Impact of PD-L1 gene polymorphism and its interaction with cooking with solid fuel exposure upon susceptibility to tuberculosis

doi:10.21203/rs.3.rs-1601334/v1

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Impact of PD-L1 gene polymorphism and its interaction with cooking with solid fuel exposure upon susceptibility to tuberculosis

https://doi.org/10.21203/rs.3.rs-1601334/v1

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Given that PD-L1 is a crucial immune checkpoint in regulating T cell responses, the aim of this study was to explore the impact of PD-L1 gene polymorphism and its interaction with cooking with solid fuel on susceptibility to tuberculosis (TB) in Chinese Han populations. A total of 503 TB patients and 494 healthy controls were enrolled in this case-control study. Mass spectrometry (MS) technology was applied to genotype rs2297136 and rs4143815 of PD-L1 genes. The associations between SNPs and TB were assessed using unconditional logistic regression analysis. Marginal structural linear odds models were used to estimate the gene-environment interactions. Compared with genotype CC, genotypes GG and CG + GG at rs4143815 locus were significantly associated with susceptibility to TB (OR: 3.074 and 1.506, respectively, P < 0.05). However, no statistical association was found between rs2297136 SNP and TB risk. Moreover, the relative excess risk of interaction (RERI) between rs4143815 of the PD-L1 gene and cooking with solid fuel was 2.365 (95% CI 1.922,2.809), suggesting positive interactions with TB susceptibility. In conclusion, the rs4143815 polymorphism of the PD-L1 gene was associated with susceptibility to TB in Chinese Han populations. There were significantly positive interactions between rs4143815 and cooking with solid fuel.

tuberculosis

gene-environment interaction

PD-L1

cooking with solid fuel

Tuberculosis (TB) is a major disease accounting for a large number of cases and deaths worldwide. According to the Global Tuberculosis Report 2020 by the World Health Organization (WHO)¹, approximately 10 million new TB cases occurred, and approximately 1.2 million people died from TB globally in 2019. China ranked third among countries with the highest TB burden, next to India and Indonesia, involving approximately 8.4% of the world's TB cases.

Generally, humans infected with Mycobacterium tuberculosis (Mtb) have a wide spectrum of clinical severity, suggesting a complex host-pathogen interaction. The polarized effector T cell response is believed to be critical for combating Mtb in the human immune system, and this process is regulated by various costimulatory signals to maintain homeostatic balance². Programmed cell death-1 (PD-1) is a cell-surface co-inhibitory receptor upregulated on CD4 + and CD8 + T cells in patients with TB³, and its ligand PD-L1 (also called CD274 and B7-H1) is an immune checkpoint glycoprotein expressed broadly on immune cells and tumor cells². Previous studies have demonstrated the induction of PD-L1 on T cells and antigen-presenting cells, such as macrophages and dendritic cells, during the process of Mtb stimulation. Furthermore, upon ligation with PD-L1, the PD-1 cytoplasmic domain is tyrosine phosphorylated and binds with src homology 2-domain-containing tyrosine phosphatase (SHP-2), leading to dephosphorylation and deactivation of TCR signaling molecules and finally accelerated apoptosis of activated T cells⁴. Blockade of the PD-1/PD-L1 axis is supposed to restore T cell functions and increase resistance to tumor growth and various infectious diseases^3,5. However, regarding Mtb infection, both clinical and mouse studies reported enhanced susceptibility to TB after PD-1/PD-L1 blockade, which indicates a more complicated relationship between them⁶.

Single nucleotide polymorphisms (SNPs) play a vital role in altering gene expression and the function of the encoded protein. To date, several SNPs of the PD-1 gene have been identified in relation to cancers, autoimmune diseases, and infectious diseases such as HBV and HCV infection⁷. A few studies have investigated the associations with Mtb infection and have suggested significant results in selected PD-1 variants. Similarly, polymorphisms of the PD-L1 gene, such as rs2297136 and rs4143815, etc. have been proved to be associated with diseases such as cancer and type 1 diabetes^8,9, and few research has reported the relevance of polymorphisms to TB risk. Considering the important role of PD-L1 in immune response and its tight relationship with PD-1, we speculated that genomic variations in PD-L1 may play a role in TB development.

Furthermore, indoor air pollution (IAP) like kitchen smoke has been suspected and proven to contribute to TB¹⁰, particularly in children^11–13, despite controversial results in some studies^14,15. Fuel types used in households are mainly categorized into solid fuel (coal and biomass) and non-solid fuel worldwide. People cooking or heating with coal and biomass are exposed to harmful kitchen smoke containing various chemical constituents, such as nitrogen oxides and particulate matter¹², which could compromise the immune function of the respiratory system and make individuals more vulnerable to infections¹⁶. Population-based studies have suggested a possible association between cooking with solid fuel and predisposition to TB. Moreover, biological evidence has shown that IAP including smoke from solid fuel may initiate an inflammatory response in the lung and lead to T cell proliferation and cytokine production, whereas lowering the antimycobacterial activity of macrophages and alteration of gene expression has been reported^12,17. Therefore, we speculated that there might be associations between the harmful smoke and PD-L1 on TB.

This study aimed to explore the impact of PD-L1 variations on TB in Chinese Han populations and examine whether there is any interaction between the PD-L1 gene and cooking with solid fuel.

Source of subject

We estimated the sample size of 445 subjects for patients and controls, respectively, based on the unmatched case-control study (estimated minor allele frequency (MAF) in the rs2297136 locus was 0.21, OR = 1.65, α = 0.05, β = 0.1). Stratified sampling was used to select the study samples. According to the two-stage sampling principle, four centers for disease control (CDCs) (i.e., Hongjiang City CDC, Qidong County CDC, Yueyanglou District CDC, and Yueyang County CDC) at the county level out of 122 CDCs were randomly chosen across the province, and TB cases newly diagnosed were randomly selected as case groups. All cases were confirmed according to the unified TB diagnostic criteria formulated by the Ministry of Health of China¹⁸. The control group was selected using the same strategy, in which the eligible controls were randomly selected from permanent residents of Xin'ansi Community. Our previous study outlined the specific inclusion criteria¹¹.

For both groups, all subjects were Chinese Han population aged ≥ 18 years and were not related within three generations. In addition, we excluded people with primary immune deficiency, HIV infection, severe malnutrition, long-term hormone use, tumors, diabetes and organ transplants.

Information and sample collection

A self-designed questionnaire was used to collect demographic and environmental information, including gender, educational background, body mass index (BMI), BCG vaccination history, alcohol consumption, tea-drinking, kitchen ventilation facilities, and exposure to solid fuel fumes from cooking, etc. In this study, household cooking fuels were classified as solid fuel and non-solid fuel. The former included wood, coal, and crop wastes, etc.; the latter included liquefied and natural gas, etc. Information on fuel exposure mainly covered the type of primary cooking fuel, exposure frequency, and duration. Individuals who cooked for their households using solid fuels were classified as cooking with solid fuel.

Furthermore, we collected five milliliters of venous blood from each participant and stored it at 4°C until use, using ethylenediaminetetraacetic acid (EDTA) anticoagulant tubes. Thereafter, we extracted the genome from peripheral white blood cells using the Wizard Genomic DNA kit and stored at -80°C.

Selection of SNPs and Genotyping

The selected SNPs must fulfill at least one of the following criteria: being associated with TB or other infectious diseases according to existing evidence. Only polymorphisms with MAF > 5% were included to ensure statistical efficacy. After searching the dbSNP database for the corresponding SNPs and their frequencies (http://www.ncbi.nlm.nih.gov), we finally determined two SNPs (rs2297136 and rs4143815) of the PD-L1 gene. Using Assay Design 3.1 (Sequenom) and the site sequences of the two SNPs identified in the gene bank, we designed suitable primers for genotyping. Quality of the synthesized primers was checked by MALDI-TOF (matrix-assisted laser desorption ionization time-of-flight mass spectrometry).

A 5-ul PCR reaction system was used, including 1 ul PCR primer mix, 0.1 ul dNTP (25mM), 1.8 ul ddH₂O, 0.2 ul Hotstar, 0.5 ul 10*PCR buffer, 0.4 ul MgCl₂ (25mM), and 1 ul DNA (20-50ng). Predegeneration was conducted for 2 min at 95°C, amplification was carried out for 45 cycles (56°C for 30 s, 95°C for 30 s, 72°C for 60 s), followed by extension at 72°C for 5 minutes.The digestive enzyme reaction was carried out with 0.3 ul SAP enzyme, 0.17 ul SAP buffer, and 1.53 ul ddH₂O. The reaction time was 40 minutes at 37°C, followed by 5 minutes at 85°C. One-base extension reactions required 0.041 iplex enzyme, 0.2 ul terminator mix, 0.2 ul iplex buffer, 0.94 ul extend primer mix, and 0.619 ul ddH₂O. The conditions for the reaction were 94°C predegeneration for 30 sec, 40 cycles of amplification containing 3 min extension at 72°C and 5 cycles at 80°C, 52°C, and 94°C, respectively, for 5 sec. Subsequently, we used a 6-mg resin plate and 384-well SpectroCHIP (Sequenom) chip for resin purifying and spotting (MassARRAY Nanodispenser RS1000). Molecular weight differences can be interpreted as differences in base composition due to SNP polymorphisms and finally used for determining SNP typing. More details were described in our previous publication¹¹.

Statistical analysis

We used Epidata 3.0 and SAS 9.2 for data input and analysis, and the chi-square test for grouped data and Hardy-Weinberg equilibrium. We used unconditional logistic regression models with adjustments for possible confounders like marital status, etc. to estimate the odds ratios and 95% CIs, and the relative excess risk of interaction (RERI) to analyze the additive gene-environment interactions if the main effect of SNPs in the PD-L1 gene on TB was meaningful. Marginal structural linear odds models¹⁹ were used for the point estimation and interval estimation of RERI. An RERI > 0 indicates a positive interaction.

Ethics declarations

The studies involving human participants were reviewed and approved by the Medical Ethical Committee of Xiangya School of Public Health, Central South University (Ref No. XYGW-2018-11). All experiments obeyed the Declaration of Helsinki. And we obtained the informed consent from participants of the study.

A case-control study was used to explore the associations of the selected factors with TB susceptibility, in which 503 TB patients and 494 healthy controls were included. Statistically significant differences (P < 0.05) were found in terms of BMI, history of BCG vaccination, smoking, alcohol consumption, tea drinking, cooking with solid fuel and kitchen ventilation facilities, and. However, no statistical significance (P > 0.05) was observed in sex, age, marital status and educational background between the two groups (Table 1).

Table 1

Demographic characteristics and associated risk factors in tuberculosis patients vs healthy controls.
	TB patients (n = 503)		Healthy controls (n = 494)		χ²	P value
	n	%	n	%	χ²	P value
Sex
Male	369	73.36	348	70.45	1.048	0.306
Female	134	26.64	146	29.55
Age, yr
18–30	68	13.52	78	15.79	1.908	0.592
31–50	190	37.77	178	36.03
51–70	167	33.20	153	30.97
> 70	78	15.51	85	17.21
Marital status
Married	345	68.59	330	66.80	0.364	0.546
Other	158	31.41	164	33.20
Educational background
Primary school or below	198	39.36	220	44.53	2.824	0.244
Junior high school	161	32.01	148	29.96
Senior high school or above	144	28.63	126	25.51
BMI, kg/m²
< 18.5	180	35.79	169	34.21	9.310	0.010^*
18.5–24.9	297	59.05	274	55.47
≥ 25.0	26	5.17	51	10.32
History of BCG vaccination
Yes	105	20.87	141	28.54	7.884	0.005^*
No	398	79.13	353	71.46
Smoking
Yes	298	59.24	240	48.58	11.403	< 0.001^*
No	205	40.76	254	51.42
Alcohol drinking
Yes	91	18.09	77	15.59	1.116	0.291
No	412	81.91	417	84.41
Tea drinking
Yes	247	49.11	293	59.31	10.457	0.001^*
No	256	50.89	201	40.69
Cooking with solid fuel
Yes	299	59.44	250	50.61	7.864	0.005^*
No	204	40.56	244	49.39
Kitchen ventilation facilities
Unavailable	295	58.65	217	43.93	21.620	< 0.001^*
Available	208	41.35	277	56.07

TB: Tuberculosis; BMI: Body mass index; BCG: Bacillus Calmette–Guérin.

^* P < 0.05.

The genotypic frequencies of PD-L1 polymorphisms are shown in Table 2. After adjusting for the covariates of sex, age, marital status, educational background, body mass index, smoking, alcohol consumption, tea-drinking, BCG vaccination, cooking with solid fuel and kitchen ventilation facilities, multivariate unconditional logistic regression analysis showed that rs4143815 of the PD-L1 gene was associated with susceptibility to TB. In detail, genotypes GG and CG + GG at rs4143815 (compared with genotype CC) were significantly associated with increased risk of TB, with adjusted ORs reaching 3.074 and 1.506, respectively. However, no statistical association was observed between the rs2297136 variant and TB risk (Table 2).

Table 2

PD-L1 gene polymorphisms in tuberculosis patients vs healthy controls.
		TB patients		Healthy controls		OR_c (95%CI)	OR_a^* (95%CI)
		n	%	n	%	OR_c (95%CI)	OR_a^* (95%CI)
rs4143815	CC	320	63.62	370	74.90	1	1
	CG	143	28.43	110	22.27	1.503 (1.125–2.009)^*	1.296 (0.941–1.787)
	GG	40	7.95	14	2.83	3.304 (1.765–6.183)^*	3.074 (1.609–5.871)^*
	CG + GG	183	36.38	124	25.10	1.706 (1.299–2.241)^*	1.506 (1.115–2.035)^*
rs2297136	TT	277	55.07	290	58.70	1	1
	TC	203	40.36	181	36.64	1.174 (0.906–1.522)	1.131 (0.864–1.482)
	CC	23	4.57	23	4.66	1.047 (0.574–1.909)	0.777 (0.412–1.466)
	TC + CC	226	44.93	204	41.30	1.160 (0.902–1.491)	1.088 (0.838–1.413)

TB: Tuberculosis; OR: Odds ratio.

^aAdjusted for the covariates of sex, age, marital status, educational background, body mass index, smoking, alcohol drinking, tea drinking, BCG vaccination, cooking with solid fuel and kitchen ventilation facilities.

^* P < 0.05.

Furthermore, marginal structural linear odds models were used to examine the interactions between the selected sites of the PD-L1 gene and the selected environmental factors. After adjusting for the covariates of sex, age, marital status, educational background, body mass index, smoking, alcohol consumption, tea-drinking, BCG vaccination, and kitchen ventilation facilities, the relative excess risk of interaction (RERI) between rs4143815 of the PD-L1 gene and cooking with solid fuel was 2.365 (95% CI 1.922, 2.809), suggesting positive interactions with TB susceptibility (Table 3).

Table 3

Impact of interactions between rs4143815 and cooking with solid fuel on incidence of tuberculosis.
	rs4143815		RERIc	RERIa^a (95%CI)
	CC	CG + GG	RERIc	RERIa^a (95%CI)
Cooking with solid fuel
No	1	1.121	1.247	2.365 (1.922, 2.809)^*
Yes	1.104	2.472	1.247	2.365 (1.922, 2.809)^*

RERI: Relative excess risk of interaction. RERI > 0 suggests positive interactions.

^aAdjusted for the covariates of sex, age, marital status, educational background, body mass index, smoking, alcohol drinking, tea drinking, BCG vaccination, and kitchen ventilation facilities.

^* P < 0.05.

Tuberculosis involves complex Mtb-human interactions, in which many different cell types, including T cells, dendritic cells, macrophages, and natural killer cells, participate in the progression from asymptomatic form to clinical disease²⁰. As a cell-surface receptor expressed on most of these cells, PD-L1 exerts a modulatory role in human innate and particularly adaptive immune responses by binding to PD-1, expanding Tregs, and suppressing efficient clearance against pathogens and tumor cells^2,21. The human gene PD-L1 is located on chromosome 9p24.2²², where numerous variants are associated with several diseases, except TB^9,23. Therefore, this study aimed to evaluate the possible relationship between PD-L1 polymorphisms and TB and gene-environment interactions with cooking with solid fuel.

The results showed that mutations of rs4143815 in the PD-L1 gene were associated with susceptibility to TB. Individuals with GG/CG + GG genotypes at the locus displayed a significantly increased vulnerability to TB than those carrying the CC genotype. To our knowledge, this finding is novel, since no relevant study has been reported previously. The variant rs4143815 is located at the 3'-untranslated region (3'-UTR) of the PD-L1 gene, and previous investigations have shown that structural variations such as duplications and translocations would cause aberrant PD-L1 expression in several cancers²⁴. Furthermore, studies have shown that miRNAs can bind to the 3'-UTR of messenger RNA (mRNA) and regulate gene translational repression^22,25. As a genetic variation within 3'-UTR of the PD-L1 gene, SNP rs4143815 is supposed to disturb the suppressive function by affecting the binding capacity of PD-L1 mRNA to its corresponding miRNA miR-570, thus leading to aberrant PD-L1 expression.

To date, numerous cancer types have been associated with the rs4143815 variant. Xie et al.²⁶ found that the rs4143815 GG genotype had higher levels of PD-L1 and was associated with an increased risk of hepatocellular carcinoma (HCC) compared with CC genotypes, whereas individuals with the CC genotype displayed better prognosis compared with the CG and GG genotypes. Similarly, several studies have demonstrated that G allele carriers confer an increased susceptibility to cancers including gastric adenocarcinoma, ovarian cancer compared with CC genotypes^25,27. Moreover, an elevated PD-L1 expression among them was reported, suggesting that the G allele in rs4143815 of PD-L1 may increase PD-L1 expression by affecting the binding force between miR-570 and mRNA^25,27. In addition, pathological features, including tumor size, differentiation degree, and tumor node metastasis (TNM) stage, were associated with mutations at the locus²⁶. However, controversy still exists regarding the function of PD-L1 rs4143815 in diseases. In a previous study, the GG genotype of rs4143815 decreased the risk of breast cancer²⁸. In addition, an insignificant association of mutations in rs4143815 with the risk of colorectal cancer, non-small cell lung cancer (NSCLC), and esophageal squamous cell carcinoma has been reported in previous studies^29–31. Further, research on type 1 diabetes suggested a larger stem-loop structure for G allele carriers, which might facilitate the interaction between the 3'-UTR of PD-L1 and miR-570, resulting in lower PD-L1 expression⁹. Overall, discrepancies among studies may be attributed to the essential differences between these diseases, and the substantial heterogeneity of study designs, ethnicities, and confounders control might have some role. In this study, the mechanism mentioned above may explain our findings; however, further investigations on genetic mutations and PD-L1 expression among TB patients should be conducted to confirm this.

In the rs2297136 variant in PD-L1, our results suggested no significant association with TB risk. However, previous studies showed that it is a binding site for miR-324-5p located in the 3'-UTR of the PD-L1 gene. The mechanism by which the rs2297136 polymorphism acts on the expression of PD-L1 protein is supposed to be similar to that of the rs4143815 SNP, with the vital step being the interaction between miR-324-5p and PD-L1 mRNA^8,26. Several studies have been performed to confirm the process and examine the associations of the rs2297136 SNP with multiple diseases. Previous studies proposed that rs2297136 TT and TC genotypes contributed to the poor prognosis of multiple myeloma (MM) and colorectal cancer, respectively^32,33, and a higher level of PD-L1 mRNA was demonstrated³⁴. In contrast, Xie et al.²⁶ revealed a significant association between the TT/TC genotypes and better prognosis of HCC. In non-small cell lung cancer (NSCLC), Du et al.³⁰ reported a higher risk of NSCLC among G allele carriers, with the transcriptional activity of the PD-L1 gene being suppressed in a luciferase assay. Lee et al.³⁵ found a better prognosis for patients carrying the C allele after chemotherapy. In addition, another study showed that individuals with GG genotypes had lower PD-L1 expression levels and poor prognosis of gastric cancer⁸, indicating the complex role of mutation genotypes on PD-L1 expression and disease progression. Moreover, the current knowledge regarding the correlations between rs2297136 and infectious diseases, including TB, is limited, more studies should be conducted despite a preliminary view of the field provided by this study.

Furthermore, marginal structural linear odds model analysis suggested that rs4143815 of the PD-L1 gene had positive interactions with cooking with solid fuel on TB susceptibility. It is well known that cooking with solid fuel is one of major sources of indoor air pollution, which has been implicated in the occurrence and sequela of various diseases. However, evidence remains inconsistent in TB research currently. Many epidemiological studies have attempted to clarify the dose-response relationship but the results were equivocal. Some studies reporting a significant association^10,11, whereas others did not³⁶. The discrepancy among studies may be due to the substantial heterogeneity in exposure definitions, accuracy of exposure monitoring, and quantitative effect estimates. In addition, kitchen ventilation facilities and room structures may have indirect effects by altering the exposure concentration. Although conflict exists in population studies, biological evidence supports these associations. Basic studies have shown that biomass smoke from different types of solid fuels contains a complex mixture of approximately 200 chemicals, such as carbon monoxide, varying sizes of particulate matter (PM), sulphur and nitrogen oxides, polycyclic aromatic hydrocarbons (PAH), aldehydes, free radicals and non-radical oxidising species and volatile organic compounds. Chronic exposure to these hazardous substances can impair mucociliary clearance of the lung and facilitate persistent inflammation through the secretion of pro-inflammatory cytokines¹⁷. PAH can inhibit the immune function thereby weakening the immunity of the human body¹¹. In addition, particulate matter such as PM2.5 can act as a carrier for several toxic components, promote inflammatory responses, and influence gene transcription¹⁷. These mechanisms provided the biological plausibility for associations between the risk factor of interest and Mtb infection. They revealed that there might be some cross-talk in the mechanism between the environmental factor and the PD-L1 pathway. In this regard, our findings indicate that those with mutations in rs4143815 of the PD-L1 gene are at a higher risk of contracting TB if exposed to cooking with solid fuel, and behavioral interventions in these aspects may lower TB incidence. The novel linkages between modifiable factors and gene mutations may provide new directions for TB prevention and are helpful in understanding precise prevention strategies among different populations.

This study had some limitations. First, we detected limited SNPs of the PD-L1 gene, and many other genetic and environmental backgrounds among the population may cause some improbability in the study. Hence, more studies on gene-gene, gene-environment, and environment-environment interactions should be conducted to better elucidate the etiology of TB. Second, this study did not examine the relationships between levels of PD-L1 protein and mutations in specific SNPs, leaving deep mechanisms behind the observed associations on TB susceptibility not been determined. Thus, further in-depth studies are still needed to validate our findings on molecular levels. Third, the participants were all limited to Chinese Han population. Considering the probable existence of genetic deviations among different ethnic populations, our results might only apply to the specific population studied. Thus, external validation studies in other populations are still required to determine the generalisability of our findings. Despite these limitations, this study precisely defined exposure to cooking with solid fuel, and adjusting for covariates such as age, smoking, alcohol consumption, and kitchen ventilation facilities, the results should be reliable.

This study suggests that rs4143815 of the PD-L1 gene is associated with a significantly increased risk of TB in a Chinese population, and there were positive interactions between rs4143815 SNP and cooking with solid fuel. These findings are helpful for studying the pathogenesis of TB infection and identifying the high-risk populations of acquiring TB, which may contribute to implementing the more targeted measures against developing TB. Further studies in larger populations are needed to verify these findings.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Author Contributions

M.W. and J.W. conceived and planned the study. K.T., M.W., M.C., H.Z. and Q.W. were involved in planning and supervised the data collection. Z.L., C.W., R.A., Y.L. and H.T. contributed to the data collection. K.T., J.W., Q.W., Z.L. and H.Z. performed the statistical analyses. K.T. wrote the draft and the final version of the manuscript. K.T., M.W., M.C., H.Z., Q.W., H.T. and L.C. contributed to the literature search, language editing, and manuscript revision. M.W. and J.W. contributed to the overall project supervision and manuscript revision. All authors read and approved the final version of the manuscript.

Competing interests

The authors declare no competing interests.

Funding

This research was funded by Mega Project of Research on the Prevention and Control of HIV/AIDS, Viral Hepatitis Infectious Diseases, grant number 2018ZX10302302001008; National Natural Science Foundation of China, grant number 81803298 and 81800275; and Hunan Provincial Natural Science Foundation of China, grant number 2020JJ4762. The funding organization played no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript.

Acknowledgements

We thank our partners Dr. Bai Liqiong and Dr. Xu Zuhui (Hunan Institute of Tuberculosis Prevention and Treatment) for their input into this work.

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No competing interests reported.

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Impact of PD-L1 gene polymorphism and its interaction with cooking with solid fuel exposure upon susceptibility to tuberculosis

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