Association between autoimmune disorders and prostate cancer: a Mendelian Randomization Study

doi:10.21203/rs.3.rs-3224738/v1

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Association between autoimmune disorders and prostate cancer: a Mendelian Randomization Study

https://doi.org/10.21203/rs.3.rs-3224738/v1

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Background:

Although many epidemiological studies or meta-analyses have reported an association between autoimmune disorders and prostate cancer, no studies have reported a clear causal relationship and the direction of the association. The purpose of our research was to explore the potential causal relationship between autoimmune disorders and prostate cancer through mendelian randomization study(MR).

Method:

We retrieve literature through the pubmed using key words of "Autoimmune disorder" AND "cancer", and find that more than ten autoimmune disorders and cancer are potentially related. We continue to use the keywords of “autoimmune disorder” AND “prostate cancer” to find more clues on the correlation between prostate cancer and autoimmune disease. According to the above literature support, we selected 16 common autoimmune disorders that may be associated with prostate cancer. We extracted and selected disease-related single nucleotide polymorphisms (SNPs) from the largest and public genome-wide association study (GWAS) summary data. Inverse variance weighted (IVW) method was applied as our primary analyses for the two-sample Mendelian randomization and multivariate mendelian randomization analysis to estimate the OR value and 95% confidence interval. In addition, we conducted other two analyses to verify the reliability of the conclusion: weighted median method and MR-Egger method. We further verified the robustness of the conclusions by a series of sensitivity analyses.

Results:

The autoimmune diseases we selected included rheumatoid arthritis, ankylosing spondylitis, coxarthrosis, gonarthrosis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, celiac disease, primary sclerosing cholangitis, asthma, type I diabetes, systemic lupus erythematosus, multiple sclerosis, autoimmune hyperthyroidism, psoriatic arthritis, and polymyalgia rheumatica. The results of IVW methods suggest that six immune diseases have been associated with the development of prostate cancer. Three diseases that may be significantly associated with higher risk of prostate cancer are rheumatoid arthritis (OR: 1.03, 95%CI,1.01-1.05, p=0.001), coxarthrosis (OR: 1.17, 95%CI,1.08-1.26, p < 0.001), and gonarthrosis (OR: 1.17, 95%CI,1.05-1.3, p=0.008). Three possible protective factors for prostate cancer are primary sclerosing cholangitis (OR: 0.97, 95%CI,0.95-0.99, p=0.001), autoimmune hyperthyroidism (OR: 0.97, 95%CI,0.94-0.99, p=0.011), and psoriatic arthritis (OR: 0.97, 95%CI,0.95-0.99, p=0.001). Multivariate Mendelian randomization found no association between Crohn's disease or ulcerative colitis and prostate cancer. Horizontal pleiotropy was not found in MR-Egger intercepts.

Conclusion:

Our findings provide genetic predictive evidence of an association between autoimmune disorders and prostate cancer, and these findings have important implications for screening and management in clinical practice.

Prostate cancer

Autoimmune disorders

Causal relationship

Mendelian randomization

Autoimmune disorders are a series of diseases in which the body attacks its own tissues due to the dysfunction of the immune system. When lymphocytes (T cells and B cells) are under the influence of different external and internal factors, they may attack various tissues and organs of our body, causing them to denature, damage and dysfunction. People with autoimmune disorders suffer from chronic inflammation for a long period, and inflammation can affect almost every organ and system in the body.

Chronic inflammation is a type of systemic inflammation which sustains for months or years and is related to almost every health problem and disease. At present, more and more studies suggest that there may be a close relationship between inflammation and the occurrence and development of cancer. Inflammation may precede or accompany the development of tumor. Examples of cancer caused by long-term chronic inflammation are well established: Helicobacter pylori infection and stomach cancer, human papillomavirus infection and cervical cancer, as well as rheumatoid arthritis and lung cancer. With the introduction of the concept of immune microenvironment in tumor tissue, people are increasingly aware of the existence of a large number of immune cells in the tumor microenvironment. Immune cells regulate each other through cytokines, and play an important role in the process of tumor initiation, progression, invasion and metastasis.

The morbidity of prostate cancer ranks the second among male malignant tumors in the world. In the United States, the incidence rate of prostate cancer has surpassed lung cancer, becoming the most serious malignant tumor that endangers men's health[1, 2]. Although the morbidity of prostate cancer in China is lower than that in western countries, it has increased substantially in recent years, especially in coastal developed areas, and prostate cancer has become the first malignant tumor in the incidence of male reproductive system. At present, the mechanism of immune function in prostate cancer is one of the main research focuses.

an increasing number of study support the close association between autoimmune disorders and tumors. There are two hypotheses on this topic. First, autoimmune disorders originate from overactivation of the immune system, leading to enhanced immune surveillance and recognition, which helps to find and eliminate cancer cells. In contrast, some scholars believe that the overactivated immune system triggers chronic inflammation in cells, leading to mutations in the DNA of dividing cells, which can cause cancer. autoimmune disorders that increase the risk of prostate cancer may indicate a common genetic structure between these diseases. We retrieve literature through the pubmed using key words of "Autoimmune disorder" AND "cancer", and find that more than ten autoimmune disorders and cancer are potentially related. We continue to use the keywords of “autoimmune disorder” AND “prostate cancer” to find more clues on the correlation between prostate cancer and autoimmune disease. According to the above literature support, we selected 16 common autoimmune disorders that may be associated with prostate cancer, and tried to explore the causal relationship between them and prostate cancer through Mendelian randomization analysis. One study also found that the use of ADTs in PCA patients was associated with a reduced risk of autoimmune disorders. It provides further evidence for a potential link between the them[3].

Mendelian Randomization (MR) is an epidemiological analysis method used to verify etiological hypotheses and inferences[4]. Specifically, it used genetic variation as instrumental variant (IV) to infer the causal correlation between exposure and outcome. An exposure refers to the research object has been exposed to a certain substance to be studied or a certain state or characteristics to be studied. An outcome is defined in epidemiology as a consequence of exposure, usually refers to a disease. In the past epidemiological studies, we are prone to some confounding factors, leading to inaccuracy of the association. At the same time, many risks cannot be randomly assigned for practical or moral reasons. Last but not least, it is possible to find reverse causation when studying associations between diseases. In traditional research, the causal relationship between exposure and outcome can only be studied through randomized controlled studies(RCT). But RCTs take time, effort and money, and is also limited by ethical factors. Mendelian randomized analysis selects genetic variants from random allocation of parental alleles, which is similar to randomized controlled studies in principle, so it can make up for the above shortcomings. It uses instrumental variants to replace exposure factors that could not be experimentally studied. By measuring the correlation among genetic variation, exposure and outcome, it inferred the causal relationship between exposure and outcome[5, 6]. Therefore, in order to clarify the causal relationship between chronic inflammatory and autoimmune disorders and prostate cancer, genome-wide association analysis (GWAS) data are used for MR analysis.

For the results of Mendelian randomization to be reliable, three basic assumptions must be satisfied: 1. correlation: Instrumental variables are strongly correlated with exposure factors (pval < 5E-08); 2. Independence: Instrumental variables cannot be associated with any other possible confounding factors; 3. Exclusivity: Instrumental variables cannot be directly related to results.

Study Samples and Measures:

To obtain a causal relationship between immune diseases and prostate cancer, we used the largest public GWAS data available to compute. Among them, the data of immune diseases mainly come from open databases such as GWAS catalog(https://www.ebi.ac.uk/gwas/), IEU OpenGWAS(https://gwas.mrcieu.ac.uk/project), FinnGen Consortium(https://www.finngen.fi/en) and UK biobank cohort(http://www.nealelab.is/uk-biobank)[7–17](Table1). Each data include specific information but not limite to screening procedures and diagnostic criteria, which is recorded in open databases or original published literature. The data samples we used are all of European ancestry, and there is no significant overlap between the samples used for analysis.

The summary GWAS data for prostate cancer is derived from the PRACTICAL consortium. The study included 79,148 cases and 61,106 controls. The number of SNPS measured included 20,346,368. The summary data is obtained from seven previous prostate cancer GWAS and genotypic data from the 1000 Genomes Project's which based on high density SNP panel of European ancestry.

Table 1

Characteristics of the prostate cancer and autoimmune disease GWAS cohorts
Expoure	ncase	ncontrol	number of SNPs	PMID/consortium
Asthma	56,167	352,255	34,551,291	34103634
Celiac disease	12,041	12,228	38,037	22057235
Primary sclerosing cholangitis	2,871	12,019	7,891,603	27992413
Type 1 diabetes	9,266	15,574	12,783,129	32005708
Systemic lupus erythematosus	5,201	9,066	7,071,163	26502338
Rheumatoid arthritis	14,361	43,923	13,108,512	33310728
Ankylosing spondylitis	9,069	13,578	99,962	23749187
Coxarthrosis	10,709	172,834	16,380,348	FinnGen biobank
Ulcerative colitis	12,366	33,609	9,474,559	28067908
Crohn's disease	12,194	28,072	9,457,998	28067908
Multiple Sclerosis	47,429	68,374	6,304,359	31604244
Irritable Bowel Syndrome	53400	430957	9,885,498	34741163
Autoimmune hyperthyroidism	962	172,976	16,380,189	FinnGen biobank
Psoriatic arthropathies	1,553	147,221	16,380,141	FinnGen biobank
Polymyalgia rheumatica	1,523	213,145	16,380,452	FinnGen biobank
Gonarthrosis	22,796	172,834	16,380,379	FinnGen biobank
Prostate cancer	79,148	61,106	20,346,368	29892016

Instruments Selection:

To select genetic variation tools from 16 immune disease GWAS, we used subset function to extract SNPS significantly associated with exposure at GWAS (p < 5E-08), in which p < 5E-07 was used for significance threshold to screen in multiple sclerosis and rheumatic myalgia due to few SNPS extracted. Then the LDproxyR tool of TwoSampleMR package was used to remove the possible unbalance effect between SNPS (clumping window of 10,000 kb, a clumping cutoff r² of 0.001). This tool can also remove variants with palindromic sequences. Subsequently, the immune disease-related SNPs filtrated were merged with GWAS date of prostate cancer, and the SNPs selected in this study were finally affirmed through harmonization step. If the results are heterogeneous, we can eliminate outliers by MR-PRESSO and re-evaluate the effect value.

Study design:

Our data analysis mainly includes three aspects. First, the association among autoimmune disorders and prostate cancer were investigated using the two-sample Mendelian randomization method. Second, because Crohn's disease and ulcerative colitis overlap a significant number SNPs, we used multivariable MR analyses to distinguish their direct association with prostate cancer. Finally, we applied a series of sensitivity analysis to evaluate the reliability of the results, further eliminate possible confounding factors and improve the accuracy of the conclusion.

Statistical Analysis:

We conducted a two-sample Mendelian randomization study mainly using the TwoSampleMR package. We calculated wald ratio of each SNP, and meta-analyzed the effect value of each SNP using IVW and other three methods to generate a conclusive β estimate, and then the OR value and 95% confidence interval were converted as analysis results. The causal relationship between exposure and outcome were evaluated based on a type-I error of 0.05. The IVW method is sensitive to pleiotropy and provides the most reliable estimates of causality[18]. In addition to IVW, the other two methods in Mendelian analysis were used as supplementary analysis to further verify the stability of IVW results, namely MR-Egger and Weighted median. weighted median tolerance for genetic tools is high, and the assessment of causality is reliable when more than 50% of SNPS are effective[19]. MR Egger can also correct for pleiotropy in his causal assessment[20]. In addition, we tested the heterogeneity of the conclusion by Cochran's Q test of MR-Egger and IVW methods. When p < 0.05, it means heterogeneity exists in the study. We further found and eliminated SNPs that may produce heterogeneity through MR Presso analysis, and re-performed MR analysis after eliminating outliers[21]. Finally, in order to verify the second and third hypotheses, we use MR Egger to conclude whether horizontal pleiotropy exists[22]. In addition, we provide scatter plots for visualizing the relationship between exposure and outcome. Finally, in order to verify the reliability of the positive results, we also carried out the leave one out analysis and drew the funnel diagram. All data analysis were based on R software(version4.2.1). We mainly used TwoSample MR (https://github.com/MRCIEU/TwoSampleMR) and MVMR for the analysis of MR[23, 24].

According to our IVW results, among the 16 common chronic inflammatory diseases or autoimmune disorders, IVW results suggest that genetically predicted 6 immune diseases were significantly associated with the risk of prostate cancer(Table 2). Three diseases that may increase risk of prostate cancer are rheumatoid arthritis (OR: 1.03, 95%CI,1.01–1.05, p = 0.001), coxarthrosis (OR: 1.17, 95%CI,1.08–1.26, p < 0.001), and gonarthrosis (OR: 1.17, 95%CI,1.05–1.3, p = 0.008). Three possible protective factors for prostate cancer are primary sclerosing cholangitis (OR: 0.97, 95%CI,0.95–0.99, p = 0.001), autoimmune hyperthyroidism (OR: 0.97, 95%CI,0.94–0.99, p = 0.011), and psoriatic arthropathies(OR: 0.97, 95%CI,0.95–0.99, p = 0.001)(Fig. 1). For rheumatoid arthritis, coxarthrosis and primary sclerosing cholangitis, the weighted median method and MR-Egger showed the same results in the same direction (p < 0.05). The weighted median method showed the same results for gonarthrosis, autoimmune hyperthyroidism, and psoriatic arthritis (p < 0.05). Horizontal pleiotropy was not found in MR-Egger intercepts. Multivariate Mendelian randomized analysis results are consistent with the previous results, we did not find an association among Crohn's disease and ulcerative colitis and prostate cancer(Table 3). In addition, the scatter plots visually demonstrate the association between chronic inflammatory and autoimmune disorders and prostate cancer.

Table 2

The ORs express effects of liability to each exposure on prostate cancer risk computed by two-sample Mendelian randomization analysis
Expoure	N SNP	IVW			weighted median			MR Egger
		OR	CI	p	OR	CI	P	OR	CI	p
Asthma	70	1.044	0.999–1.091	0.055	1.065	1.008–1.126	0.024	1.079	0.965–1.206	0.189
Celiac disease	15	0.989	0.969–1.010	0.304	0.992	0.974–1.010	0.371	1.003	0.974–1.032	0.851
Primary sclerosing cholangitis	18	0.971	0.955–0.988	0.001	0.971	0.955–0.988	0.001	0.967	0.944–0.992	0.019
Type 1 diabetes	39	1.006	0.989–1.025	0.445	1.018	0.995–1.042	0.118	1.021	0.981–1.061	0.321
Systemic lupus erythematosus	40	0.996	0.984–1.008	0.516	1.001	0.985–1.017	0.931	0.992	0.965–1.019	0.56
Rheumatoid arthritis	84	1.026	1.009–1.043	0.002	1.024	1.001–1.048	0.041	1.039	1.014–1.065	0.003
Ankylosing spondylitis	24	1.061	0.963–1.169	0.229	1.099	1.001–1.207	0.047	1.089	0.925–1.284	0.316
Coxarthrosis	6	1.165	1.079–1.258	<0.001	1.142	1.041–1.252	<0.001	0.933	0.588–1.479	<0.001
Ulcerative colitis	51	0.989	0.968–1.010	0.318	0.973	0.946–1.001	0.061	0.936	0.884–0.993	0.033
Crohn's disease	79	0.987	0.974–1.002	0.085	0.991	0.971–1.011	0.381	1.001	0.964–1.038	0.975
Multiple Sclerosis	85	1.007	0.993–1.021	0.36	1.007	0.985–1.030	0.513	1.016	0.996–1.037	0.118
Irritable Bowel Syndrome	5	0.953	0.781–1.162	0.632	0.918	0.716–1.176	0.499	0.157	0.016–1.530	0.209
Autoimmune hyperthyroidism	6	0.965	0.939–0.992	0.011	0.958	0.935–0.982	0.001	0.938	0.876–1.004	0.138
Psoriatic arthropathies	4	0.972	0.955–0.989	0.001	0.969	0.950–0.989	0.002	0.953	0.905–1.003	0.206
Polymyalgia rheumatica	5	1.017	0.977–1.058	0.404	1.028	1.001–1.056	0.037	1.034	0.935–1.144	0.557
Gonarthrosis	5	1.166	1.040–1.308	0.008	1.09	0.957–1.243	0.194	2.118	0.933–4.805	0.17

Table 3

The ORs express effects of liability to each exposure on prostate cancer risk computed by multivariate Mendelian randomization analysis
Exposure	SNP	β	SE	OR(95%CI)	P
Ulcerative colitis	46	0.012	0.014	0.987(0.959–1.016)	0.394
Crohn's disease	73	-0.003	0.011	0.996(0.974–1.019)	0.765

Sensitivity analysis:

We use two methods to conduct Cochran's Q test to detect the heterogeneity among samples. We found heterogeneity in 12 of the 16 diseases. After heterogeneity was found, MR Presso analysis was carried out to find SNPs that might cause heterogeneity, in which the parameter NbDistribution = 10000. MR Analysis and sensitivity analysis were performed again after the corresponding SNPs were removed (Table4). When heterogeneity exists, we mainly use random effects model of IVW method to evaluate effect values. MR Egger was used to detect the existence of horizontal pleiotropy. In this study, p values of the analysis results were all > 0.05 which did not provide evidence of horizontal pleiotropy.

For 6 immune diseases, leave-one-out method was used to assess the impact of each SNP on the overall causal estimates, that is, after each exclusion of one SNP, the remaining SNPs were re-analyzed as instrumental variables. The results of the reserve method in rheumatoid arthritis, coxarthrosis, gonarthrosis, and primary sclerosing cholangitis showed that after the SNPs were sequentially removed, the results of the IVW analysis of the remaining SNPs were similar to the results of the analysis of all SNPs included, and no SNPs were found to have a significant effect on the estimate of causal association. Autoimmune hyperthyroidism and psoriatic arthropathies each have one SNP crossed the origin due to the few number of SNP itself. We also check the stability of the results by looking at the symmetry of the funnel plot.

Table 4

Sensitivity analysis, heterogeneity, and pleiotropy, investigating MR assumption violation
Exposure	Heterogeneity test						pleiotropy			MR-PRESSO
	MR-Egger			Inverse variance weighted			MR-Egger			global test	distortion test	outliver SNP
	Q	Q_df	Q_pvalue	Q	Q_df	Q_pvalue	Intercept	se	p	p	p
Irritable Bowel Syndrome	2.447	3	0.485	4.931	4	0.301	0.076	0.049	0.217	NA	NA
Autoimmune hyperthyroidism	9.578	4	0.048	11.515	5	0.042	0.016	0.018	0.419	0.153	NA
Coxarthrosis	4.431	4	0.35	5.449	5	0.36	0.025	0.027	0.392	NA	NA
Asthma	108.355	68	0.001	108.974	69	0.001	-0.002	0.004	0.535	0.001	NA	rs10486391 rs2412099 rs7936312 rs9260752 rs9272226
Celiac disease	22.624	11	0.02	26.084	12	0.01	-0.007	0.006	0.221	< 1e-04	0.575	rs130078 rs13198474
Primary sclerosing cholangitis	37.432	16	0.002	37.913	17	0.003	0.003	0.006	0.656	0.007	NA
T1D	56.924	37	0.019	57.772	38	0.021	-0.004	0.005	0.462	< 1e-04	0.0476	rs9273363 rs689 rs506770 rs4566101
Systemic lupus erythematosus	66	39	0.004	69.312	40	0.003	0.007	0.005	0.169	0.002	0.08
Rheumatoid arthritis	140.149	82	6.74E-05	143.299	83	4.45E-05	-0.003	0.002	0.178	< 1e-04	0.644	rs112733823 rs11754264 rs1611236
Ankylosing spondylitis	54.411	38	0.041	54.572	39	0.049	0.001	0.005	0.739	0.002	0.085	rs2517655
Ulcerative colitis	74.431	49	0.011	80.221	50	0.004	0.009	0.005	0.056	< 1e-04	0.94	rs2212434 rs6062496
Crohn's disease	96.787	77	0.063	97.5	78	0.067	-0.002	0.003	0.453	< 2e-04	0.809	rs11236797 rs6062496 rs6808936
Multiple Sclerosis	138.343	83	<0.01	141.186	84	<0.01	-0.002	0.002	0.195	< 2e-04	0.871	rs11711621
Psoriatic arthropathies	1.042	2	0.594	1.684	3	0.641	0.012	0.014	0.507	NA	NA
Polymyalgia rheumatica	10.53	3	0.015	11.007	4	0.026	-0.007	0.019	0.737	0.204	NA
Gonarthrosis	3.113	3	0.374	5.263	4	0.261	-0.049	0.034	0.246	NA	NA	rs1558902 rs224329

Inflammation plays a double-edged role in the body, protecting it from pathogens and monitoring abnormal cells. But chronic inflammation can lead to tissue damage. Previous research have identified how inflammation leads to cancer. Cancers of the stomach, liver and cervix are thought to be associated with inflammation definitely. In recent years, the relationship between chronic inflammation and autoimmune disorders and cancer has attracted more and more attention, but there are few studies in the field of prostate cancer. In this study, we conducted Mendelian randomized analysis on 18 chronic inflammatory or autoimmune disorders and prostate cancer to systematically and comprehensively demonstrate the correlation between the two diseases. By using Mendelian randomization, we further corroborate previously reported observational findings, laying the foundation for exploring deeper associations. In order to prove the reliability of the results of this study, we apply a series of analysis methods to make the results meet the three core assumptions of Mendelian randomization analysis, and improve the robustness and validity of the results.

Based on the method of Mendelian randomization, we comprehensively explore the causal association between chronic inflammatory diseases and autoimmune disorders and prostate cancer from the genetic level.

Previous observational studies have found the association between rheumatic diseases and prostate cancer. Wheeler.AM et al. published a retrospective cohort study in 2022 which is the largest clinical research of RA and prostate cancer, involving 283,798 patients (＞56,000 RA patients) and 6,550 prostate cancer patients (RA patients＞1,400 cases). They found that RA was associated with an increased risk of prostate cancer (adjusted for HR 1.14 [95% CI 1.06 - 1.22]), but cohort bias were inevitable[25]. We further support that rheumatoid arthritis may be a risk factor for prostate cancer through Mendelian randomized analysis. Another study found that higher cytokine/chemokine concentrations in RA patients were associated with an increased risk of cancer, particularly lung cancer and lymphoproliferative cancer, suggesting that elevated circulating cytokines and chemokines predicted risk of cancer in patients with rheumatoid arthritis[26]. Two meta-analyses showed that systemic lupus erythematosus might reduce the incidence of prostate cancer, which was inconsistent with our findings[27, 28]. This may be because men with SLE tend to have low levels of androgens, which is an important mechanism that leads to the proliferation of prostate cancer cells. However, it is worth noting that Song-L et al. found that SLE was positively associated with most cancers, and only prostate cancer and cutaneous melanoma were negatively associated. At present, several important co-stimulators have been shown to play an important role in the carcinogenic process of SLE[29]. Thus, these stimulators may neutralize or reverse the effects of testosterone levels on prostate cancer. However, observational studies have not been able to exclude the effect of rheumatic drugs such as NSAIDs, which is confused due to horizontal pleiotropy[30]. At the same time, because SLE is more common in females, observational studies on male cases are relatively insufficient. Similarly to our conclusion, Ward.MM et al. found that older patients with knee and hip osteoarthritis (KHOA) or ankylosing spondylitis were more likely to develop prostate cancer in a retrospective cohort study based on US Medicare data from 1999 to 2015[31]. Our study found no association between ankylosing spondylitis and prostate cancer after removing the SNPs that lead to pleiotropy, so there may be confounding factors interfering. A large matching clinical study showed that patients with rheumatic myalgia were 6 percent more likely to develop cancer in the six months following diagnosis than patients without rheumatic myalgia[32]. There was a slight increase in prostate cancer, but the number of cases was too small to be directly compared. And that association weakens over time[33]. So a larger clinical research is needed to support it.

Epidemiological studies also suggest an association between gastrointestinal immune diseases and prostate cancer. In addition to an increased risk of gastrointestinal malignancies, patients with inflammatory bowel disease may also have an increased risk of extraintestinal tumors[34]. A matched retrospective cohort study showed that inflammatory bowel disease was associated with an increased risk of prostate cancer[35]. A meta-analysis further demonstrated that patients with ulcerative colitis (UC) had a higher risk of PCa by subgroup analysis, while Crohn's disease (CD) was not associated with PCA[36]. Although the cohort study selected 1; 9 cases, but only 1000 cases of IBD, limited data. Current studies suggest that intestinal microecological environment may affect prostate inflammation and the occurrence of prostate cancer[37, 38]. The meta-analysis selected were both cohort studies and case-control studies, so we could not infer whether inflammatory bowel disease caused the occurrence of prostate cancer or whether the incidence of cancer was caused by immunosuppressive drugs in inflammatory bowel patients. More targeted studies are needed for further verification. Primary sclerosing cholangitis(PSC), celiac disease, and irritable bowel syndrome, which are associated with the development of inflammatory bowel disease, were also included in the study to explore their association with prostate cancer. PSC has a low incidence and is characterized by multifocal bile duct stenosis and advanced liver disease. No previous studies have reported an association between PSC and prostate cancer. One reason that may prevent prostate cancer from developing is that PSC disrupts male estrogen levels in patients by causing liver failure.

For central system immune diseases, studies on systemic sclerosis and prostate cancer are ambiguous. However, a newly published meta-analysis that pooled the results of all studies showed no association between systemic sclerosis and prostate cancer[39]. But it is important to note that testosterone levels are significantly reduced in people with MS, which may have implications for the development of prostate cancer[40].

For chronic diseases, Harding.JL et al. found that type 1 diabetes was associated with a reduced incidence of prostate cancer, but not with mortality[41]. In contrast, Kang.J et al. found that type 1 diabetes was associated with a higher morbidity of a Gleason score of 8 to 10 rather than 7 PCa[42]. Hyperimmune function and hyperglycemia may promote the proliferation of tumor cells. In addition, exogenous insulin and insulin-like growth factor (IGF-1) can promote cancer[43, 44]. But a high insulin state also leads to a drop in testosterone levels, which seems to lower the risk of prostate cancer[45]. In order to solve the current disputes, we selected the largest GWAS data of T1D for Mendelian randomization analysis, and finally found no causal correlation between them.

Severi et al., who first conducted a cohort study in Melbourne in 2010, found a small increased risk of prostate cancer in patients with asthma (HR: 1.25, 95% confidence interval (95% CI)=1.05-1.49). It is important to note that long-term follow-up is difficult to separate the effects of glucocorticoids from the effects of asthma on prostate cancer risk[46]. A recent meta-analysis of 14 clinical studies on asthma and prostate cancer showed no association between asthma and prostate cancer in the general population, white population or Asian population by subgroup analysis[47].

We also found for the first time that autoimmune hyperthyroidism and psoriatic arthropathies may act as potential protective factors for prostate cancer. Due to the few number of cases of both diseases, larger samples and prospective studies are needed to explore this.

Our study is currently the most comprehensive Mendelian randomized study to explore the association between immune diseases and prostate cancer, but still has several shortcomings. First the GWAS data we selected are all from European ancestry, and the results of this study need to be further verified by demographic stratification before they can be generalized to other races. Second, the exposure variance explained by SNPs is small, so a large sample size is needed to ensure the robustness of the results. For some exposure data, the insignificance of the results may be false negative due to insufficient sample size which lack efficacy, such as rheumatic myalgia. There are still some immune diseases or chronic inflammatory diseases where MR analysis cannot be performed due to the absence of appropriate GWAS data. Third, mendelian randomization can only make rough judgments about causality, so it is difficult to explore the underlying physiological mechanism. Autoimmune disorders or chronic inflammation represent a complex state of the human body, involving more biological mechanisms than a single biomarker signaling pathway. More research is needed to explore the deeper mechanisms behind their association. Fourth, we do not have access to the raw data, so we cannot conduct subgroup analysis, so it is difficult to draw more detailed causal conclusions. Larger sample and long-term trials are needed in the future to verify these results.

This study suggests that chronic inflammatory diseases and autoimmune disorders play a certain role in the pathogenesis of prostate cancer, and the early screening of prostate cancer in patients with rheumatoid arthritis, coxarthrosis and gonarthrosis is of great significance for the management of prostate cancer in clinical practice.

Funding:

This work was supported by the National key R&D plan of China(2022YFC3602904); the National Natural Science Foundation of China(No:81974395, No:82173036); Guangdong Basic and Applied Basic Research Foundation(No: 2019A1515011437); International Science and technology cooperation project plan of Guangdong Province (No: 2021A0505030085) ; Sun Yat-Sen University Clinical Research 5010 Program (No: 2019005) ; Beijing Bethune Charitable Foundation(mnzl202001);Guangzhou Science and Technology Key R&D Project(202206010117); Beijing CSCO Clinical Oncology Research Foundation (Y-tongshu2021/ms-0162) ：Beijing CSCO Clinical Oncology Research Foundation(Y-MSDZD2022-0760); Open research funds from the Sixth Affiliated Hospital of Guangzhou Medical University，Qingyuan People's Hospital; Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation (No:2020B1212060018OF006); Guangdong Provincial Clinical Research Center for Urological Diseases(2020B1111170006) to Hai Huang.

The National Natural Science Foundation of China (No. 82173088), Natural Science Foundation of Guangdong (No. 2022A1515012383), the Guangzhou Science and Technology Fund (No. A202201011299)；Baiqiuen Fund to Kaiwen Li.

Acknowledgments

Haoran Tao, Sun-Yat-Sen memorial hospital, is grateful for his assistance in the execution of this data analysis. The authors express their gratitude to the participants and personnel of Sun Yat Sen Memorial Hospital for their efforts.

Author Contributions

Peixian Chen, Zhi Xiong and Tianlong Luo performed the literature search, drafted the manuscript and contributed equally to this manuscript. Kaiwen Li and Hai Huang reviewed the article after conducting a review of the current related literature. All authors critically revised the manuscript and approved the final version.

Availability of data and materials

The datasets generated and analyzed during the current study are available in the GWAS catalog(https://www.ebi.ac.uk/gwas/), IEU OpenGWAS(https://gwas.mrcieu.ac.uk/project), FinnGen Consortium(https://www.finngen.fi/en) and UK biobank cohort(http://www.nealelab.is/uk-biobank).

Ethical Approval and consent to participate

Not applicable.

Consent for Publication

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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No competing interests reported.

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Association between autoimmune disorders and prostate cancer: a Mendelian Randomization Study

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