By using the large-scale GWASs summary statistics, our bidirectional MR study investigated a causal relationship of HAA on liver diseases, and vice versa. We found that HAA positively correlated with circulating GGT levels. In addition, GGT also has a significant causal relationship on HAA. Importantly, our study was the first to explore the causal relationship between HAAs and GGT. These findings may help us to understand the phenomenon of abnormal increase of GGT level in high-altitude population.
It is well known that GWASs may uncover genetic variants associated with disease susceptibility(26). Here we used data from the largest known GWASs to assess the casual effect between HAA and liver diseases/traits. Clinically, serum GGT has been commonly used as an biomarker of hepatobiliary diseases, and increased GGT levels accompanied by elevated free radical and a risk of imbalanced glutathione (GSH)(27). GGT locates on the cell surface and hydrolyzes the γ-glutamyl bonds of extracellular reduction and oxidation of GSH(28). In addition, GGT plays a crucial role in antioxidant, detoxification and inflammation(29). Several recent studies showed the causal relationships of type 2 diabetes(30), stroke(27), calculus of kidney(31) on GGT. At present, there are few reports on the relationship between HAA and GGT. The physiological role of GGT in high-altitude populations is largely unknown.
Several epidemiological evidence have indicated that GGT in plateau acclimated populations (Tibetans) surpass those in plateau emigrants (Han)(7, 32). He et al. defined high levels of GGT as one of the characteristic phenotypes of HAA on the Tibetan(7). Hypoxia can lead to hepatocyte dysfunction, hypoxic hepatitis, and liver fibrosis(33–35). The increased GGT may be the cost of adapting to hypoxia. GGT has been shown to be an independent predictor of hepatitis(36), and it also may be attributed to the high incidence of hepatitis in Tibetans(37).
People with high GGT levels are more capable of adapting to the high-altitude environment. Mechanistically, the characteristics of GGT regulate the balance of oxidative stress in the body and stimulate the biosynthesis of GSH, which is a rich antioxidant factor in cells. GGT is integral in maintaining redox homeostasis by hydrolyzing GSH and enabling cysteine recovery for cells(38). Therefore, the upregulation of GGT makes the cells more resistant to oxidative stress, and the high-altitude is accompanied by an extreme hypoxic environment, and hypoxia is a catalyst for oxidative stress, which may explain that people with high GGT are more easily adapted to the altitude environment(39).
The results of our MR analysis were robustness as our MR analysis was from a disciplined process of instrument selection and validation. Moreover, this study enhances statistical power by using GWAS data with large sample size, and does not entail concerns related to personal privacy. The employment of genetic variations as instrumental variables reduces environmental confounding compared to clinical Trials.
As for limitations, first, we were unable to validate our results due to the unavailability of GWAS summary data for HAA in other plateau adaption people. Further validation analyses are required to verify the causative of HAA on GGT. Second, the study population we used was only East Asian population. Previous studies have shown that various populations adapt to highland environments in distinct ways because of genetic diversity(40).
Overall, GGT may serve as a marker of HAA. In the future, GGT may be used as one of the biological indicators to build biological models of HAA populations. It can also provide risk assessment for highland journey for patients with chronic liver diseases(10).
In general, this MR results showed that increased HAA capacity will lead to a corresponding increase in GGT, and vice versa. These findings might contribute to the development of screening and prevention strategies for diseases associated with GGT abnormalities in plateau populations.