We used two-sample Mendelian Randomization to test the association in GDF-15 level and CVD, including AIS, CES, LAS, SVS, AF, HF, CAD and MI. The result was suggested GDF-15 level could impact on the incidence of CES , AF,CAD and MI, whereas an obvious relation could not be concluded when coming to other CVDs. Therefore, our study maybe support a causal relation in GDF-15 and the incident of CES, AF,CAD and MI and further indicated a crucial role for GDF-15 -targeted interventions to lessen the epidemic of CVD. However, the evidence was not straightforward since MR-Egger did not refuse the null hypothesis.
Our result corresponds to a slice of previous randomized and observational studies. In community-based Individuals[25], postoperative patients[26] and hypertrophic cardiomyopathy (HCM) folks[27] who had a higher GDF-15 level were more vulnerable to AF than those remaining lower level. Rienstra, M., et al. suggest that was associated with incident AF with the hazards ratios of 1.31 after adjusted for age and sex[25]. Similarly, GDF-15 was reckoned independently associated with paroxysmal AF after multivariable analyses in a study where a significantly higher serum level of GDF-15 was found in patients with paroxysmal AF than controls (1473.14 ± 628.52 vs. 1233.592 ± 262.76 pg/ml, P < 0.05)[28]. In contrast, Santema BT, et al. and Lamprea-Montealegre JA, et al. suggested that serum GDF-15 level was undifferentiated with AF or not in folks with HF from BIOSTAT-CHF trial[29] and people with chronic kidney disease(CKD) from CRIC study[30] respectively. Dissimilitude could have been explained for specific reasons. GDF-15, belonging to transforming growth factor 𝛽(TGF-β) cytokine superfamily, may be a sensitive but not specific biomarker. It involved in the progress of inflammatory and oxidative stress [31], which participated in the process of diverse conditions, such as HF, CAD and CDK[32-34] and may lead the course of disease to a varying degree. Besides, GDF-15 might be an early warning, a composite sign of disease and a reflection determined by various but general elements[35]. Nevertheless, in our research, MR could avoid confounding factors to clarify causality between exposure (GDF-15 level) and outcome (AF). Mechanisms association of increased GDF-15 levels with enhancive incidence of AF are unknown and need to be dug deeper. We assumed that GDF-15 expression, just similar to TGF-β, may promote ionic and structural remodeling of the atria leading vulnerability to AF by PI3K/Akt signaling and SMAD2/ 3 signaling[36, 37]. Besides, GDF-15 was demonstrated strongly related to p53[38] which induced fibrotic signaling, endothelial dysfunction and cardiac inflammation[39-41], linking to AF. However, though our result suggested the causal relation between GDF-15 and AF, it needs more genetic instruments for GDF-15 to identify the relationship.
Cardioembolic strokes were tripled in the past few decades and could triple by 2050 worldwide which AF is the most common risk [42]. Our study developed a new perspective that GDF-15 could positively correlate to cardioembolic strokes. Similar states that the incidence of any stroke could be predicted by GDF-15 in individuals with AF[43] and CVD[7, 8]. In ENGAGE AF-TIMI 48 trial, GDF-15 levels from the baseline of 1661 pg/mL to 12 months of 1711 pg/mL were independently associated with a >2-fold higher rate of stroke or systemic embolic events in patients with AF[44]. Likely, during 1.9 years of follow-up, an annual rate of stroke or systemic embolic events was 2.03% in AF patients with GDF-15 in the highest quartile (>2052 ng/L) while 0.90% in the lowest quartile (≤977 ng/L) in ARISTOTLE trial[45]. Mechanistically, on the one hand, systemic inflammation especially IL-1β, IL-6 and TNF-α was a potential mechanism promoting the formation of cerebral cardioembolism[46] and GDF-15 was proved related to them [47] [48]. On the other hand, AF, HF, CAD were one of the precondition of cardioembolic strokes which were affiliated to augment of serum GDF-15 [49].
In line with the previous works, our result suggested that there was a negative correlation between GDF-15 and CAD, though MR-Egger analyses were insignificant. Also, we reckoned that GDF-15 inversely correlated with MI. Johnen et al. believed GDF-15 may have an protective effect on atherosclerosis process for overexpression of GDF-15 in macrophages significantly attenuates atherosclerotic lesions in the ApoE(−/−) mouse model of atherosclerosis[50]. While, for most researches, experimental results tended to a higher GDF-15 associated with higher CAD and MI risk. Martinez CH, et al found that relative to the lower GDF-15 tertile, mid- and highest tertiles had 1.19-fold and 2.10-fold increases, respectively[51]. And In people with non-ST-elevation acute coronary syndrome, GDF-15 was regarded as the most promising biomarker for the risk of death or nonfatal MI at 6 months with OR 2.4[52]. Its underlying mechanism could be included that GDF-15 exhibited a complex pattern with beneficial and harmful functions. When come to the CAD and MI, beneficial function weighted the harm. Besides, GDF-15 may not involve principal process of CAD and MI. So higher expressing which tried to delay the progression of CAD and MI could not counteract the effect mayor factor made. Whereas, our result should be treated with caution for the MR-Egger analyses was insignificant.
However, our result did not support that incremental GDF-15 had a causality with HF. The arguments were prevailing that GDF-15 concentration had not only a promising value of diagnosis but also a superior prognostic biomarker [53]. Presumably, it is HF that promoted the concentration of GDF-15. Furthermore, the severer state of HF, the more comorbidities existed liking hypertension diabetes, aging, renal dysfunction, which may influence the expression of GDF-15 and needed to be eliminated.
There are certain strengths in the study. Our work provided an alternative perspective to clarify the role of GDF-15 in CVD unprecedentedly and supported an intrinsically positive relationship between GDF-15 and AF, CES, CAD, MI. Further investigations in therapies of GDF-15 control were demanded for it may be rewarding for patients with those. Besides, these selected SNPs were not associated with the other CVDs, indicating that the relationship between the SNPs of GDF15 and some related phenotypes could not confound the null association. Furthermore, it needs to remain aware of metformin employing in individuals with high risks of AF , CES, CAD and MIsince metformin could facilitate the expression of GDF-15, possibly leading to sick and exacerbate.
Limitations were inevitable. Many of them shared common problems of Mendelian randomization[54]. Firstly, the SNPs we selected could not satisfy the demand of independence principle. However, our study found a fresh vision to the relationship between GDF-15 and CVD. Besides, The MR is not sensitive to confounders from environmental exposures and might violate exclusion restriction unless we took into consideration all influence of GDF-15. Also, our statistics based on European populations, limiting the generalizability of our work.