han ethnicity and who without BCG scar had increased risk for TB infection/being active TB. CONCLUSION: There was not enough evidence from our data to support that Beijing strains were more infective than non-Beijing strains in TB transmission in school setting.

Tuberculosis Transmission in Households and Classrooms of Adolescent Cases Compared to the Community in China.

The aim of this paper is to evaluate the link between the history of exposure to tuberculosis (TB) in the household and diagnosed TB cases at school, and to compare the detection rate of active TB among household contacts and classroom contacts of adolescent TB cases with the rates among contacts of healthy controls. From November 2016 to December 2017, a prospective matched case-control study was conducted using passively identified index adolescent student cases from the TB surveillance system and healthy controls (matched by county, school type, sex, age and ethnicity). Contacts in households and classrooms of index cases and of controls were investigated. Matched tabulation of 117 case-control pairs revealed exposure to TB in the household as a strong risk factor (odds ratio (OR) = 21.0, 95% confidence interval (CI): 3.4, 868.6). Forty-five (case detection rate 0.69%) and two (case detection rate 0.03%) new active TB cases were detected among 6512 and 6480 classroom contacts of the index cases and controls, respectively. Having an index case in the classroom significantly increased the risk of classmates contracting active TB (OR = 22.5, 95% CI: 5.9, 191.4). Our findings suggested that previous exposure to TB in the household could lead a child to catch TB at school, then spread TB to classmates.

Risk factors associated with Tuberculosis (TB) among people living with HIV/AIDS: A pair-matched case-control study in Guangxi, China.

BACKGROUND: As one of the poorest provinces in China, Guangxi has a high HIV and TB prevalence, with the annual number of TB/HIV cases reported by health department among the highest in the country. However, studies on the burden of TB-HIV co-infection and risk factors for active TB among HIV-infected persons in Guangxi have rarely been reported. OBJECTIVE: To investigate the risk factors for active TB among people living with HIV/AIDS in Guangxi Zhuang autonomous region, China. METHODS: A surveillance survey was conducted of 1 019 HIV-infected patients receiving care at three AIDS prevention and control departments between 2013 and 2015. We investigated the cumulative prevalence of TB during 2 years. To analyze risk factors associated with active TB, we conducted a 1:1 pair-matched case-control study of newly reported active TB/HIV co-infected patients. Controls were patients with HIV without active TB, latent TB infection or other lung disease, who were matched with the case group based on sex and age (± 3 years). RESULTS: A total of 1 019 subjects were evaluated. 160 subjects (15.70%) were diagnosed with active TB, including 85 clinically diagnosed cases and 75 confirmed cases. We performed a 1:1 matched case-control study, with 82 TB/HIV patients and 82 people living with HIV/AIDS based on surveillance site, sex and age (±3) years. According to multivariate analysis, smoking (OR = 2.996, 0.992-9.053), lower CD 4+ T-cell count (OR = 3.288, 1.161-9.311), long duration of HIV-infection (OR = 5.946, 2.221-15.915) and non-use of ART (OR = 7.775, 2.618-23.094) were independent risk factors for TB in people living with HIV/AIDS. CONCLUSION: The prevalence of active TB among people living with HIV/AIDS in Guangxi was 173 times higher than general population in Guangxi. It is necessary for government to integrate control planning and resources for the two diseases. Medical and public health workers should strengthen health education for TB/HIV prevention and treatment and promote smoking cessation. Active TB case finding and early initiation of ART is necessary to minimize the burden of disease among patients with HIV, as is IPT and infection control in healthcare facilities.

Drug Resistance in Newly Presenting and Previously Treated Tuberculosis Patients in Guangxi Province, People's Republic of China.

Drug-resistant Mycobacterium tuberculosis strains are a major threat to the control of tuberculosis (TB), but the prevalence of drug-resistant TB is still unknown in the southern ethnic region of China. A cluster-randomized sampling method was used to include the study population. Isolates were tested for resistance to 6 antituberculosis drugs, and genotyped to identify Beijing strains. Overall, 11.3% (139/1229) of new cases and 33.0% (126/382) of retreated cases had drug-resistant tuberculosis. Multiple previous TB treatment episodes and multiple treatment interruptions were risk factors for both drug-resistant and multidrug-resistant TB among retreated cases. A total of 53.2% of the patients were infected with a Beijing strain of M tuberculosis. Infection with a Beijing strain was significantly associated with drug resistance among new cases (odds ratio, 1.44; 95% CI, 1.01-2.07). Novel strategies to rapid diagnosis and effective treatment are urgently needed to prevent the development of drug resistance.