Gene–environment interactions in respiratory system diseases among different ethnic groups: a meta-analysis

UDC 575:616.2

Gene–environment interactions in respiratory system diseases among different ethnic groups: a meta-analysis

Tulepbekova S.Zh.

Master's student, L.N. Gumilyov Eurasian National University, Astana, Kazakhstan

Scientific supervisor: Bulgakova O.V.

ABSTRACT. Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are leading causes of death worldwide. Their development depends on environmental factors, mainly tobacco smoking and residential radon, and on individual genetic susceptibility. The aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) with LC and COPD, to compare these associations among ethnic groups, and to determine whether they depend on the radon level in the study region. A meta-analysis of case–control studies was performed for 20 SNPs (10 for LC and 10 for COPD) using Comprehensive Meta-Analysis software under homozygous, dominant and recessive genetic models. Indoor radon levels were assigned to each study from the original article or from national and regional residential surveys. Seven SNPs showed a statistically significant association: TP53 rs1042522, OGG1 rs1052133 and CYP1A1 rs1048943 with LC, and EPHX1 rs1051740, MMP9 rs3918242, IL6 rs1800795 and VDBP rs7041 with COPD. Most associations were stronger in Asian populations. Almost all included studies were conducted in low-radon regions, which indicates that the identified associations are independent of radon exposure.

Keywords: lung cancer, chronic obstructive pulmonary disease, single nucleotide polymorphism, meta-analysis, radon, gene–environment interaction, ethnic groups.

Introduction

Diseases of the respiratory system remain a major problem of modern medicine. Lung cancer is the leading cause of cancer death in the world, and chronic obstructive pulmonary disease is one of the three leading causes of death overall. Both diseases develop as a result of long-term exposure to harmful environmental factors.

Tobacco smoking is the main risk factor for both LC and COPD. The second most important factor is radon, a natural radioactive gas that accumulates in homes. According to the World Health Organization, radon is the second leading cause of lung cancer after smoking and the leading cause among never-smokers [1].

A pooled analysis of 13 European case–control studies showed that lung cancer risk increases linearly with residential radon concentration [2]. Radon has also been linked to COPD: in a large American cohort, COPD mortality increased by 13% for every 100 Bq/m³ of radon (HR 1.13; 95% CI 1.05–1.21) [3]. However, a systematic review concluded that the evidence on radon and COPD is still limited [4].

In addition, smoking-induced changes in the lungs of COPD patients may increase the bronchial radiation dose from radon [5].

Not all people exposed to smoke or radon develop disease, which points to the role of genetic susceptibility. SNPs in genes involved in DNA repair, metabolism of carcinogens, inflammation and tissue remodelling can change individual risk. The frequency of these variants differs among ethnic groups, so the same SNP may have different effects in Asian and European populations. Previous research in the Kazakh population showed that the TP53 Arg72Pro polymorphism is associated with radon-induced lung cancer [6]. Nevertheless, few studies have analysed SNP associations together with environmental factors and ethnicity.

The aim of this study was to evaluate the association of SNPs with LC and COPD, to compare these associations among ethnic groups, and to determine whether they depend on residential radon levels.

Materials and methods

Literature search and study selection. Case–control studies were searched in the PubMed (including PubMed Central), Google Scholar and ScienceDirect databases. The included studies were published between 1999 and 2020. Search terms included the gene name, "polymorphism", "lung cancer" and "chronic obstructive pulmonary disease". Studies were included if they: (1) had a case–control design; (2) studied LC or COPD in humans; (3) reported genotype frequencies in cases and controls. For each SNP, at least five studies were included. In total, 20 SNPs were analysed: 10 for LC and 10 for COPD. The 38 studies included in the analyses of the seven significant SNPs are listed in the references [6, 13–49].

Data extraction. For each study, the following data were collected: first author, year, country, ethnicity, number of cases and controls, and genotype counts. Hardy–Weinberg equilibrium in control groups was checked.

Statistical analysis. The meta-analysis was performed in Comprehensive Meta-Analysis (CMA) software [7]. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for three genetic models: homozygous (AA vs aa), dominant (AA + Aa vs aa) and recessive (Aa + aa vs AA). Heterogeneity was evaluated with the I² statistic [8]; a random-effects model was used when I² > 50%, otherwise a fixed-effects model was applied. Publication bias was assessed with Egger's regression test [9]. A p-value < 0.05 was considered statistically significant. Subgroup analysis was performed by ethnicity (Asian and non-Asian populations).

Radon assessment. For each study, the indoor radon level was taken from the original article if reported. Otherwise, it was assigned according to the sampling location using national or regional residential radon surveys [10–12]. Country-level data were preferred; city-level data were used if national data were unavailable. Regions were classified as low (< 100 Bq/m³, WHO reference level), medium (100–148 Bq/m³) or high (> 148 Bq/m³, US EPA action level) [1, 12]. A SNP was considered radon-independent if its association with disease was observed in low-radon populations.

Results

Of the 20 SNPs, seven showed a statistically significant association with disease (Table 1). The remaining 13 SNPs were not significant under any genetic model (p > 0.05).

Table 1 – SNPs significantly associated with lung cancer and COPD

Ethnic differences. Subgroup analysis showed that the associations of TP53 rs1042522 (dominant model, p = 0.002), OGG1 rs1052133 (homozygous, p = 0.016), MMP9 rs3918242 (homozygous, p = 0.003) and VDBP rs7041 (dominant, p = 0.014) were significant in Asian populations but not in non-Asian populations. In contrast, CYP1A1 rs1048943 (recessive, p < 0.001) and IL6 rs1800795 (homozygous, p = 0.028) were significant only in non-Asian populations. EPHX1 rs1051740 was associated with COPD in both groups.

Radon levels. Indoor radon levels for all 38 included studies are summarised in Table 2.

Table 2 – Radon levels in the study regions

No study was conducted in a high-radon region. For all seven SNPs, the majority of studies came from low-radon regions. For EPHX1 rs1051740, the association was significant in low-radon studies and not significant in medium-radon studies. Therefore, all seven SNPs were classified as radon-independent.

Discussion

The seven identified genes take part in different biological processes that are important for lung damage caused by environmental factors.

TP53 encodes the p53 tumour suppressor protein, which controls the cell cycle, DNA repair and apoptosis. The Arg72Pro polymorphism changes the ability of p53 to induce apoptosis, which may allow damaged cells to survive. In the study of Bulgakova et al., the Pro allele was associated with radon-induced lung cancer in Kazakhs [6], whereas in the present meta-analysis the association was also found in the low-radon LC group and in other low-radon populations. This suggests that TP53 rs1042522 affects lung cancer risk regardless of radon.

OGG1 encodes 8-oxoguanine DNA glycosylase, a key enzyme of base excision repair that removes oxidative DNA damage. The Ser326Cys variant reduces repair activity. Since both tobacco smoke and radon alpha particles produce reactive oxygen species, reduced OGG1 activity may increase the accumulation of mutations.

CYP1A1 encodes a phase I enzyme that activates polycyclic aromatic hydrocarbons from tobacco smoke into carcinogenic metabolites. The rs1048943 variant is associated with higher enzyme activity, which may explain the link with smoking-related lung cancer.

EPHX1 encodes microsomal epoxide hydrolase, which detoxifies reactive epoxides from cigarette smoke. The rs1051740 (Tyr113His) variant reduces enzyme activity and may increase oxidative stress in the airways.

MMP9 encodes matrix metalloproteinase-9, which degrades the extracellular matrix. The −1562C/T (rs3918242) promoter variant increases gene expression, which may promote destruction of alveolar walls and emphysema.

IL6 encodes interleukin-6, a key pro-inflammatory cytokine. The −174G/C (rs1800795) variant influences IL-6 production and therefore the intensity of chronic airway inflammation in COPD.

VDBP (GC) encodes vitamin D-binding protein, which transports vitamin D and can be converted into a macrophage-activating factor. The rs7041 variant changes these functions and may affect the immune response in the lungs.

The differences between Asian and non-Asian populations may be explained by different allele frequencies, lifestyles and smoking patterns. Most SNPs were more strongly associated in Asian populations, which may also reflect the larger number of Asian studies.

The absence of radon-dependent SNPs is mainly explained by the fact that almost all included studies were performed in low-radon regions. Therefore, our results do not exclude a role of these SNPs in radon-induced disease; they show that the associations exist even at low radon levels.

This study has several limitations. First, the number of studies per SNP was small (5–6). Second, radon levels were assigned at the country or city level and not measured in individual participants. Third, for some countries (Turkey, Mexico) only a range of values was available. Fourth, a large number of comparisons increases the risk of false-positive results. Finally, smoking status was not yet analysed and will be the subject of further work.

Conclusion

1. Of the 20 analysed SNPs, seven are significantly associated with respiratory diseases: TP53 rs1042522, OGG1 rs1052133 and CYP1A1 rs1048943 with lung cancer, and EPHX1 rs1051740, MMP9 rs3918242, IL6 rs1800795 and VDBP rs7041 with COPD.

2. The associations differ among ethnic groups: TP53, OGG1, MMP9 and VDBP are associated mainly in Asian populations, while CYP1A1 and IL6 are associated mainly in non-Asian populations.

3. All seven SNPs are associated with disease regardless of radon exposure, since the associations were observed in low-radon regions.

4. Further studies in high-radon regions, including Kazakhstan, and analysis of smoking status are needed to identify gene–radon and gene–smoking interactions.

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