Gender-specific dimorphic association between bicarbonate and uric acid serum levels among healthy adults. Qatar Biobank data

doi:10.21203/rs.3.rs-1655375/v1

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Gender-specific dimorphic association between bicarbonate and uric acid serum levels among healthy adults. Qatar Biobank data

https://doi.org/10.21203/rs.3.rs-1655375/v1

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Background: Uric acid is the end product of purine metabolism. When present at a high level it may predispose individuals to multiple chronic diseases such as Gout, atherosclerosis, hypertension, and renal diseases. This study aimed to evaluate the gender-specific association between serum bicarbonate and uric acid levels among healthy Qataris using Qatar biobank data.

Methodology: The study was carried out in the General healthy population using a retrospective cross-sectional design including the data of 2989 healthy Qatari adults (36.4 ± 11.1 years) from the Qatar biobank database. The analysis included the estimation of serum uric acid and bicarbonate serum levels alongside other serological markers. The study participants were divided into four quartiles based on the level of serum bicarbonate.

Results: In men, low serum uric acid was significantly associated with the higher serum bicarbonate levels after adjustment for age. The association remained significant after further adjustment for BMI, smoking, and renal function. The restricted cubic spline method confirmed a significant dose-response association between the variation coefficients of uric acid by serum bicarbonate level in men with adjustments for age, BMI, smoking, and renal function. While in women, no significant association was found between quartiles of serum bicarbonate and uric acid level following the same adjustments. However, using the restricted cubic spline method, a significant bidirectional relation was demonstrated between serum bicarbonate and the variation coefficients of uric acid that was positive for serum bicarbonate levels below 25 mEq/L and negative at higher levels.

Conclusion: Serum bicarbonate levels are linearly associated with reduced serum uric acid levels among healthy Qatari men. This might be one of the privileges in men to protect against the complications of hyperuricemia. However, this finding demand further investigations to outline the underlying mechanisms.

bicarbonate

uric acid

Qatar biobank

Renal function

eGFR

gender

Uric acid is the end metabolic product of purine catabolism formed in the liver, and intestines by the xanthine oxidase enzyme from the oxidation of hypoxanthine and xanthine (1). The presence of uricase in other mammals tends to contribute significantly to achieving low serum levels while in humans, the normal level of Uric acid ranges from 3–6 mg/dL in women and up to 7 mg/dL in men (2). Although the heterocyclic compound is also a strong reducing agent (electron donor) that covers approximately 50% of the plasma antioxidant capacity (3, 4); however, hyperuricemia is a pro-inflammatory condition that leads to endothelial dysfunction, sclerosis, and oxidative stress due to the high expression of cytokines, and other mediators of inflammation (5).

The staggering complications of hyperuricemia are attributed to its precipitation due to its low solubility limit which is set at the level of 6.8 mg /dL; this level is notably close to its normal limit in plasma. Further, the solubility of uric acid is also affected by the pH level in which the solubility is reduced by six-folds at acidic pH of 5.3 (6). Therefore, high levels of serum uric acid can precipitate easily as urate salt crystals in the kidneys and joints leading to kidney stones, and gout arthritis (7). In addition, hyperuricemia may act independently to increase the risk for coronary artery disease, hypertension, renal diseases, diabetes, and metabolic syndrome (3).

The common risk factors for hyperuricemia include old age, male gender, alcohol use, obesity, renal diseases, and diabetes mellitus (8). Hyperuricemia might be attributed to either increased production or reduced elimination or both. The overproduction of Urate happens due to purine-rich diets, increase purine production due to genetic metabolic defects, and rapid cell turnover in tumors; however, these causes are uncommonly responsible for hyperuricemia (9). 90% of hyperuricemia cases tend to occur due to problems in renal handling because 70% of uric acid is filtered through the kidneys with 90% reabsorbed in the proximal convoluted tubules back into the blood (10). Therefore, hyperuricemia may happen either due to decreased glomerular filtration, decreased tubular secretion in renal diseases, or increased tubular reabsorption (4).

Several reports had confirmed the therapeutic properties of serum bicarbonate in improving the prognosis of patients with chronic renal diseases and facilitating the renal handling of many electrolytes and drugs (11, 12). The supplementation of bicarbonate as sodium bicarbonate helped in reducing the mortality of chronic kidney diseases by improving the glomerular filtration (13). Bicarbonate is the endogenous buffer that helps to maintain the blood pH within its normal range which is about 25 mEq/L. This study aimed to evaluate the association of serum bicarbonate levels with serum uric acid among the healthy Qatari population to delineate the possible confounding factors contributing to the association.

Qatar Biobank Data: The cohort database is based on the gathering of biological samples, anthroprometeric measurements, and medical history of individuals from the general population in Qatar according to giudlines and regulations approved by the ministry of public health in Qatar.

Ethical Statement

The study protocol was approved by the institutional review board of Qatar University and Qatar biobank (E -2018-QBB-RES-ACC-0112-0054). The blood samples were collected from Qatar Biobank. Written informed consent has been taken from all participants enrolled in the study.

all methods of sample collection and analysis were performed in accordance with the relevant guidelines and regulations set by the ministry of public health.

Subjects

all methods of sample collection were performed in accordance with the relevant guidelines and regulations The study included 2,981 healthy volunteers with age between 18 to 70 years old. The exclusion criteria included patients with cancer or chronic disorders of the heart, lung, liver, kidney, and brain. Patients with diabetes, high cholesterol, and high blood pressure were also excluded. After consenting to the study, the blood samples were collected from the participants by an authorized nurse in Qatar Biobank. The self-administered questionnaire was designed to obtain socio-demographic characteristics such as age, height, weight, gender body mass index (BMI), and smoking history. During the interview session, other health-related information including past medical history was collected.

Biochemical analysis:

A routine profile of biochemical tests was conducted to measure serum analytes such as uric acid, calcium, phosphorus, hormones, liver enzymes, and serum creatinine. The estimated glomerular filtration rate (eGFR) was calculated using an equation according to the serum creatinine level, and gender (14).

Statistical Analysis

The statistical analysis was done using Stata 17 (Stata Statistical Software: Release 17. College Station, TX: Stata Corp LLC, USA). Data were expressed as mean values ± SD or frequencies (%). Univariate analyses were completed using One-way ANOVA and Chi-square tests as appropriate. The unadjusted relation between serum bicarbonate and uric acid levels was assessed by Pearson correlation analysis. Multiple regression model analysis was conducted to evaluate the independent association between serum bicarbonate and uric acid levels after adjustments with different confounding factors. Statistical significance was indicated with p-values less than 0.05.

Study characteristics:

The baseline characteristics of participants by quartile levels of serum bicarbonate level in the total population are shown in Table 1. A total of 2,981 Qatari participants were included in the study. The mean age was 36.4 ± 11.1 years. The mean level of serum bicarbonate was within the normal range (26.02 ± 2.12). As shown in Table 1, the univariate analysis demonstrated a significant association between bicarbonate quartiles level and other variables such as age, gender, BMI, smoking, renal function, and uric acid levels (p-value <0.01). Serum uric acid level was gradually increasing with the increase of serum bicarbonate level (p-value <0.001). The age, gender distribution, body mass index (BMI), and the number of smokers also gradually increased with the increase in bicarbonate level. However, the estimated glomerular filtration rate gradually decreased with the increased levels of serum bicarbonate (p-value <0.001).

Table 1. Sample characteristics per quartiles of bicarbonate among participants attending the Qatar Biobank Study

	Total	Q1	Q2	Q3	Q4	p-value
	N=2,981	N=748	N=915	N=580	N=738
Bicarbonate (mEq/L)	26.02 (2.12)	23.32 (1.05)	25.51 (0.47)	26.86 (0.30)	28.72 (1.07)	<0.001
Age	36.4 (11.1)	34.1 (10.3)	36.3 (11.0)	37.0 (11.3)	38.3 (11.4)	<0.001
Sex						<0.001
Men	1,430 (48.0%)	250 (33.4%)	406 (44.4%)	294 (50.7%)	480 (65.0%)
Women	1,551 (52.0%)	498 (66.6%)	509 (55.6%)	286 (49.3%)	258 (35.0%)
Smoking						0.001
Non-smoker	2,022 (67.8%)	529 (70.7%)	646 (70.6%)	394 (67.9%)	453 (61.4%)
Ex-smoker	189 ( 6.3%)	48 ( 6.4%)	47 ( 5.1%)	41 ( 7.1%)	53 ( 7.2%)
Current smoker	770 (25.8%)	171 (22.9%)	222 (24.3%)	145 (25.0%)	232 (31.4%)
Uric acid (umol/L)	296.53 (81.89)	283.29 (85.55)	296.08 (82.54)	297.58 (81.59)	309.69 (75.26)	<0.001
BMI (kg/m2)	28.4 (5.9)	28.8 (6.3)	28.8 (5.8)	28.1 (5.6)	27.8 (5.6)	0.003
Calcium (mmol/L)	2.28 (0.08)	2.27 (0.08)	2.28 (0.07)	2.28 (0.08)	2.29 (0.07)	<0.001
Phosphorus (mmol/L)	1.15 (0.17)	1.15 (0.16)	1.15 (0.16)	1.16 (0.18)	1.16 (0.17)	0.28
Thyroid Stimulating Hormone (mIU/L)	1.61 (1.15)	1.63 (1.05)	1.57 (0.97)	1.56 (0.92)	1.68 (1.53)	0.14
Total Testosterone	9.72 (10.67)	6.48 (8.58)	8.84 (10.45)	10.08 (10.34)	13.79 (11.73)	<0.001
Estradiol (pmol/L)	231.12 (281.04)	290.68 (298.82)	247.35 (294.62)	215.32 (296.50)	163.11 (208.55)	<0.001
AST (GOT) (U/L)	19.69 (10.72)	19.09 (11.83)	19.05 (7.67)	20.05 (10.88)	20.81 (12.43)	0.002
ALT ( GPT ) (U/L)	22.57 (18.24)	21.34 (19.98)	21.82 (14.36)	22.54 (14.90)	24.75 (22.44)	0.001
eGFR (mL/min/1.73m2)	111.35 (15.07)	115.16 (14.84)	111.46 (14.84)	110.28 (14.82)	108.19 (14.96)	<0.001
eGFR<90 mL/min/1.73m2	256 ( 8.6%)	42 ( 5.6%)	77 ( 8.4%)	52 ( 9.0%)	85 (11.5%)	<0.001

BMI: body mass index; AST: Alanine aminotransferase; ALT: Alanine Aminotransferase; eGFR: estimated glomerular filtration rate

Association between Serum bicarbonate and uric acid levels:

Gender-specific correlation pattern was also evident in this study in which there was a negative correlation between serum bicarbonate and uric acid levels in men without adjustments as shown in figure 1. While in the female gender, no association was evident between serum bicarbonate and uric acid levels.

To further analyze the association, a multivariate regression analysis with variably adjusted associations was conducted between the quartiles of bicarbonate and serum uric acid. As shown in Table 2, two models were adjusted in which compared to the first quartile, the second, third, and fourth quartiles of serum bicarbonate were independently associated with lower serum uric acid levels after adjustment for age, BMI, smoking, and kidney function.

Table 2 Regression coefficients (95%CI) for the association of serum uric acid by quartiles of bicarbonate in men and women Qatari adults attending Qatar Biobank

	Serum Bicarbonate level
	Q1	Q2		Q3		Q4		P for trend value
Men
Model 1	0.00	-14.05	(-24.76 - -3.35)	-18.74	(-30.19 --7.29)	-25.79	(-36.17 --15.40)	0.000
Model 2	0.00	-12.32	(-22.69 - -1.95)	-11.50	(-22.65 --0.35)	-15.59	(-25.88 --5.30)	0.011
Women
Model 1	0.00	6.68	(-0.54 -13.91)	-0.01	(-8.54 - 8.53)	1.34	(-7.70 -10.38)	0.980
Model 2	0.00	6.48	(-0.49 -13.45)	3.13	(-5.14 -11.41)	3.51	(-5.19 -12.21)	0.492

Model 1 adjusted for age; Model 2 further adjusted for BMI, smoking, and eGFR<90 mL/min/1.73m². The mean serum bicarbonate levels in Men (Q1: 23.39, Q2: 25.56, Q3: 26.90, and Q4: 28.77); in women (23.27, 25.47, 26.8, and 28.6 respectively).

To confirm the dose-response association in men, the association was tested for nonlinearity using the restricted cubic spline regression method following the same adjustments for age, BMI, smoking, and renal function. As shown in Figure 2, there was a significant linear association between serum bicarbonate and the regression coefficients of uric acid confirming the dose-response effect in men. In women, no significant association was found between quartiles of serum bicarbonate and uric acid level following the same adjustments. Interestingly, upon using the same restricted cubic spline method, a significant association with binomial distribution was demonstrated at the serum bicarbonate level of 25 mEq/L. The association between serum bicarbonate and the variation coefficients of uric acid seemed to be positive at lower levels and negative at higher levels as shown in Figure 2.

Bicarbonate is one of the important buffers in the human body that helps in maintaining the internal environment. This buffer is rapidly produced by the carbonic anhydrase enzyme in the red blood cells from carbon dioxide and water. Several reports confirmed the protective properties of bicarbonate in maintaining renal function (15, 16). A U shape relation was described in a study between serum bicarbonate, morbidity, and mortality in chronic renal disease patients (17). In which bicarbonate levels lower than 25 mEq/L were associated with metabolic acidosis and bad prognosis among chronic renal disease patients.

The results of this study showed an interesting gender-specific pattern in the association between serum bicarbonate and uric acid levels. The study demonstrated a negative linear association in men while in women, a positive linear association was evident for bicarbonate levels below 25 mEq/L. Such variation in women could be attributed to serum bicarbonate levels that are determined by the homeostatic pH limits for acidosis leading to dimorphic associations between serum bicarbonate and renal function (18). Notably, at acidic pH levels, the solubility of uric acid tends to decrease leading to poor excretion and higher levels. However, in our study, the dimorphic effect was only observed in women. In men, lower serum bicarbonate levels were inversely associated with Uric acid in a linear dose-dependent pattern.

Thus, it is important to understand the gender variation and the physiological mechanisms controlling uric acid to explain the findings in this study. As mentioned earlier, the renal handling of uric acid is the main regulatory mechanism that determines its level by the reabsorption and excretion processes by different transporter proteins in the proximal convoluted tubule of the nephron (19-21). The homeostatic regulation of uric acid by the kidney includes the initial reabsorption of 95% of the initial filtered uric acid by OAT family transporters (organic anion transporter 3,4,10 and GLUT9 (22). Half of the filtered uric acid is then secreted again into the lumen of the proximal tubule by another group of transporters including ATP Binding Cassette Subfamily G Member 2 (ABCG2), sodium-phosphate transporters (NPT1 and NPT4) (19) Towards the terminal part of the proximal convoluted tubule, 40% of the filtered uric acid is reabsorbed back to the circulation by uric acid transporter proteins ( URATs - encoded by SLC22A12 and SLC2A9) (23). Studies have indicated sex differences in the expression, distribution, and activities of these transporter proteins.

The genome-wide association studies helped in identifying several gene loci of the transporter proteins and their relation with serum uric acid levels in the general population. From the list of screened polymorphisms, the genes of ABCG2 and URAT were identified and explained for the variations in uric acid levels in both genders (24). Interestingly, ABCG2 was associated with higher uric acid levels in men, while URAT2 was associated with lower uric acid levels in women indicating the increased activity of both proteins in specific genders.

Consistently, postmenopausal women have a four times increase in the risk to develop hyperuricemia compared to their young counterparts; such risk is mitigated when estrogen and or progesterone hormonal replacement therapy is initiated indicating the significant hormonal influence on the kidney function (25, 26). On the other hand, variations in response to bicarbonate treatment were generally described in both genders without understanding the underlying mechanisms (27). Higher sensitivity to bicarbonate ions was confirmed among men compared to women and was attributed to the gender physiological variations.

Several reports had shown better renal handling of uric acid and resistance to uric acid attributed pathologies in women compared to men (28-30). However, this privilege is lost once pathologies start to happen; leading to more aggressive outcomes among women (31, 32). Women with hyperuricemia were found to be at higher risk to develop hypertension compared to their male counterparts (33). As such, the risk of developing chronic renal diseases is more common in hyperuricaemic women compared to hyperuricaemic men.

Taking all these observations into account, the observed difference in the association between bicarbonate and uric acid may be attributed to differences in urate handling and sensitivity to bicarbonate in both genders assuming other mechanisms regulated by bicarbonate ions that continue to regulate uric acid levels at acidic pH levels in men. This demands more experimental studies to examine the mechanisms by which bicarbonate ions control uric acid and how these mechanisms are affected by gender-specific factors such as sex hormones and their relation with the function and distribution of uric acid transporters.

Serum bicarbonate is negatively associated with serum uric acid levels among healthy adults. This might demonstrate a protective effect of serum bicarbonate against the development of Gout and other related disorders. However, it seems that bicarbonate doesn’t provide the same effect among women when present below the normal levels. Thus, these gender-specific differences at subnormal levels of bicarbonate may be attributed to gender-specific confounding factors which demand further investigations to outline the underlying mechanisms that might pave the way for novel therapeutic strategies for individuals with hyperuricemia.

DATA AVAILABILITY STATEMENT

The data used and generated in this study are subjected to restrictions and can only be requested from Qatar Biobank (https://www.qatarbiobank.org.qa/).

AUTHOR CONTRIBUTIONS

WI conceptualized the topic, wrote and edited the manuscript, and contributed to data curation and statistical analysis. A.A edited the manuscript. ZS completed the statistical analysis and reviewed the manuscript. MA-M project administration, and reviewing the manuscript. All authors contributed to the article and approved the submitted version.

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No competing interests reported.

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Gender-specific dimorphic association between bicarbonate and uric acid serum levels among healthy adults. Qatar Biobank data

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