The causal relationship between circulating micronutrients and urolithiasis: a Mendelian randomization study

doi:10.21203/rs.3.rs-5228461/v1

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Research Article

The causal relationship between circulating micronutrients and urolithiasis: a Mendelian randomization study

https://doi.org/10.21203/rs.3.rs-5228461/v1

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Objective

Previous epidemiological and experimental studies have yielded conflicting results regarding the impact of human micronutrient levels on the risk of urolithiasis. In our study, we conducted two sample Mendelian randomization (2SMR) and multivariable Mendelian randomization (MVMR) surveys to explore the association between 15 human micronutrients (copper, calcium, carotene, folic acid, iron, magnesium, potassium, selenium, zinc, vitamin A, vitamin B12, vitamin B6, vitamin C, vitamin D, and vitamin E) and genetic susceptibility to urolithiasis.

Method

Fifteen instrumental variables (IVs) for micronutrients were selected from published genome-wide association studies (GWAS). After selecting the appropriate IVs, we conducted an MR study using the inverse variance weighting (IVW) method as our primary estimation tool, using sensitivity analyses to judge heterogeneity, pleiotropy and leave-one-out sensitivity analyses.

Result

Our study found that genetic susceptibility to elevated vitamin D levels reduced the risk of developing Calculus of kidney and ureter; The genetic susceptibility to elevated vitamin C concentration increases the risk of developing Calculus of lower urinary tract. However, there was no statistically significant association between the other 13 micronutrients and the risk of urinary stones.

Conclusion

Vitamin D may have a protective effect on the occurrence of Calculus of kidney and ureter; Vitamin C may have a harmful effect on the occurrence of Calculus of lower urinary tract.

Micronutrients

Urinary stone syndrome

Mendelian randomization

Causal risk factors

Urolithiasis can be divided into two categories based on the location: upper urinary tract stones (kidney stones, ureteral stones) and lower urinary tract stones (bladder stones, urethral stones). It is one of the common diseases of the urinary system, and its harm to health mainly manifests in the local damage of stones to the urinary tract, urinary tract obstruction caused by stones, and concurrent urinary tract infections. 2–20% of people worldwide suffer from urolithiasis, and the recurrence rate within 5 years is approximately 30–50%.¹ In recent years, with the prevalence of irregular diet and obesity, the incidence rate of urolithiasis is on the rise and tends to be younger.^{2, 3} In addition, due to the high recurrence rate of urolithiasis, the economic burden on patients is constantly increasing. Unfortunately, there is no other effective treatment for urolithiasis except for surgical lithotripsy in the later stage.^4–6 However, the onset of urolithiasis is caused by a combination of multiple factors and the pathogenesis is not fully understood. Therefore, further exploration of the exact etiology of urolithiasis is of great significance.

As essential organic compounds for maintaining health, it is crucial to study the impact of micronutrients on urolithiasis. Early studies have shown that a decrease in vitamin A can lead to an increase in intestinal absorption of calcium oxalate, which in turn increases urinary oxalate and uric acid excretion, promoting stone formation. When vitamin B6 decreases, oxalic acid formation increases, promoting the formation of calcium oxalate stones; At the same time, when vitamin B6 is elevated, the level of citric acid in urine increases, thereby inhibiting the formation of calcium oxalate stones. When the intake of vitamin C exceeds 2-4g, the concentration of uric acid will increase, thereby promoting the formation of stones.⁷ The correlation between vitamin D intake and urolithiasis has been controversial.^8–10 Vitamin E has free radical scavenging and anti glycation effects, which can reduce the deposition of calcium oxalate crystals. When vitamin E increases, it can lead to a decrease in kidney tissue sedimentation, thereby inhibiting the formation of urinary tract stones. Similarly, vitamin K also has the effect of inhibiting stone formation. Excessive intake of calcium can lead to increased absorption in the small intestine, resulting in increased urinary calcium and promoting the formation of stones.^{7, 11, 12} Fluoride can enhance the mineralization ability of urine, increase the accumulation of calcium in stones, and promote the formation of urinary stones along with silicon, cadmium, and lead. Cadmium and lead can damage the renal tubular basement membrane, leading to increased calcium deposition.¹³ Zinc can inhibit the formation of urinary stones, mainly by forming soluble complexes with oxalic acid; Adhering to the crystal surface, limiting the growth of active sites on the surface of calcium oxalate; Affects the enzyme system involved in purine metabolism, which in turn affects uric acid metabolism and inhibits the formation of urinary tract stones. When the citric acid/iron ratio increases, it can inhibit calcium phosphate stones; When citric acid/iron decreases, it will inhibit calcium oxalate stones.¹⁴ Copper can inhibit the transformation of calcium oxalate stones into hydrated calcium oxalate crystals, aluminum can reduce gastrointestinal absorption of oxalic acid, lower exogenous urinary oxalate sorting, and high concentrations of magnesium can increase solubility, reducing calcium oxalate supersaturation. Therefore, copper, aluminum, and magnesium inhibit the growth and aggregation of calcium oxalate. There is a negative correlation between serum selenium levels and a history of kidney stones.^{13, 15} Meanwhile, the bicarbonate formed by the complexation of organic acids with potassium helps to increase the pH value of urine, reduce the precipitation of uric acid and cystine, and prevent the formation of stones.¹⁶ Higher dietary carotenoid intake was associated with a reduced prevalence of kidney stones.¹⁷ As for folic acid and vitamin B12, there is no relevant research indicating their impact on urolithiasis.

Mendelian randomization (MR) is a genetic epidemiological technique that uses genetic variation to infer causal relationships between modifiable exposure and outcome variables. More and more evidence proves the reliability of MR, such as Yiwei Lin et al. confirming through MR analysis that fresh fruit intake is a protective factor for urolithiasis.¹⁸ In addition, many scholars have confirmed the genetic causal relationship between smoking,¹⁹ tea drinking,²⁰ coffee and caffeine intake,²¹ as well as depression,²² obesity,^{23, 24} anxiety²⁵ and kidney stones. However, studying the causal relationship between micronutrients and urolithiasis through MR analysis is limited.

This study used a large-scale genome-wide association study (GWAS) dataset to analyze micronutrients that may have a causal relationship with urolithiasis through 2SMR and MVMR. We identified 15 micronutrients associated with urolithiasis, including copper,²⁶ calcium,²⁷ carotenoids,²⁸ folic acid,²⁹ iron,³⁰ magnesium,³¹ potassium,²⁶ selenium,²⁶ zinc,²⁶ vitamin A,³² vitamin B12,³³ vitamin B6, ²⁵ vitamin C,³⁴ vitamin D,³⁵ and vitamin E,³⁶ and evaluated the following two risks: Calculus of kidney & ureter and Calculus of lower urinary tract.

2.1 Research Design

To investigate the causal relationship between micronutrients and urolithiasis, we searched the Open GWAS catalog for published GWAS evaluating individuals of European ancestry (the last search was conducted in August 2024). We have identified a total of 15 potential micronutrients of interest: copper, calcium, Carotene, folic acid, iron, magnesium, potassium, selenium, zinc, vitamin A, vitamin B12, vitamin B6, vitamin C, vitamin D, and vitamin E. Then, we performed MR analysis on 15 micronutrients and two result data from the FinnGen database, namely Calculus of kidney & ureter and Calculus of lower urinary tract. To ensure the reliability of the results, three basic assumptions must be met for each MR analysis:³⁷ (1) IVs are solidly correlated with exposure, (2) IVs are not related to any confounders influencing both exposure and outcome, (3) the impact of IVs on outcomes is only through their influence on exposure, not any other causal pathway (Fig. 1)

2.2. Data source

15 micronutrient exposure data were obtained from the OpenGWAS database (https://gwas.mrcieu.ac.uk/, accessed on 21 August 2024) and 2 outcome data were obtained from the FinnGen database (https://www.finngen.fi/en/access_results, accessed on 28 August 2024). Among them, the summary data of Calculus of kidney & ureter includes 11650 patients and 441039 controls. The summary data of the Calculus of lower urinary tract includes 1681 patients and 441039 controls. Both exposure and outcome cohorts were limited to participants of European descent to reduce bias in population stratification.³⁸ All data used in this study were obtained from studies with the consent and ethical approval of relevant participants, therefore, this study does not require ethical approval from the Institutional Review Board.

2.3. Selection of instrumental variables

To ensure effective IV, the three basic model assumptions of MR analysis should be met. The selected IVs have a significant correlation with exposure levels, and IVs that meet the exposure criteria have no confounding factors. The selected IVs only affect the results through exposure. Firstly, we obtained SNPs closely related to exposure (P < 5 × 10^− 6). Second, the regional range of linkage disequilibrium with kb = 10,000 and r² < 0.001 were used to ensure independence between the selected snp. Then, when the SNP cannot be obtained from the GWAS results, the SNP is obtained from the "ElementMR05.SNP2eaf.R" package. Finally, weak instrumental variables were removed, and the F-statistic used was calculated using the following formula: F = R² × (N-2) / (1-R²),³⁹ where N represents the sample size and R2 represents the exposure variance explained by IVs.⁴⁰ When the calculated F-statistic is greater than 10, we consider the genetic variation used to be strong IV, and the data will be retained for further analysis.

2.4. Mendelian randomization analysis

Use the "TwoSampleMR" R package (version 0.6.6, Stephen Burgess, Chicago, Illinois, USA) for dual sample MR analysis between exposure and results. The IVW method was used as the main analysis method, and MR-Egger, weighted median, simple mode, and and weighted mode were used as the auxiliary analysis method. If the assumption is met that all included SNPs can be used as effective IVs, the IVW method provides an accurate estimate.^19–25 To determine whether independent micronutrients have causal effects on the resulting data, we used MVMR analysis for further analysis.

2.5 Sensitivity analysis

Firstly, the disease-related exposure factors were screened: (1) the Pval obtained by IVW method was less than 0.05; (2) The OR values obtained from the five methods are all greater than or less than 1; (3) the pleiotropy Pval is greater than 0.05. Only micronutrients that meet the above conditions have a causal relationship with the disease, and subsequent analysis will be conducted. Secondly, Cochrane's Q heterogeneity test was conducted on the screened results to evaluate the degree of heterogeneity, where P < 0.05 indicates a high level of heterogeneity. If heterogeneity is detected, the multiplicative random effects IVW method was used to avoid bias in the association of heterogeneity IV.⁴¹ To evaluate the level of pleiotropy effect, the Pval of MR Egger regression intercept was used.⁴² When the Pval is less than 0.05, it indicates the existence of high pleiotropy bias. Then, plot scatter plots, forest plots, and funnel plots for exposure factors and outcome data with causal relationships. Finally, sensitivity analysis using the leave-one-out method can determine the impact between the comprehensive effect value obtained after removing one SNP and the overall comprehensive effect value. In summary, outliers that have a significant impact on causal effects can be identified.⁴³ In MVMR analysis, we conducted heterogeneity and pleiotropy tests. When the heterogeneity and pleiotropy Pval < 0.05, it indicates that the micronutrient has an independent causal effect on the resulting data.

3.1 MR analysis

IVW and MR Egger analysis showed a negative correlation between vitamin D and Calculus of kidney & ureter (P = 0.031425268, OR = 0.742089216; P = 0.043228971, OR = 0.316459367) (Table S1). IVW analysis showed a positive correlation between vitamin C and Calculus of lower urinary tract (P = 0.01901564, OR = 2.634275702). Weighted median also showed a positive correlation between vitamin E and Calculus of lower urinary tract (P = 0.026444517, OR = 2.902846637) (Table S2). Use sensitivity analysis to verify the reliability of IVW results. Heterogeneity tests of MR egger and IVW under Calculus of kidney and ureter showed heterogeneity in Vitamin B12 (Cochran's Q test P = 1.10E-05, 1.73E-05) and Iron (Cochran's Q test P = 0.003758168, 0.006681574), as well as heterogeneity in Calcium (Cochran's Q test P = 0.013755815) under IVW (Table S3). Meanwhile, MR egger and IVW heterogeneity tests under Calculus of lower urinary tract showed heterogeneity between Carotene (Cochran's Q test P = 0.024529808, 0.012903459) and Magnesium (Cochran's Q test P = 0.029763447, 0.01901253). For other micronutrients in both aforementioned outcome data, no heterogeneity was observed (Table S4). In the pleiotropy test, there was no pleiotropy (P < 0.05) between micronutrients and Calculus of kidney & ureter or Calculus of lower urinary tract (Table S5-6).

3.2 2SMR analysis

The results mainly analyzed the causal relationship between micronutrients and diseases after calibration of multiple tests (Fig. 2). The scatter plot and forest plot showed that vitamin D had a causal relationship and protective effect in Calculus of kidney and ureter (IVW P < 0.05), with an OR value of 0.742 (0.566 to 0.974); The screening results of Calculus of lower urinary tract showed a causal relationship between vitamin C and the disease, with a dangerous trend (IVW P < 0.05) and an OR value of 2.634 (1.172 to 5.919) (Table 1, Fig. 3A、A'、B、B'). At the same time, under MR Egger and IVW analysis, there was no heterogeneity (Cochran's Q test P = 0.740405707, 0.546887288; 0.260681927, 0.340040685) or pleiotropy (P = 0.106176652; 0.821958646) of vitamin D and C in related diseases(Table S7-10). Furthermore, by observing the sensitivity analysis results of the leave-one-out method, it was found that removing one SNP had no significant effect on the overall results (Fig. 4A, A'). The funnel plot also showed no significant inhibitory effect (Fig. 4B, B').

Table 1

2SMR results
ID.exposure	Outcome	Exposure	Method	Nsnp	Beta	Pval	OR	OR_lci95	OR_uci95
ukb-b-19390	Calculus of lower urinary tract	Vitamin C	MR Egger	10	1.213401878	0.318081484	3.364912225	0.360484237	31.40951283
ukb-b-19390	Calculus of lower urinary tract	Vitamin C	Weighted median	10	0.830594698	0.115823468	2.294682979	0.814935907	6.461330183
ukb-b-19390	Calculus of lower urinary tract	Vitamin C	Inverse variance weighted	10	0.968608268	0.01901564	2.634275702	1.172458281	5.918682641
ukb-b-19390	Calculus of lower urinary tract	Vitamin C	Simple mode	10	0.989899257	0.29655762	2.690963363	0.467175359	15.50014076
ukb-b-19390	Calculus of lower urinary tract	Vitamin C	Weighted mode	10	0.704963703	0.358041135	2.023773227	0.486011208	8.427085646
ukb-b-18593	Calculus of kidney and ureter	Vitamin D	MR Egger	13	-1.150560429	0.043228971	0.316459367	0.117902924	0.849398193
ukb-b-18593	Calculus of kidney and ureter	Vitamin D	Weighted median	13	-0.20614526	0.287548323	0.813714868	0.556515871	1.189780778
ukb-b-18593	Calculus of kidney and ureter	Vitamin D	Inverse variance weighted	13	-0.298285805	0.031425268	0.742089216	0.56552347	0.973781699
ukb-b-18593	Calculus of kidney and ureter	Vitamin D	Simple mode	13	-0.168456625	0.614654679	0.844967913	0.446069526	1.600581821
ukb-b-18593	Calculus of kidney and ureter	Vitamin D	Weighted mode	13	-0.202660296	0.482940244	0.816555582	0.471754697	1.413368056

3.3 MVMR analysis

Finally, we conducted a MVMR analysis, with heterogeneity P = 0.14683462 in the Calculus of kidney and ureter; pleiotropy P = 0.747556048; Under Calculus of lower urinary tract, heterogeneity P = 0.205518413; pleiotropy P = 0.213075967 (Table S11-12)。 Both showed heterogeneity and pleiotropy with Pval < 0.05, indicating that no vitamins produced an independent causal effect on the outcome data (Fig. 5).

MR analysis shows that vitamin D is negatively correlated with Calculus of kidney and ureter, while vitamin C is positively correlated with Calculus of lower urinary tract. MR has great potential in analyzing causal relationships between diseases and traits. This study is the first to explore the genetic causal relationship between micronutrients and urolithiasis, making an important contribution to the study of the pathogenesis of urolithiasis.

On the one hand, the active metabolite of vitamin D, calcitriol, may theoretically increase the risk of developing urolithiasis by increasing urinary excretion of calcium, phosphate, and oxalate.⁴⁴ On the other hand, vitamin D is believed to have anti-inflammatory, antioxidant, and anti angiogenic activities, and may even help prevent stone formation.^{45, 46} The above two viewpoints are contradictory, therefore the impact of vitamin D on kidney stones has been controversial. Through literature research, experimental studies in ABCC6 gene mouse KO have shown that supplementation with vitamin D and calcium can lead to the formation of Randall plaques,^{47, 48} resulting in the formation of calcium oxalate stones. Differently, we found that the prevalence of vitamin D deficiency in patients with urolithiasis exceeds 80%, but most existing evidence does not indicate an increased risk of kidney stone formation associated with high vitamin D storage. And for those who develop stones with insufficient vitamin D, the standard course of vitamin D supplementation does not seem to increase urinary calcium excretion, although the effectiveness of long-term maintenance of vitamin D treatment remains to be determined.^{9, 10} AAt the same time, a prospective analysis of 193551 health professionals showed no statistical correlation between vitamin D intake and the risk of kidney stone formation, but it cannot be ruled out whether high-dose vitamin D may have a high risk.⁴⁹ Currently, there is evidence that maintaining 25-OH-vitamin D levels between 20 and 100 ng / ml does not result in increased stone incidence; however, levels below 20 ng / ml are associated with a high risk of developing kidney stones and at least two times higher.⁵⁰ Thus, vitamin D deficiency is a risk factor for urolithiasis, which is consistent with our findings.

Generally speaking, long-term high concentrations of oxalate in urine are necessary for stone formation. For example, higher basal levels of uric acid were found in patients with urinary tract stones. Similarly, compared to non urinary tract stone patients, taking vitamin C can induce higher levels of uric acid in these patients and temporarily increase uric acid excretion.^51–56 To clarify the relationship between vitamin C intake and urolithiasis, B.L. Auer et al. observed the effects of taking high doses of ascorbic acid continuously for 8 days before and after hematuria in male subjects. The results showed that intake of vitamin C before hematuria increased oxalate excretion by about 350% and ascorbic acid concentration sharply, but it seemed to reach the maximum plateau value. After intake of vitamin C, the relative supersaturation of calcium oxalate and the Tiselius risk index increased, and a large amount of calcium oxalate dihydrate crystal aggregation was observed under blood and urine scanning electron microscopy. Therefore, consuming high doses of ascorbic acid can lead to harmful calcium oxalate crystal urine, resulting in the formation of urolithiasis.⁵⁷ In prospective cohort studies, oral doses of vitamin C exceeding 1g significantly increased the risk of stone formation by 41%.⁵⁸ Therefore, the daily dose of vitamin C should not exceed 1 gram.⁵⁵ Another study showed that higher total vitamin C intake and higher vitamin C supplement intake were not associated with the risk of kidney stones in women population, but is considered relevant in the male population.⁵⁹ The above research results are consistent with the MR analysis results, that is, vitamin C is positively correlated with urolithiasis.

This study provides new ideas for the treatment of urolithiasis and lays the foundation for addressing the impact of vitamin D on this disease. Its main advantage lies in the design of MR, which verifies the causal relationship between micronutrients and the risk of urolithiasis. In addition, we examined these associations in two independent populations, and consistent results ensured the robustness of the research findings. But this study also has limitations. We limited the study population to individuals of European descent, which limits population bias. However, this may limit the generalizability of our research results in other populations. Meanwhile, there is a significant overlap between the exposed data and the resulting data in the sample, which may lead to overfitting of the model and a tendency for causal estimation to observe associations. But by removing weak instrumental variables (F > 10), the bias caused by sample overlap may be minimized. In addition, we used MVMR method to verify the effect of vitamins on urolithiasis; However, causal estimation may still be influenced by other potential confounding factors.

This study provides genetic evidence for the causal relationship between circulating micronutrients and the risk of urolithiasis. Specifically, an increase in circulating vitamin D may reduce the risk of ureteral and kidney stones; The increase in circulating vitamin C may be associated with an increased risk of Calculus of lower urinary tract cancer. This provides more insights for the rational use of micronutrients to prevent urinary stones, which will inspire us to have a more comprehensive understanding and treatment intervention for urinary stones. In the future, further research and clinical trials are needed to investigate the potential mechanisms of the relationship between vitamin D, C, and 13 other micronutrients on urolithiasis. More data samples related to urolithiasis and micronutrients are also needed to further update and supplement this conclusion.

Disclosures

All the authors declared no competing interests.

Author Contribution

AUTHOR CONTRIBUTIONSGuangyue Wang has designed research, performed research, collected data, analyzed data, wrote paper and reviewed the last version; Yiwen Zhang has designed research, performed research and wrote paper; Denghui Yu designed research and analyzed data; Xueyan Li has wrote paper; Zhaoyi Yang: has collected data, analyzed data and reviewed the last version; Yuening Zhang has analyzed data and reviewed the last version; Yong Li has designed research, performed research and wrote paper.

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The causal relationship between circulating micronutrients and urolithiasis: a Mendelian randomization study

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Abstract

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Introduction

Method

2.1 Research Design

2.2. Data source

2.3. Selection of instrumental variables

2.4. Mendelian randomization analysis

2.5 Sensitivity analysis

Results

3.1 MR analysis

3.2 2SMR analysis

3.3 MVMR analysis

Discussion

Conclusion

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Author Contribution

References

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