Figure 1 shows our study design and framework of this research. According to our criteria, a total of 217 SNPs were used as instrumental variables for the 27 cytokines which are divided into three categories: interleukin family, chemokines, and growth factors (supplement Table S1). For each pair of cytokines and outcomes, F-statistics were greater than or equal to 33.49, which is considered as no weak instrumental bias (supplement Table S6). The diseases (outcomes) included in the study (supplement Table S2) are divided into five categories: cancer and its subtypes, cardiovascular diseases, neurological and mental diseases, endocrine diseases, and autoimmune diseases.
Figure 2 shows IVW estimates of the causality between cytokines and human complex diseases. For cancers and its subtypes, MIG and SCF increased the risk of endometrioid ovarian and ER + breast cancer by 55% and 29% [ORs (95%CIs): 1.55 (1.05–2.30), 1.29 (1.06–1.57)], respectively. SCGFb was positively associated with high grade serous ovarian cancer (OR = 1.09, 95%CI = 1.00-1.19) and malignant neoplasm of colon (OR = 1.49, 95%CI = 1.01–2.19). However, MIF was negatively associated with low grade serous ovarian and breast cancer (Oncoarray) [ORs (95%CIs): 0.51 (0.27–0.95), 0.84 (0.75–0.95)], respectively. For cardiovascular diseases, MCP1 was positively associated with HF, stroke, ischemic stroke (IS) (large arteries), and IS (small blood vessels), [ORs (95%CIs): 1.16 (1.02–1.32), 1.09 (1.03–1.15), 1.22, (1.07–1.39), 1.15, (1.05–1.30)], respectively. TRAIL increased the risk of CHD (OR = 1.03, 95%CI = 1.01–1.06) and MI (OR = 1.03, 95%CI = 1.00-1.06). However, SCGFb decreased the risk of CHD (OR = 0.94, 95%CI = 0.90–0.99) and MI (OR = 0.94, 95%CI = 0.89-1.00). For neurological and mental diseases, MIG was positively associated with schizophrenia (OR = 1.17, 95%CI = 1.01–1.36) and AD (OR = 1.38, 95%CI = 1.10–1.72). Similarly, MIP1b increased the risk of AD (OR = 1.05, 95%CI = 1.01–1.09) and PD (OR = 1.06, 95%CI = 1.02–1.10), but decreased the risk of depression (OR = 0.95, 95%CI = 0.92–0.98). Additionally, the interleukin family include IL5, IL7, IL10, IL12p70 and IL13 increased the risk of anxiety disorders by 39%, 16%, 18%, 16% and 12%, [ORs (95%CIs): 1.39 (1.10–1.75), 1.16 (1.05–1.28), 1.18 (1.06–1.31), 1.16 (1.08–1.24), 1.12 (1.05–1.20)], respectively. And IL5, IL7, IL10 and IL13 decreased the risk of CHD by 12%, 6%, 7% and 4%, [ORs (95%CIs): 0.88 (0.78–0.99), 0.94 (0.89-1.00), 0.96 (0.92-1.00)], respectively.
Figure 3 shows the results of MR-BMA for selecting causal risk factors of human complex diseases from a large number of candidate cytokines. It shows the top models (i.e.sets of cytokines) ranked according to their model PP, and the top cytokines according to their MIP. In the interleukin family, IL2ra, IL13, IL16, IL18, and IL17 were the top risk factor for multiple sclerosis (MS) (OR = 1.27; PP = 0.13), anxiety disorders (OR = 1.12; PP = 0.22), ER- breast cancer (iCOGS) (OR = 1.11; PP = 0.07), systemic lupus erythematosus (SLE) (OR = 1.17; PP = 0.11), inflammatory bowel disease (IBD) (OR = 1.17; PP = 0.14), respectively. In the chemokines, MCP1 was the top risk factor for HF (OR = 1.18; PP = 0.08), stroke (OR = 1.09; PP = 0.16), and gout (OR = 1.16; PP = 0.17). MIP1b was the top risk factor for AD (OR = 1.05; PP = 0.21), PD (OR = 1.07; PP = 0.19), and rheumatoid arthritis (RA) (OR = 0.95; PP = 0.17). MIG and Eotaxin were the top risk factor for the IS (large artery) (OR = 1.21; PP = 0.12) and schizophrenia (OR = 0.94; PP = 0.31), respectively. For the growth factors, PDGFbb was the top risk factor for IS (cardioembolic) (OR = 1.16; PP = 0.17) and type 2 diabetes (OR = 0.91; PP = 0.11). SCGFb was the top risk factor for malignant neoplasm of colon (OR = 1.49; PP = 0.03) and type 1 diabetes (OR = 1.12; PP = 0.07), and SCF was the top risk factor for high grade serous ovarian cancer (OR = 1.13; PP = 0.2), clear cell ovarian cancer (OR = 1.29; PP = 0.04), and hypertensive diseases (OR = 1.07; PP = 0.08). More details about the results of MR-BMA can be found in the supplement Table S4.
As is shown in Fig. 4, the bidirectional MR study was used to test whether human complex diseases altered circulating cytokine levels. Most types of cancers were not associated with an increase or decrease of circulating cytokine levels, only high-grade serous ovarian cancer had a suggestive association with increased IL2ra (β = 0.112) and HGF (β = 0.088). However, endocrine diseases are causally related to a wide range of cytokines, such as type 1 diabetes influenced the circulating levels of IL16 (β = 0.048), IP10(β = 0.082), MIG (β = 0.101), CTACK (β=-0.047), and gout increased the circulating levels of IL5 (β = 0.145), MIF (β = 0.100). Autoimmune diseases include RA and SLE increased the circulating levels of chemokines and growth factors. RA increased the circulating levels of IL5 (β = 0.074), IL17 (β = 0.069), MIG (β = 0.105), MIP1b (β = 0.065), and SCGFb (β = 0.061). SLE increased the circulating levels of IP10 (β = 0.044), MIG (β = 0.054), and bNGF (β = 0.037).
We also performed the above statistical test on the causal relationship between cytokines and risk factors (anthropometric indicators, blood biochemistry, life behavior), which is found in the supplementary Table S3, S5, S7 and Figure S1-S4. IVW results showed that all of the IL8, IL7, MIG, MIPb, Eotaxin, PDGFbb, and MIF have causal effects on more than four kinds of risk factors. For life behavior: IL10, IL18, GROa, and IP10 were the top risk factor for age at menopause, cigarettes per day, cognitive performance, systolic blood pressure. Eotaxin was the top risk factor for waist circumference and age of smoking initiation. About blood biochemistry, IL18, IL10, IL17, MIG, MIP1b, CTACK, and TRAIL were the top risk factor for Vitamin B12, Leptin, Lipoprotein A, Albumin, Urate, Apolipoprotein B, Omega-6 fatty acids, respectively.