The association between polymorphisms in long non-coding RNA and lung cancer in non-smoking women


 Background

The relationship between long non-coding RNA and lung cancer has become a research hotspot.
Methods

Four polymorphisms, including rs10188946, rs11246867, rs2288947, and rs8105637 were evaluated in 556 patients with lung cancer and 395 age-matched controls in the present study.
Results

This study showed that the associations of the four polymorphisms of long non-coding RNA with the risks of lung cancer were not statistically significant. In the age stratification study, AG of rs2288947 was associated with the reduce risk of both lung cancer and adenocarcinoma (OR = 0.597,P = 0.017 and OR = 0.506, P = 0.005,respectively), and AG of rs8105637 was also protected both lung cancer and adenocarcinoma (OR = 0.636,P = 0.037and OR = 0.577, P = 0.023,respectively). We found that when the risk genotypes of the three SNPs rs10188946, rs11246867, rs2288947 and oil exposure worked together, the risk of lung cancer was higher than either of these two risk factors acted alone.
Conclusions

Four polymorphisms (including rs10188946, rs11246867, rs2288947, and rs8105637) were not associated with lung cancer risks in the present study. After age stratification, rs2288947 and rs8105637 were associated with the risks of lung cancer and adenocarcinoma among the individuals older than 60.


Subject characteristics
The study consisted of 556 case groups and 395 controls, all of whom were Non-exposure-smoking women. The average ages of the case group and the control group were 56.74±11.695 and 56.13±11.642, respectively. The difference in age between the case group and the control group was not statistically signi cant, and there was no difference in age between the case group and the control group (t=-0.797, P=0.905).Of the 556 patients in the case group, 371 (66.7%) were adenocarcinomas, 96 (17.3%) were squamous cell carcinomas, and 89 (16.0%) were small cell carcinomas. We observed that the polymorphisms of the four genotypes in the control group all conformed to Hardy-Weinberg's law ( P=0.427 for rs10188946,P=1 for rs11246867, P=0.759 for rs2288947, P=0.608 for rs8105637).
The relationship between lncRNA polymorphisms and lung cancer, lung adenocarcinoma and lung squamous cell carcinoma Table 1 shows that there is no statistically signi cant association between four SNPs and lung cancer risk. Table 2 shows that there is no statistically signi cant association between the four SNPs and the risk of adenocarcinoma and squamous cell carcinoma. Due to various factors such as immune aging, the incidence of cancer in older people is higher than that of young people [26][27]. So we made a strati ed analysis of age. Tables 3 and 4 re ect the relationship between these four SNPs and the risk of lung cancer and adenocarcinoma. When the age is greater than 60, we found that rs2288947 is associated with the risk of lung cancer, the risk of heterozygous AG was lower than that of AA (OR=0.597, P=0.017). The recessive model was associated with the risk of lung cancer, that is, the risk of genotype GG was higher than that of AA+AG (OR=2.887, P=0.038).We also found that rs2288947 is associated with the risk of adenocarcinoma, and the risk of heterozygous AG is lower than that of AA (OR=0.506, P=0.005). The dominant model is associated with the risk of adenocarcinoma, that is, the risk of genotype GG+AG lower than AA (OR=0.598.P=0.025). We also found that rs8105637 was associated with the risk of lung cancer and the risk of heterozygous AG was lower than that of GG (OR=0.636, P=0.037). We found that rs8105637 was associated with the risk of adenocarcinoma, and the risk of heterozygous AG was lower than that of GG (OR=0.577, P=0.023).
Tables 5 and 6 re ect the interaction of oil exposure with these four SNPs. In our study, the number of people exposed to oil in the case group was 100 (37.3%), and the number of oil exposed in the control group was 66 (24.8%). The number of oil exposed in the case group was more than that of the control group (= 9.739, P=0.002). The risk of lung cancer in exposed was higher than in those without exposure (OR=1.804, 95%CI=1.243-2.618, P=0.002). We also found that for the AG+AA genotype of the gene rs10188946,the risk of lung cancer from exposure to oil was higher than that from Non-exposure-oil exposure (OR=1.912, P=0.009). Furthermore, the risk of lung cancer was higher in patients whose genotypes were GG and exposed to oil than those whose genotypes were AG+AA but not exposed to oil (OR=2.000, P=0.014).
For the GG genotype of rs11246867, the risk of lung cancer from exposure to oil was higher than that from non-exposure-oil exposure (OR=1.736, P=0.005). The risk of lung cancer in AG+AA genotypes exposed to oil was higher than that in GG genotypes that were not exposed to oil (OR=3.325, P=0.043). For the AG+GG genotype of the gene rs2288947, the risk of lung cancer was higher in oil exposure than non-exposure-oil exposure (OR=2.782, P=0.000). Moreover, the risk of lung cancer was higher in patients whose AA genotypes were exposed to oil at the same time than those whose AG+GG genotypes were not exposed to oil (OR=1.778, P=0.034). For the AG+AA genotype of the gene rs8105637, exposure to oil was more likely to have lung cancer than those without exposure to oil (OR=2.783, P=0.000). We did not nd that the additive models of gene environment interactions make sense.

Discussion
As far as we know, the factors that affect lung cancer are very complicated. The in uence of smoking on lung cancer is more deeply rooted in many factors. And it is estimated that the relative risk of lung cancer in long-term smokers is 10-30 times larger than that of non-smokers [28]. Even so, we still nd about 5% of lung cancer cases among non-smokers [29], and the smoking rate of Chinese women is not high (only 2.4% of women older than 15 years old) [30], so we need to study the factors affecting lung cancer in non-smoking women. The same, factors that affect lung cancer in non-smokers are also complex. In our study, we investigated the relationship between four genotypes and lung cancer in female non-smokers.
The study by Yongbin Zheng et al. showed that the rs2288947 and rs8105637 were associated with the susceptibility of colorectal cancer, and allele G was a protective factor for rs2288947 (OR = 0.77, 95% CI = 0.67-0.88, P = 0.00012) and allele A was a risk factor for rs8105637 (OR = 1.22, 95% CI = 1.09-1.37, P = 0.00062). Rs2288947 and rs8105637 were associated with the occurrence of lymphatic metastasis in colorectal cancer, while allele G decreased the risk of lymphatic metastasis (OR = 0.77, 95%CI = 0.63-0.94, P = 0.011) and allele A increased the risk of lymphatic metastasis (OR = 1.22, 95%CI = 1.03-1.43, P = 0.019)[31].Ma et al.'s study showed that rs2288947 was associated with the risk of gastric cancer in Chinese. Compared with genotypes AG, GG, AG + GG, and allele G, AA genotype and allele A increased the occurrence of gastric cancer .Genotype polymorphisms are associated with gastric cancer most in young people, men, and non-smokers [21].In our study, rs2288947 and rs8105637 were associated with lung cancer and adenocarcinoma. When the age was greater than 60 years, We found that rs2288947 and rs8105637 were associated with the risk of lung cancer, while the risk of heterozygous AG for rs2288947 was lower than that of AA (OR = 0.597, P = 0.017) and the risk of heterozygous AG for rs2288947 was lower than that of GG (OR = 0.636, P = 0.037) .We also found that rs2288947 and rs8105637 were associated with the risk of adenocarcinoma, while the risk of heterozygous AG for rs2288947 was lower than that of AA (OR = 0.506, P = 0.005) and the risk of heterozygous AG for rs8105637 was lower than that of GG (OR = 0.577, P = 0.023). The dominant model of rs2288947 was associated with the risk of lung cancer, that is, the risk of genotype GG + AG was lower than that of AA (OR = 0.598. P = 0.025).The population in our study was older than 60, women, and nonsmokers. The AG genotype of the rs2288947 gene reduced the incidence of gastric cancer among young people, men, and non-smokers, and decreased the incidence of lung cancer in people older than 60 years, women, and nonsmokers. The AG genotype of the rs8105637 was a risk factor, while in our study AG genotype was a protective factor. Zheng Y et al. found that TINCR can bind with STAU1 in order to in uence the stability of CDKN2B mRNA. That means the transcription of TINCR accelerated gastric cancer [22].
Studies have shown that the air pollution of Chinese cooking was associated with lung cancer [32, 33]. Zhong L et al.'s population-based case-control study con rmed that people who exposed to indoor air pollution in Chinese cooking may increase the risk of lung cancer [34-36]. Our study also explored the interaction between the four genotypes and oil exposure in non-smoking females in China. In our study, we found that the negative multiplication models between the rs2288947, rs8105637 and the environment were meaningful and we did not nd the additive models of four SNPs interacting with the environment are meaningful.
Our study also had some limitations. All of our subjects came from hospitals. Even if the subjects came from different hospitals, the Berkson bias still existed. Since we were researching non-smoking women, our sample size may not be particularly large because of this conditional restrictions. Therefore, we hope to increase the sample size for more powerful statistical analysis. This study was just a statistical analysis, the speci c mechanism needs further experimental study.
Our study did not nd any of these four SNPs associated with lung cancer. According to age strati cation, we found that rs2288947 and rs8105637 were associated with lung cancer and adenocarcinoma when the age was older than 60.

Abbreviations
LncRNA long non-coding RNA SNP Single-nucleotide polymorphism Declarations Ethics approval and consent to participate The study was approved by the Institutional Review Board of China Medical University and informed consent was obtained from each participant.Each subject contributed 10 ml of venous blood and collected relevant baseline data when they were admitted to hospital.

Consent for publication
All of the authors have read and approved the content, and agree to submit the whole article in your journal.

Availability of data and materials
All data generated or analysed during this study are included in this published article and its supplementary information les.

Competing interests
The authors declare that the research was conducted in the absence of any commercial or nancial relationships that could be construed as a potential con ict of interest.