Our study aimed to investigate the effect of cigarette smoking on the clinical phenotype of patients registered in the Chinese Systemic Lupus Erythematosus (SLE) Treatment and Research (CSTAR) group registry database, the first online registry of Chinese patients with SLE.
A prospective cross-sectional study of Chinese SLE patients was conducted using the CSTAR. Our case-control analysis was performed on age- and gender-matched subjects to explore the potential effect of cigarette smoking on the clinical manifestation of SLE.
Smokers comprised 8.9% (65/730) of patients, and the ratio of females/males was 19/46. Thirty-nine patients were current smokers, and 26 were ex-smokers. Data showed significant differences between smokers and nonsmokers in the following areas: nephropathy (58.5% vs. 39.2%; p = 0.003), microscopic hematuria (30.8% vs. 19.1%; p = 0.025), proteinuria (53.8% vs. 34.4%; p = 0.002), and SLE Disease Activity Index(DAI) scores (12.38±8.95 vs. 9.83±6.81; p = 0.028). After adjusting for age and gender, significant differences between smokers and nonsmokers were found with photosensitivity (35.9% vs. 18%; p = 0.006), nephropathy (59.4% vs. 39.8%; p = 0.011), and proteinuria (54.7% vs. 35.2%). Although smokers tended to have greater disease severity compared with nonsmokers (SLEDAI scores: 12.58±8.89 vs.10.5±7.09), the difference was not significant (p = 0.081).
Citation: Xu D, You X, Wang Z, Zeng Q, Xu J, Jiang L, et al. (2015) Chinese Systemic Lupus Erythematosus Treatment and Research Group Registry VI: Effect of Cigarette Smoking on the Clinical Phenotype of Chinese Patients with Systemic Lupus Erythematosus. PLoS ONE 10(8): e0134451. doi:10.1371/journal.pone.0134451
Editor: Song Guo Zheng, Penn State University, UNITED STATES
Received: January 30, 2015; Accepted: July 10, 2015; Published: August 17, 2015
Copyright: © 2015 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This work was funded by the Chinese National Key Technology R&D Program, Ministry of Science and Technology (2008BAI59B02), and the Chinese National High Technology Research and Development Program, Ministry of Science and Technology (2012AA02A513), both received by XFZ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multisystem involvement and generation of multiple autoantibodies. Although the etiology and pathogenesis of SLE are still unclear, exposure to environmental factors, such as infectious agents, drugs, occupational pollutants, and smoking, may play an important and complex role. Of these, smoking is one of the few potential causative factors that can be controlled by patient behavior. Cigarette smoke is known to affect the development and prognosis of many autoimmune diseases, especially rheumatoid arthritis. To date, the association between smoking and SLE has been controversial [1–6]. Most studies have shown that smoking is a risk factor for the development and severity of SLE in different races [2, 7–9]. Due to resource limitations, data on the relationship between SLE and smoking in the Chinese population has not been reported. Therefore, the Chinese SLE Treatment and Research group (CSTAR) developed the first online registry of Chinese patients with SLE, supported by the Chinese National Key Technology Research &Development Program. This registry has enabled the characterization of major clinical manifestations of SLE in Chinese patients  and provides the opportunity to prospectively study the effects of cigarette smoking on SLE clinical phenotypes in a representative cohort of Chinese patients.
This prospective cross-sectional analysis was based on the online CSTAR registry, which includes patients from 104 high-ranking rheumatology centers, covering 30 provinces in China. This study was approved by the Medical Ethics Committee of Peking Union Medical College Hospital (PUMCH), which was the lead research site; most centers accepted Ethics Committees(EC) from PUMCH as the leading site, some approved by their own EC, included Beijing Tongren Hospital, the General Hospital of TianJing Medical University, and the Second Affiliated Hospital of Guangzhou Medical College. Patients were registered only if they provided written informed consent. Patients with SLE were included only if they met the 1997 revised American College of Rheumatology criteria. Furthermore, patients were excluded if they presented with overlapping systemic sclerosis, rheumatoid arthritis, polymyositis, or other undifferentiated connective tissue diseases. This ongoing registry was launched in April 2009, and the cut-off for this study was February 2010.
All CSTAR centers used the same protocol-directed methods to provide uniform evaluations and patient data. All investigators received training on diagnostic confirmation of disease, evaluation of disease activity, as well as data input and quality control. Demographic data were also collected. Systemic manifestations (nervous system, vasculitis, arthritis, myositis, nephritis, rash, oral ulceration, pleuritis, pericarditis, and fever) were assessed using the SLE Disease Activity Index (SLEDAI), and all occurrences were classified according to SLEDAI definitions. Laboratory findings were also recorded, including leukocytopenia, thrombocytopenia, hypocomplementemia, and autoantibodies. Autoantibody levels were measured at local laboratories and included anti-double-stranded (ds) DNA, anti-Smith, anti-SSA/Ro, anti-SSB/La, anti-ribonucleoprotein (RNP) and anti-ribosomal RNP antibodies. SLE disease activity was evaluated in all patients by SLEDAI.
Smoking definition and data collection
Patients who smoked at least one cigarette per day for three consecutive months were classified as smokers. Patients, who fulfilled the smoker criteria, but had given up smoking for at least 1 year prior to enrollment, were classified as ex-smokers. Patients who did not fulfill the criteria of smokers, were classified as nonsmokers. Because history of smoking was not mandatory in the CSTAR, information regarding smoking behavior was obtainable in only 730 patients of 2104 who registered. The primary data of smoker in SLE patients are indicated in S1 Table.
For all subjects belonging to the smokers group, further analyses were performed to eliminate the confounding factors of gender and age. Gender and age were matched according to a 1:2 ratio for the recruitment of controls in CSTAR.
The Statistical Package for the Social Sciences (SPSS) version 13.0 software (SPSS Inc, Chicago, IL, USA) was used for data processing and analysis. Variables were described using counts and/or percentages or medians and ranges. Gender and age were matched according to a 1:2 ratio, and smokers were compared to nonsmokers in a case-control study. Chi-squared and Fisher’s exact tests were used to compare categorical data, and independent sample Student’s t-tests were used to compare quantitative data between the groups. P-values <0.05 were considered to be statistically significant.
Out of 730 patients, 65 (8.9%) were either current or past smokers. Among these 65 patients, 19 were female, including 13 current and six ex-smokers, and 46 were male, including 26 current and 20 ex-smokers. Although SLE is a predominantly female disease, males are much more likely to smoke than females in the Chinese population. Thus, the ratio of female: male smokers in our SLE cohort was near 1:2.
Clinical and laboratory findings
Compared to nonsmokers, there were more male smokers (46/65 vs.27/665), as well as more smokers patients with nephropathy (58.5% vs. 34.4%), microscopic hematuria (30.8% vs. 19.1%), proteinuria (53.8% vs. 34.4%), and highly active disease (SLEDAI scores: 12.38 ± 8.95 vs. 9.83 ± 6.81) (p<0.05). There was not a significant difference in autoantibodies between smokers and nonsmokers; however, anti-dsDNA positivity was slightly higher in smokers (p = 0.655; Tables 1 and 2).
Because one male smoker was 78-years-old and no matching patients could be found, this patient was excluded from the case-control study. In total, 64 SLE smokers and 128 SLE nonsmokers were included in the case-control analysis. Compared to nonsmokers, there was more nephropathy (59.4% vs.39.8%), proteinuria (54.7% vs. 35.2%), and photosensitivity (35.9% vs. 18%) found in smokers (p<0.05). There was no significant difference in autoantibody production between smokers and nonsmokers, although smokers tended to show more anti-dsDNA positivity (p = 0.358). Smokers also tended to have more active disease (SLEDAI scores: 12.58 ± 8.89 vs.10.5 ± 7.09), but these differences were not significant (p = 0.081; Tables 3 and 4).
It is well-known that cigarette smoking is harmful to human health and increases the risk of pulmonary carcinoma. However, the relationship between smoking and SLE is still controversial. Previous studies have mostly focused on the risk of developing SLE. Ghaussyet al. reported a markedly higher odd’s ratio (OR) than that of other studies in a predominantly Hispanic population: 6.7 for current smokers and 3.7 for ever smokers, whereas others reported ORs ranging from 0.9 to 3.06 for current smokers and 0.6 to 1.2 for ever smokers [6,9,12–16]. Two studies showed that higher daily or cumulative exposure to cigarette smoking was associated with a higher risk of SLE [14,16], suggesting that smoking status may confer an immediate risk for SLE onset, while cessation of smoking decreased this risk. On the other hand, two large prospective cohort studies failed to observe an association between cigarette smoking and development of SLE [17,18]. Similarly, Simard et al., found that exposure to cigarette smoke in early life did not increase the risk of development of SLE in adult women [19,20]. However, few studies have investigated the relationship between cigarette smoking and clinical manifestations in SLE patients other than those involving the skin.
Following adjustments for age and gender, our study showed that photosensitivity was more frequent in smokers. This finding is consistent with a study by Bourré-Tessier et al. , which also showed that current smoking was associated with active SLE rash, and ever smoking was associated with discoid rashes, as well as the American College of Rheumatology total cutaneous score. Similar results were found in other studies [22–24], which reported that smoking was a risk factor for development of cutaneous lupus and associated with the severity of cutaneous lesions. However, our study did not show an association between smoking and rashes. This may be due to the unavailability of differential diagnose of cutaneous diseases from CSTAR. Of particular note, past history of smoking was not associated with active skin rash raised the potential of a reversible influence: cessation of smoking may decrease active skin disease . Unfortunately, our study was unable to further dissect this hypothesis with available data due to the limited number of subjects. In addition, mechanisms underlying the relationship between smoking and active SLE rash are still unknown, with some reports suggesting that smoking may decrease the effectiveness of antimalarial agents and exacerbate skin lesions . In contrast, other studies have not observed an association between smoking and antimalarials[21,26].
Lupus nephritis is a common and severe complication that worsens the prognosis in SLE patients, especially if proteinuria is present. We observed that SLE patients who smoke had more nephropathy and proteinuria. However, in a separate study, the incidence of lupus nephritis itself was not associated with smoke exposure . Till now, the relationship between smoking and renal disease has been investigated mostly in the general population. Cigarette smoking is an independent risk factor for progression of established chronic kidney disease, as well as development of hyperfiltration and proteinuria in the general population, especially men [28–34]. Smoking cessation could reduce the rate of decline inglomerular filtration rate and increase dialysis-free survival in patients with progressive kidney disease . In addition, Ward et al. observed that among patients with lupus nephritis, those who smoked had accelerated development of end-stage renal disease . The median time to end-stage renal disease among smokers was 145 months and among nonsmokers was greater than 273 months. In summary, smoking appeared to be an important, potentially modifiable factor influencing the prognosis of patients with lupus nephritis .
Other clinical manifestations have been reported to be associated with smoking in SLE patients. Rubin et al. reported that current smokers had more episodes of pleuritis, peritonitis, and neuropsychiatric symptoms than former or nonsmoker SLE patients . A study by Moraes-Fonteset al. showed neuropsychiatric SLE was associated with a higher frequency of smoking (78%) compared to the non-neuropsychiatric SLE group (26%) . In our study, no differences were found in the above manifestations between smokers and nonsmokers. In addition, smoking has also been associated with a higher instance of thrombotic events and vascular necrosis among SLE patients [38–40]. Some studies have shown that cigarette smoking has an independent effect on cardiovascular disease and is the only significant risk factor for peripheral vascular disease in SLE patients [41,42].
Autoantibodies are one of the characteristic features of SLE. In the present study, we did not find any association between smoking status and all autoantibodies examined in our cohort. Previous studies have mostly focused on anti-dsDNA, an antibody known to correlate with disease activity in SLE. Different results have been reported in previous studies. In a retrospective case-control analysis, Freemeret al. found a positive association between current smoking status and the presence of anti-dsDNA antibodies (OR = 4.0; 95% confidence interval: 1.6–10.4). Former smokers, however, were not found to be at increased risk for these antibodies compared to nonsmokers . Preliminary analysis of smaller groups of Hispanic, Asian, and African American patients with SLE from the same cohort were also performed. Although not statistically significant, current smoking was associated with dsDNA seropositivity in Hispanic patients with SLE (OR = 5.02; 95% confidence interval: 0.19 to 134). No such associations were found among African American or Asian patients . However, an earlier study reported a negative association between smoking and immunoglobulin G anti-DNA autoantibodies, both in human and murine SLE . In this study, a negative correlation between smoking and immunoglobulin G anti-dsDNA antibodies in newly diagnosed SLE patients was reported and, in accordance with the mouse model, patients who discontinued smoking prior to diagnosis had higher levels of dsDNA antibodies than current and nonsmokers. Another study reported similar findings, with current smokers having significantly lower levels of anti-dsDNA antibodies than ex-and nonsmokers . These findings suggest that humoral immune suppression may occur with the initiation of smoking, but a rebound effect with increased levels of these antibodies may manifest after cessation of smoking. Results from Young et al. were consistent with our finding that smoking is not associated with autoantibody production in SLE patients . It is likely that differences in genetics and race, different autoantibody detection methods, and the attenuation of anti-dsDNA titers by pharmacological treatment may serve to explain the reported discrepancies. On the other hand, Young et al. also observed a decreased rate of anti-nRNP68 antibody seropositivity and increased rate of anti-nRNP A seropositivity in SLE patients that smoke .
Similar to anti-dsDNA results, the association between smoking and SLEDAI scores has been controversial in previous studies. In our study, we observed higher SLEDAI scores in smokers. Although adjusting for age and gender showed that this difference was not significant (p = 0.081), smokers still had higher SLEDAI scores than nonsmokers (12.58 ± 8.89 versus 10.5 ± 7.09, respectively). Likewise, Ghaussyet al. also found that SLEDAI scores were significantly higher in current smokers compared to former and nonsmokers in their retrospective study . This is consistent with the increased anti-dsDNA positivity found by Freemer and colleagues. Some have suggested that a biological mechanism linking smoking and SLE is the association between current smoking behavior and the presence of anti-dsDNA antibodies. This would also explain the epidemiologic association of active cigarette use with increased severity of SLE reported previously . On the other hand, unlike the common phenomenon that severe SLE disease activity is often associated with a low serum complementation, we found less hypocomplementemia (60% vs. 69.5%) in smokers compared with non-smokers, though not significant. The reason maybe was that both microscopic hematuria and proteinuria were 4 scores each and hypocomplementemia was only 1 score in SLEDAI score, hypocomplementemia had less influence on disease activity compared with microscopic hematuria and proteinuria. Thus, it is accessible that a little decreased frequency of hypocomplementemia was found in smokers even though they had greater disease severity. In contrast, other studies did not find significant associations between smoking and SLEDAI scores [3,4,44].
In summary, cigarette smoking may be a trigger for the development and worsening of SLE, especially with respect to renal damage. Our findings suggest that smoking cessation should be particularly encouraged in Chinese patients with SLE.
S1 Table. Primary data of smokers in SLE patients.
Demographic data and clinical manifestations are included. Systemic involvement was measuredby SLE classification criteria, which includedmalar rash, discoid lesion, photosensitivity, oralulcers, arthritis, serositis, hematologic involvement,nephropathy, and neurologic involvement.
We would like to thank CSTAR co-authors as following for assistance with the collections of cases.
¶ CSTAR Co-authors:
1. Peking Union Medical College Hospital: Hongmei Song, Xuejun Zeng, Wen Zhang, Xiaomei Leng, Qingjun Wu, Jinmei Su, Qun Shi, Wenjie Zheng, Ying Jiang, Yong Hou, Min Shen, Hua Chen, Xiaodan Gan, Chaojun Hu, Suxian Liu.
2. The Affiliated Drum Tower Hospital of Nanjing University Medical School: Lingyun Sun.
3. Anhui Provincial Hospital: Xiangpei Li, Xiaomei Li.
4. The Affiliated Hospital of Bengbu Medical College: Zhijun Li, Changhao Xie.
5. The First Affiliated Hospital of Sun Yat-sen University: Xiuyan Yang.
6. The Second Hospital of Shanxi Medical University: Xiaofeng Li, Jinli Ru.
7. Beijing Hospital Affiliated to the Ministry of Health of PRC: Cibo Huang, Bei Lai.
8. China-Japan Friendship Hospital Affiliated to the Ministry of Health of PRC: Donghai Wu, Li Ma.
9. Beijing Chao-Yang Hospital, Capital Medical University: Yi Zheng, Xiaohong Wen.
10. Xuanwu Hospital Affiliated to Capital Medical University: Xiaoxia Li.
11. Beijing Friendship Hospital Affiliated to Capital Medical University: Ting Duan.
12. Beijing Children Hospital Affiliated to Capital Medical University: Caifeng Li.
13. Capital Institute of Pediatrics: Fengqi Wu.
14. Chinese People's Liberation Army General Hospital: Feng Huang, Jian Zhu.
15. Changhai Hospital Affiliated to the Second Military Medical University: Dongbao Zhao.
16. Changzheng Hospital Affiliated to the Second Military Medical University: Huji Xu.
17. Huashan Hospital Affiliated to Fudan University: Hejian Zou, Haomin Qiu.
18. The First Affiliated Hospital of Anhui Medical University: Jianhua Xu, Li Mu.
19. Qilu Hospital of Shandong University: Xingfu Li.
20. The Second Affiliated Hospital of Zhejiang University School of Medicine: Huaxiang Wu.
21. The Third Affiliated Hospital of Sun Yat-sen University: Jieruo Gu, Ou Jin.
22. The Second Affiliated Hospital of Guangzhou Medical College: Yi Tao.
23. Guangdong Provincial People's Hospital: Xiao Zhang, Guangfu Dong.
24. Xiangya Hospital, Central South University: Xiaoxia Zuo, Yisha Li.
25. The First Affiliated Hospital of Harbin Medical University: Zhiyi Zhang, Yifang Mei.
26. The First Hospital of China Medical University: Weiguo Xiao, Hongfeng Zhang.
27. Xijing Hospital affiliated to the Fourth Military Medical University: Ping Zhu, Zhenbiao Wu.
28. The Second Hospital of Lanzhou University: Yi Wang.
29. West China Hospital Affiliated to Sichuan University: Yi Liu.
30. The Affiliated Hospital of North Sichuan Medical College: Guohua Yuan.
31. Sichun Provincial People’s Hospital: Bin Zhou.
32. The People's Hospital of Xinjiang Autonomous Region: Lijun Wu.
33. Jiangsu Provincial People's Hospital: Miaojia Zhang.
34. The First Affiliated Hospital of Zhengzhou University: Shengyun Liu.
35. Shengjing Hospital Affiliated to China Medical University: Ning Zhang.
36. The First Affiliated Hospital of Shantou University Medical College: Qingyu Zeng.
37. Tianjin First Central Hospital: Wencheng Qi, Feng Han.
38. Peking University First Hospital: Zhuoli Zhang, Yu Wang.
39. Peking University Shougang Hospital: Shuling Han.
40. Beijing Jishuitan Hospital: Hui Song, Shumin Yan.
41. Fuxing Hospital Affiliated to Capital Medical University: Wen Luo.
42. Beijing Shunyi Hospital: Xiaomin Liu.
43. Peking University Third Hospital: Xiangyuan Liu, Xiaoli Deng.
44. South-West Hospital Affiliated to Third military Medical University: Yongfei Fang.
45. The First People's Hospital of Foshan: Guoqiang Chen.
46. Fujian Provincial Hospital: He Lin.
47. The Second Affiliated hospital of Fujian Medical University: Ling Lin.
48. Fuzhou General Hospital of Nanjing Military Region: Yinong Li.
49. Zhongshan Hospital Affiliated to Fudan University: Lindi Jiang, Lili Ma.
50. The First Affiliated Hospital of Guangxi Medical University: Cheng Zhao, Zhanrui Chen.
51. The People’s Hospital of Guangxi Autonomous Region: Jinying Lin.
52. The Affiliated Hospital of Guiyang Medical College: Long Li.
53. The Second Affiliated Hospital of Harbin Medical University: Yinhuan Zhao.
54. Hainan Provincial People’s Hospital: Feng Zhan, Shudian Lin.
55. Hebei Provincial People’s Hospital: Fengxiao Zhang, Yonglong Yan.
56. Bethune International Peace Hospital: Zhenbin Li.
57. Henan Provincial People’s Hospital: Fengmin Shao, Wei Liu.
58. The First Hospital of Qiqihar: Xiaowei Gong.
59. Tongji Hospital Affiliated to Tongji Medical School of Huazhong University of Science and Technology: Shaoxian Hu.
60. Jiangxi Provincial People’s Hospital: Youlian Wang.
61. No.202 Hospital of People’s Liberation Army: Yiping Lin, Lin Guo.
62. The Affiliated Hospital of Inner Mongolia Medical College: Hongbin Li.
63. Nanfang Hospital Affiliated to Southern Medical University: Min Yang.
64. The General Hospital of Ningxia Medical University: Yi Gong, Hong Zhu.
65. The Affiliated Hospital of QingdaoUniversityMedicalCollege: Jibo Wang.
66. The Fourth People’s Hospital of Shenzhen Affiliated to Guangdong Medical College: Zhizhong Ye, Zhihua Yin.
67. The General Hospital of TianJin Medical University: Lu Gong.
68. Beijing Tongren Hospital Affiliated to Capital Medical University: Zhengang Wang, Li Cui.
69. The Second People’s Hospital of Wuxi: Tianli Ren.
70. The People’s Hospital of Wuxi: Yaohong Zou.
71. The Second Xiangya Hospital of Central South University: Jinwei Chen, Ni Mao.
72. The First People’s Hospital of Yunnan Province: Qin Li.
73. The First Affiliated Hospital of Zhejiang University School of Medicine: Jin Lin.
74. SunYat-sen Memorial Hospital, SunYat-sen University: Lie Dai, Baiyu Zhang.
75. The First People’s Hospital of Changzhou: Min Wu, Wen Xie.
76. The Affiliated Orthopaedic Hospital of Shandong Linyi People’s Hospital: Zhenchun Zhang.
77. Zhejiang Provincial People’s Hospital: Zhenhua Ying.
78. The First Affiliated Hospital of Baotou Medical College: Yongfu Wang.
79. The Affiliated Hospital of Nantong University: Zhanyun Da, Genkai Guo.
80. The First Affiliated Hospital of Suzhou University: Zhiwei Chen.
81. Beijing Shijitan Hospital: Miansong Zhao.
82. Shandong Yantai Yuhuangding Hospital: Weiling Yuan.
83. The General Hospital of Daqing Oilfield: Xiangjie Bi.
84. First Affiliated Hospital of Medical College of Xi’an Jiaotong University: Lan He, Dan Pu.
85. Provincial Hospital affiliated to Shandong University, Jinan, China: Yuanchao Zhang, Limin Zhang.
86. Ji’nan University 2nd Cinical Medicine College, Shenzhen People’s Hospital: Dongzhou Liu, Xiaoping Hong.
87. No.285 Hospital of People’s Liberation Army: Zhu Chen.
88. The First Hospital of Shanxi Medical University: Xiumei Liu, Yiqun Hao.
89. Kailuan Hospital Affiliated to North China Coal Medical College: Liufu Cui.
90. Peking University Shenzhen Hospital: Qingwen Wang, Yi-Sheng Zhu.
91. The First Affiliated hospital of Fujian Medical University: Junmin Chen.
92. The First Hospital of Ningbo: Xiafei Xi.
93. Shanxi Provincial People's Hospital: Lihua Fang.
94. The Second Hospital of Hebei Medical University: Hongtao Jin, Huifang Guo.
95. The First Affiliated Hospital of Wenzhou Medical College: Xiaochun Zhu.
96. The Third Affiliated Hospital of Hebei Medical University: Ping Wei.
97. The First Affiliated Hospital of Xinjiang Medical University: Li Wei.
98. Qingdao Municipal Hospital: Houheng Su.
99. Wuhan Union Hospital affiliated to Tongji Medical School of Huazhong University of Science and Technology: Lingxun Shen.
100. No. 264 Hospital of People's Liberation Army: Jinli Ru, Xiaoxiang Xie.
101. Zhongda Hospital Affiliated to Southeast University: Meimei Wang.
102. The Central Hospital of Sichuan Mianyang: Jing Yang, Yu Zhang.
103. The Seventh People’s Hospital of Shenyang: Zhen Wang, Tienan Li.
Conceived and designed the experiments: DX XY ZGW XFZ. Performed the experiments: DX XY ZGW QYZ JHX LDJ LG FQW JRG YT JWC JLZ MTL YZ XFZ. Analyzed the data: JLZ MTL. Contributed reagents/materials/analysis tools: DX XY ZGW QYZ JHX LDJ LG FQW JRG YT JWC JLZ MTL YZ XFZ. Wrote the paper: DX XY ZGW QYZ.
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