The Association Between the Serum Uric Acid to Creatinine Ratio and Metabolic Syndrome,Liver Function,and Alcohol Intake in Healthy Japanese Subjects

Abstract

Background:

In patients with diabetes mellitus, the serum uric acid (UA) to creatinine (Cr) ratio (UA/Cr) has been reported to be associated with a higher risk of metabolic syndrome (MetS). In healthy subjects, however, this relationship and a possible association with pathological conditions remain undetermined.

Methods:

In total, 9104 Japanese subjects who had undergone an annual health examination and who were not receiving medication were divided into four groups based on UA/Cr values, and various markers were compared.

Results:

Anthropometric measures, blood pressure, glycemic state, lipids [except high-density lipoprotein cholesterol (HDL-C)], renal function, transaminases, and numbers of MetS components increased, according to UA/Cr quartiles, as the UA/Cr increased. In contrast, HDL-C and Cr decreased as the UA/Cr increased. UA/Cr values increased as the number of MetS increased. When UA/Cr values within each alcohol consumption group were investigated, the overall metabolic profile was the worst in subjects who consumed ≥75 grams ethanol a day with a UA/Cr of ≥6.8, except for fasting immunoreactive insulin (FIRI), homeostasis model assessment of insulin resistance (HOMA-IR), low-density lipoprotein cholesterol (LDL-C), and HDL-C values. Subjects who did not consume alcohol with a UA/Cr of ≥6.8 showed the highest FIRI, HOMA-IR, and LDL-C values.

Conclusions:

The UA/Cr was associated with components of MetS, liver function, and alcohol intake in healthy Japanese subjects. The UA/Cr might be a useful marker to distinguish subjects with high IR and dyslipidemia who do not consume alcohol.

Introduction

Serum creatinine (Cr) is considered to be one of the major markers for renal function and is, therefore, a good predictor of chronic kidney disease (CKD).¹ Raised circulating levels of Cr have been reported to be associated with an increased risk of cardiovascular disease (CVD), obesity, and hypertension.^2
–4

The association between serum uric acid (UA) and the risk of atherosclerosis,⁵ CVD,⁶ hypertension,⁷ and metabolic syndrome (MetS)⁸ has long been recognized. Recently, we reported that the serum UA level was positively associated with a number of MetS components in Japanese men.⁹ Recent studies have demonstrated that hyperuricemia might directly contribute to the development or progression of these diseases.^10
–12 However, UA has not been definitively regarded as a mediator or an etiology for these pathological conditions, but considered as merely a marker or predictor of risk.

Earlier studies^13,14 have shown that a higher serum UA/Cr correlated with a lower forced expiratory volume-first breath/forced vital capacity ratio (known as the Tiffeneau-Pinelli index), used in the diagnosis of chronic obstructive pulmonary disease. A study by Gu et al.¹⁵ suggested that the serum UA/Cr might be a better predictor of incident CKD than serum UA alone. These results appeared to be reasonable given that impaired renal function is a cofounder of a high serum UA level in CKD patients. It has recently been reported that the serum UA/Cr in patients with type 2 diabetes mellitus was strongly associated with full MetS as well as its individual components.¹⁶ However, this relationship in healthy subjects is not known, and the relationship between the UA/Cr and alcohol intake has not been studied.

This study aimed to investigate whether the UA/Cr is associated with components of MetS, alcohol consumption, and undetermined pathological conditions in healthy Japanese subjects.

Materials and Methods

Subjects

A total of 11,838 subjects undergoing annual health examinations at the Health Evaluation and Promotion Center of Tokai University Hachioji Hospital between April 2011 and March 2016 were included in this cross-sectional study. After excluding 2502 subjects who were taking medication for hypertension, diabetes mellitus, dyslipidemia, hyperuricemia, or chronic renal disease and 232 subjects with a history of stroke, coronary artery disease, or chronic renal failure, 9104 subjects were included in the final analysis. Medical histories were obtained using self-administered questionnaires and through interviews conducted by nurses.

Measurements

Waist circumference (WC) was measured at the level of the umbilicus during slight expiration, with the participant in a standing position. Blood pressure (BP) was measured on the upper right arm using an automatic BP monitor (TM-2655P; A&D, Tokyo, Japan) while the participant was seated. Blood samples were collected in heparin-coated tubes early in the morning after an overnight fast. UA levels were measured with an L-Type UA M kit based on the uricase-N-(3-sulfopropyl)-3-methoxy-5-methylaniline method (Wako Pure Chemicals, Osaka, Japan). Hyperuricemia was defined as a plasma UA level >7.0 mg/dL,¹⁷ based on UA solubility. Fasting plasma glucose (FPG) was measured with an L-type Glu 2 kit, based on the hexokinase glucose 6-phosphate dehydrogenase method (Wako Pure Chemicals). Fasting immunoreactive insulin (FIRI) levels were measured using a fluorescence enzyme immunoassay (ST AIA-PACK IRI; Toso, Tokyo, Japan). The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as follows: FPG (mg/dL) × FIRI (μU/mL)/405.¹⁸ Serum high-sensitivity C-reactive protein (hsCRP) levels were measured using latex agglutination turbidimetry. Low-density lipoprotein cholesterol (LDL-C) levels were calculated using the Friedewald formula.¹⁹ High-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels were measured using visible spectrophotometry (Determiner L HDL-C and Determiner L TG II, respectively; Kyowa Medex, Tokyo, Japan). Serum creatinine was measured by enzymatic method using Qualigent CRE (SEKISUI MEDICAL, Tokyo, Japan). Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transpeptidase (GGT) were measured using the JSCC transferable method with L-Type AST.J2 and L-Type ALT.J2 (Wako Pure Chemicals) and LaboFit γ-GT (Kanto Chemical, Tokyo, Japan).

Alcohol consumption was determined based on units of sake consumed per day, and 1 U (180 mL) was considered to be equivalent to 25 grams alcohol. Alcohol consumption was recorded in the self-administered survey as follows: nonconsumer of alcohol, social drinker, or <25, 25 to <50, 50 to <75, and ≥75 grams ethanol/day.

Verbal consent for analytical use of anonymized health records was obtained from all study participants. The study protocol was approved by the Ethics Committee of the Tokai University School of Medicine (protocol number: 14R-109).

Definition of MetS

Diagnosis of MetS was based on the presence of any three of the following five factors: central obesity, determined according to WC (≥85 cm in males, ≥90 cm in females); increased FPG levels (≥100 mg/dL); increased TG levels (≥150 mg/dL); low HDL-C levels (<40 mg/dL in males, <50 mg/dL in females); and an elevated BP (systolic BP ≥130 mmHg or diastolic BP ≥85 mmHg).²⁰ These factors were based primarily on an International Diabetes Federation criteria joint interim statement.²¹

Statistical analyses

Scheffe's multiple comparison test was used to compare mean values across three or more groups. A Student's t-test was used to compare mean values between two groups. Logarithmic transformation was applied due to the skewed distributions of TG and hsCRP. Sex, body mass index (BMI), WC, systolic and diastolic BP, FPG, FIRI, LDL-C, logarithmic transformed (ln) TG [ln(TG)], HDL-C, AST, ALT, GGT, ln(hsCRP), physical activity, alcohol intake, and smoking status were used as independent variables in multiple linear regression analysis for the UA/Cr. Participants were classified as nonsmokers or current smokers. In addition, those exercising for ≥30 min/day more than twice per week were classified as regular exercisers. Participants with a daily alcohol intake ≥25 grams were classified as regular drinkers. A stepwise procedure was used to select variables for multiple linear regression analysis. All statistical analyses were performed using SAS studio version 3.4 (SAS Institute, Cary, NC, USA). All P values were two-tailed, and a P value of <0.05 was defined as statistically significant.

Results

Table 1 shows the subjects' characteristics, stratified according to UA/Cr quartiles, in this study. Among a total of 9104 subjects, 4223 (46.4%) were women. The mean age, serum UA, and Cr levels for all subjects were 44.7 years old, 5.4, and 0.80 mg/dL, respectively, and the prevalence of hyperuricemia was 13.1%.

Table 1.

Characteristics of Study Subjects Stratified According to the Serum Uric Acid to Creatinine Ratio

	UA/Cr				Total (n = 9104)
	<5.9 (n = 2159)	5.9 to <6.8 (n = 2285)	6.8 to <7.8 (n = 2374)	≥7.8 (n = 2286)	Total (n = 9104)
Men/women (n)	969/1191	1186/1099	1372/1002	1355/931	4881/4223
Age	47.7 ± 10.8	47.5 ± 11.1	48.0 ± 11.0	47.6 ± 10.6	47.7 ± 10.9
BMI (kg/m²)	21.6 ± 2.9	22.2 ± 3.0^**	22.8 ± 3.2^**	23.8 ± 3.7^** ^,##,$$	22.6 ± 3.3
Waist circumference (cm)	76.9 ± 8.2	78.8 ± 8.7^**	80.5 ± 8.9^** ^,##	83.7 ± 10.0^** ^,##,$$	80.0 ± 9.3
Systolic BP (mmHg)	111.5 ± 15.9	113.0 ± 16.0^*	116.0 ± 16.6^** ^,##	118.7 ± 17.5^** ^,##,$$	114.9 ± 16.7
Diastolic BP (mmHg)	70.4 ± 12.2	71.3 ± 12.0	73.5 ± 12.4^** ^,##	75.5 ± 13.1^** ^,##,$$	72.7 ± 12.6
FPG (mg/dL)	96.1 ± 13.1	97.2 ± 13.3	98.1 ± 11.7^**	101.0 ± 17.0^** ^,##,$$	98.1 ± 14.0
FIRI (μIU/mL)	4.76 ± 2.81	5.17 ± 3.43^**	5.64 ± 3.44^** ^,##	6.75 ± 4.48^** ^,##,$$	5.59 ± 3.67
HOMA-IR	1.16 ± 0.88	1.27 ± 1.01^**	1.39 ± 0.94^** ^,##	1.74 ± 1.36^** ^,##,$$	1.39 ± 1.09
TG (mg/dL)	83.5 [81.5, 85.6]	92.8 [89.9, 95.7]	102.8 [100.1, 105.6]	124.6 [120.7, 128.5]	101.2 [99.7, 102.7]
LDL-C (mg/dL)	115.2 ± 23.4	118.5 ± 30.3^**	120.9 ± 32.8^**	121.2 ± 22.4^** ^,#	139.2 ± 22.5
HDL-C (mg/dL)	69.3 ± 16.8	67.6 ± 17.5^*	65.1 ± 17.1^** ^,##	63.1 ± 17.2^** ^,##,$$	66.2 ± 17.3
non-HDL-C (mg/dL)	131.9 ± 33.6	137.0 ± 34.6^**	141.4 ± 37.1^** ^,##	146.1 ± 37.1^** ^,##,$$	139.2 ± 54.4
UA (mg/dL)	4.2 ± 1.0	5.1 ± 1.0^**	5.8 ± 1.1^** ^,##	6.6 ± 1.3^** ^,##,$$	5.4 ± 1.4
Creatinine (mg/dL)	0.83 ± 0.18	0.81 ± 0.2^*	0.80 ± 0.15^** ^,##	0.75 ± 0.14^** ^,##,$$	0.80 ± 0.16
UA/Cr	5.1 ± 0.7	6.3 ± 0.3^**	7.2 ± 0.3^** ^,##	8.9 ± 1.1^** ^,##,$$	6.9 ± 1.5
eGFR (mL/min/1.73 m²)	70.0 ± 11.8	72.6 ± 11.3^**	75.4 ± 11.8^** ^,##	81.6 ± 13.9^** ^,##,$$	75.0 ± 13.0
AST (IU/L)	20.3 ± 8.1	20.8 ± 8.4	21.8 ± 17.0^** ^,#	23.8 ± 11.9^** ^,##,$$	21.7 ± 12.1
ALT (IU/L)	18.6 [18.1, 19.1]	20.5 [19.9, 21.1]^*	22.9 [21.7, 24.0]^**	26.9 [26.0, 27.8]^** ^,##,$$	22.3 [21.8, 22.7]
GGT (IU/L)	26.0 [24.9, 27.4]	30.5 [29.0, 32.0]^*	34.5 [32.9, 36.0]^** ^,#	47.2 [44.5, 49.9]^** ^,##,$$	34.7 [33.8, 35.6]
hsCRP (mg/dL)	0.10 [0.08–0.12]	0.09 [0.08–0.10]	0.09 [0.08–0.10]	0.11 [0.10–0.12]	0.10 [0.09–0.10]
No. of MetS	0.61 [0.57, 0.65]	0.77 [0.72, 0.82]^**	1.03 [0.98, 1.08]^** ^,##	1.41 [1.35, 1.47]^** ^,##,$$	0.96 [0.93, 0.99]

Variables are given as means ± standard deviations. TG, ALT, GGT, hsCRP, and No. of MetS values are presented as means and 95% CIs.

ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; BP, blood pressure; CI, confidence interval; eGFR, estimated glomerular filtration rate; FIRI, fasting immunoreactive insulin; FPG, fasting plasma glucose; GGT, gamma-glutamyl transpeptidase; HDL-C; high-density lipoprotein-cholesterol; HOMA-IR, homeostasis model assessment-insulin resistance; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; MetS, metabolic syndrome; non-HDL-C, non-high-density lipoprotein cholesterol; TG, triglyceride; UA, uric acid; UA/Cr, serum uric acid to creatinine ratio.

p < 0.01, ^* p < 0.05 (< 5.9 vs 5.9 to < 6.8, < 5.9 vs 6.8 to < 7.8, < 5.9 vs = 7.8), ^## p < 0.01, ^# p < 0.05 (5.9 to < 6.8 vs 6.8 to < 7.8, 5.9 to < 6.8 vs = 7.8), ^$$ p < 0.01, ^$ p < 0.05 (6.8 to < 7.8 vs ≥ 7.8) by Sheffe's multiple comparison test.

When the subjects were divided into four groups according to UA/Cr quartiles, anthropometric measures, BP, glycemic state, lipids (except for HDL-C), renal function, transaminases, and numbers of MetS components increased as the UA/Cr increased. In contrast, HDL-C and Cr decreased as the UA/Cr increased. No significant difference was observed for age and hsCRP among the groups.

A possible association between the UA/Cr and MetS in healthy subjects was investigated through a comparison of UA/Cr values when the subjects were divided according to numbers of MetS components (Fig. 1). UA/Cr values increased as the numbers of MetS components increased. Scheffe's multiple comparison test revealed that UA/Cr values among the groups were significantly different (P < 0.01), except between group 3 and group 4 + 5 (P = 0.1381) (Fig. 1).

FIG. 1.

A bar graph of mean UA/Cr values with 95% confidence intervals after stratifying the subjects according to the numbers of MetS components. MetS, metabolic syndrome; UA/Cr, serum uric acid to creatinine ratio.

Determinants of the UA/Cr were analyzed using multiple linear regression analysis (Table 2). Among the following variables included in this study [sex, BMI, WC, systolic and diastolic BP, FPG, FIRI, LDL-C, ln(TG), HDL-C, AST, ALT, GGT, ln(hsCRP), physical activity, alcohol intake, and smoking status], nine variables [male sex, age, WC, systolic BP, ln(TG), AST, GGT, ln(hsCRP), and alcohol intake] were selected using a stepwise procedure. The results of the analysis revealed that WC, systolic BP, ln(TG), AST, GGT, ln(hsCRP), and alcohol intake were positively associated with the UA/Cr. However, male sex and age were negatively associated with the UA/Cr.

Table 2.

Multiple Linear Regression Analysis for the Serum Uric Acid to Creatinine Ratio

	UA/Cr
	RC	SRC	t	P
Male	−0.24484	−0.08042	15.90	<0.0001
Age	−0.01422	−0.10201	−9.69	<0.0001
WC	0.02722	0.16743	13.76	<0.0001
SBP	0.00671	0.07392	6.55	<0.0001
Ln(TG)	0.35970	0.12848	11.00	<0.0001
AST	0.00583	0.04640	4.23	<0.0001
GGT	0.00209	0.06310	5.38	<0.0001
Ln(hsCRP)	0.09681	0.07305	6.81	<0.0001
Alcohol intake	0.35391	0.10306	9.95	<0.0001

Variable selection was made using a stepwise procedure.

Ln(hsCRP), logarithmic transformed hsCRP; Ln(TG), logarithmic transformed TG; RC, regression coefficient; SRC, standardized regression coefficient; WC, waist circumference.

To confirm whether alcohol consumption was positively associated with the UA/Cr, mean UA/Cr values were compared in subjects stratified according to alcohol intake (Fig. 2). As expected, the UA/Cr increased as alcohol consumption increased. Scheffe's multiple comparison test revealed that UA/Cr values among the groups were significantly different (P < 0.05).

FIG. 2.

A bar graph of mean UA/Cr values with 95% confidence intervals after stratifying the subjects according to the amount of alcohol consumed.

Since the UA/Cr increased as alcohol consumption increased, we investigated whether subjects' characteristics differed according to the UA/Cr value in each alcohol consumption group (Table 3). Metabolic profile was worse in subjects with UA/Cr ≥6.8 in the same alcohol consumption groups. The overall metabolic profile was the worst in subjects who consumed more than 75 grams ethanol a day and had a UA/Cr of ≥6.8, with the exception of the FIRI, HOMA-IR, and LDL-C values. It is noteworthy that nonconsumers of alcohol with a UA/Cr of ≥6.8 showed the highest FIRI, HOMA-IR, and LDL-C values.

Table 3.

Characteristics of Study Subjects Stratified According to Alcohol Intake and the Serum Uric Acid to Creatinine Ratio

	Nondrinker		Social drinker/alcohol <25 (grams/day)		Alcohol 25 to <50 (grams/day)
	UA/Cr		UA/Cr		UA/Cr
	<6.8 (n = 1788)	≥6.8 (n = 1509)	<6.8 (n = 2049)	≥6.8 (n = 2046)	<6.8 (n = 391)	≥6.8 (n = 583)
Men/women (n)	603/1185	569/940	1078/971	1266/780	300/91	442/141
Age	48.3 ± 11.3	48.4 ± 11.5	46.5 ± 10.7	46.5 ± 10.7	50.1 ± 10.7	49.6 ± 10.6
BMI (kg/m²)	21.5 ± 2.9	23.1 ± 3.7^a	22.0 ± 2.9	23.3 ± 3.5^a	22.4 ± 2.7	23.1 ± 3.2^a
Waist circumference (cm)	76.8 ± 8.6	81.3 ± 10.0^a	78.0 ± 8.5	82.0 ± 9.6^a	79.9 ± 7.9	82.3 ± 8.9^a
Systolic BP (mmHg)	111.4 ± 16.1	115.7 ± 17.4^a	111.5 ± 15.5	115.8 ± 16.6^a	116.5 ± 16.0	121.0 ± 16.5^a
Diastolic BP (mmHg)	69.1 ± 11.6	72.1 ± 12.2^a	70.8 ± 11.9	73.7 ± 12.8^a	75.5 ± 12.0	77.9 ± 12.5
FPG (mg/dL)	95.6 ± 12.9	98.4 ± 15.8^a	96.4 ± 11.7	99.1 ± 14.4^a	100.7 ± 18.7	100.9 ± 11.9^a
FIRI (μIU/mL)	5.12 ± 3.35	6.74 ± 4.50^a	4.88 ± 2.82	6.10 ± 3.80^a	4.66 ± 2.79	5.66 ± 3.64^a
HOMA-IR	1.24 ± 0.97	1.70 ± 1.33^a	1.19 ± 0.81	1.54 ± 1.12^a	1.19 ± 0.83	1.44 ± 0.10^a
TG (mg/dL)	85.0 [83.2–86.9]	101.3 [104.8–109.7]^a	85.1 [83.2–86.9]	111.7 [104.8–109.7]^a	104.1 [96.9–111.3]	120.0 [113.2–126.8]^a
LDL-C (mg/dL)	120.0 ± 30.9	126.2 ± 33.5^a	115.1 ± 28.7	120.3 ± 31.6^a	114.1 ± 32.7	115.8 ± 30.4
HDL-C (mg/dL)	68.9 ± 16.7	64.3 ± 17.2^a	68.0 ± 17.1	62.8 ± 16.7^a	67.4 ± 18.2	65.9 ± 17.6
non-HDL-C (mg/dL)	136.9 ± 34.9	146.5 ± 37.7^a	132.2 ± 32.8	142.6 ± 36.7^a	134.9 ± 37.0	139.8 ± 35.9^b
UA (mg/dL)	4.5 ± 1.1	5.7 ± 1.2^a	4.7 ± 1.1	6.2 ± 1.2^a	5.1 ± 1.1	6.5 ± 1.1^a
Creatinine (mg/dL)	0.79 ± 0.16	0.72 ± 0.14^a	0.83 ± 0.17	0.78 ± 0.15^a	0.87 ± 0.15	0.81 ± 0.14^a
UA/Cr	5.7 ± 0.8	7.9 ± 1.1^a	5.7 ± 0.8	7.9 ± 1.1^a	5.8 ± 0.9	8.2 ± 1.2^a
eGFR (mL/min/1.73 m²)	71.2 ± 12.1	79.1 ± 14.7^a	71.6 ± 11.3	78.4 ± 12.8^a	70.6 ± 10.8	77.0 ± 12.3^a
AST (IU/L)	20.1 ± 7.1	22.1 ± 15.4^a	20.5 ± 8.9	22.1 ± 13.8^a	21.1 ± 6.9	23.4 ± 11.8^a
ALT (IU/L)	18.5 [18.0, 19.1]	24.2 [22.6, 25.7]^a	19.8 [19.2, 20.4]	24.7 [23.7, 25.7]^a	20.4 [19.3, 21.6]	24.3 [22.6, 26.0]^a
GGT (IU/L)	22.0 [21.0, 23.1]	28.5 [27.1, 29.9]^a	28.4 [27.2, 29.7]	36.5 [34.9, 38.0]^a	40.0 [35.4, 44.6]	51.0 [45.1, 56.9]^a
hsCRP (mg/dL)	0.09 [0.08–0.10]	0.11 [0.10–0.12]^b	0.10 [0.08–0.10]	0.11 [0.10–0.12]	0.10 [0.05–0.13]	0.08 [0.06–0.09]
No. of MetS	0.57 [0.53, 0.62]	1.03 [0.97, 1.10]^a	0.67 [0.63, 0.72]	1.17 [1.11, 1.23]^a	1.03 [0.90, 1.15]	1.37 [1.26, 1.48]^a

	Alcohol 50 to <75 (grams/day)		Alcohol 50 to <75 (grams/day)
	UA/Cr		UA/Cr
	<6.8 (n = 168)	≥6.8 (n = 378)	<6.8 (n = 48)	≥6.8 (n = 144)
Men/women (n)	136/32	320/58	37/11	130/14
Age	48.2 ± 9.5	49.5 ± 9.0	47.0 ± 9.2	47.4 ± 8.9
BMI (kg/m²)	23.3 ± 3.0	23.7 ± 3.3	22.7 ± 3.1	23.8 ± 3.2^b
Waist circumference (cm)	82.1 ± 8.0	84.2 ± 8.9^b	81.2 ± 8.8	85.0 ± 9.2^b
Systolic BP (mmHg)	119.0 ± 15.2	123.4 ± 16.3^a	125.4 ± 16.9	125.1 ± 16.0
Diastolic BP (mmHg)	77.5 ± 13.7	80.7 ± 12.3^a	81.2 ± 12.2	81.5 ± 11.8
FPG (mg/dL)	101.0 ± 14.8	103.3 ± 14.4	100.0 ± 9.4	102.4 ± 12.6
FIRI (μIU/mL)	5.20 ± 4.98	5.43 ± 3.46	5.02 ± 3.27	5.55 ± 4.00
HOMA-IR	1.39 ± 1.97	1.42 ± 1.00	1.28 ± 0.93	1.46 ± 1.22
TG (mg/dL)	119.2 [106.4–132.0]	144.3 [132.2–156.3]^b	110.5 [92.9–128.1]	161.1 [139.3–182.9]^b
LDL-C (mg/dL)	114.6 ± 32.9	115.8 ± 35.6	107.9 ± 31.7	111.5 ± 34.2
HDL-C (mg/dL)	69.1 ± 19.3	66.3 ± 18.3	74.1 ± 22.5	67.3 ± 16.6^b
non-HDL-C (mg/dL)	138.4 ± 35.5	144.7 ± 38.3	130.0 ± 36.2	143.8 ± 36.8^b
UA (mg/dL)	5.2 ± 1.1	6.7 ± 1.1^a	4.9 ± 1.2	7.1 ± 1.1^a
Creatinine (mg/dL)	0.89 ± 0.15	0.82 ± 0.12^a	0.86 ± 0.17	0.82 ± 0.12
UA/Cr	5.8 ± 0.8	8.3 ± 1.2^a	5.7 ± 1.0	8.8 ± 1.4^a
eGFR (mL/min/1.73 m²)	71.0 ± 11.3	77.3 ± 10.7^a	73.5 ± 12.0	79.4 ± 12.4^a
AST (IU/L)	24.5 ± 12.8	26.1 ± 18.5	24.8 ± 7.9	29.6 ± 29.6
ALT (IU/L)	24.1 [21.8, 26.5]	26.3 [24.7, 27.9]	24.3 [20.5, 28.0]	32.1 [27.5, 236.7]
GGT (IU/L)	60.7 [47.9, 73.6]	73.3 [63.8, 82.7]	57.1 [42.9, 71.2]	101.1 [80.1, 7122.1]^b
hsCRP (mg/dL)	0.09 [0.05–0.13]	0.10 [0.07–0.12]	0.17 [0.05–0.13]	0.09 [0.07–0.11]
No. of MetS	1.29 [1.08, 1.49]	1.72 [1.57, 1.87]^a	1.34 [0.92, 1.71]	1.79 [1.56, 12.02]^b

Variables are given as means ± standard deviations. TG, ALT, GGT, hsCRP, and No. of MetS values are presented as means and 95% CIs.

ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; BP, blood pressure; CI, confidence interval; eGFR, estimated glomerular filtration rate; FIRI, fasting immunoreactive insulin; FPG, fasting plasma glucose; GGT, gamma-glutamyl transpeptidase; HDL-C; high-density lipoprotein-cholesterol; HOMA-IR, homeostasis model assessment-insulin resistance; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; MetS, metabolic syndrome; non-HDL-C, non high-density lipoprotein cholesterol; TG triglyceride; UA, uric acid; UA/Cr, serum uric acid to creatinine ratio.

P < 0.01, ^b P < 0.05 by Student's t-test.

Finally, HOMA-IR levels were compared when subjects were stratified according to alcohol intake and UA/Cr values (Fig. 3). As described above, HOMA-IR levels were highest in subjects who do not consume alcohol and had a UA/Cr of ≥6.8. HOMA-IR levels gradually increased as the UA/Cr increased in subjects who consumed <50 grams of alcohol a day. However, these increments were not observed in subjects who consumed >50 grams of alcohol a day.

FIG. 3.

A bar graph of mean HOMA-IR values with 95% confidence intervals after stratifying subjects according to the amount of alcohol consumed and the UA/Cr levels. HOMA-IR, homeostasis model assessment of insulin resistance.

Discussion

The results from this study showed that the UA/Cr was associated with components of MetS, IR, liver function, and serum lipid levels in healthy Japanese subjects. The results also suggest that the UA/Cr could be an indicator to identify individuals who do not consume alcohol and have high IR, and high LDL-C and non-HDL-C levels.

Serum Cr and UA levels shared a common feature, that is, both levels were higher in men than in women. Moreover, both serum markers positively correlated with similar pathological conditions, such as CVD, obesity, and hypertension. The application of UA/Cr values reduces interference due to sex and renal function abnormalities.²² In agreement with a previous study that reported that the serum UA/Cr may be useful as a marker in the pathogenesis of MetS, the results from our study also indicated that the UA/Cr was a good indicator for components of MetS, even in healthy subjects. Our results also suggested that the UA/Cr was a good indicator for IR, liver function, and LDL-C and non-HDL-C levels. The mean UA/Cr in this study was considerably higher than that of a previous study (6.9 vs. 4.6),¹⁶ which may be partly due to a higher percentage of male participants (53.6% vs. 40.4%). Lifestyle habits were also considered in this study, as it has been well established previously that alcohol intake is known to affect serum UA levels.²³ However, it is not known whether alcohol intake could affect the Cr level,²⁴ and it appears not to have done so in our study, as Cr levels did not increase as alcohol consumption increased (Table 2).

The new finding in this study was as follows: the UA/Cr could be a good indicator to identify subjects who do not consume alcohol with a risk of high IR and dyslipidemia. The UA/Cr was associated not only with components of MetS but also alcohol intake. Participants who did not consume alcohol and had a UA/Cr of ≥6.8 showed the highest IR, LDL-C, and non-HDL-C levels, even though their number of MetS components was not particularly high. A U-shaped relationship between alcohol and total mortality, which may reflect an inverse association for CVD mortality among light-to-moderate drinking men, has been reported.²⁵ It has also been reported that alcohol consumption of between 2.5 and 14.9 grams/day was consistently associated with a 14%–25% reduction in the risk of all outcomes assessed compared with abstaining from alcohol, according to a review of 84 studies involving alcohol consumption and CVD.²⁶ The subjects who did not consume alcohol and who had a UA/Cr of ≥6.8 showed the highest IR, LDL-C, and non HDL-C levels, which might partly explain light-to-moderate alcohol consumers' reductions in risk of death when compared with those who rarely or never consumed alcohol.

IR, which is estimated according to HOMA-IR, is a feature of disorders such as type 2 diabetes mellitus and is also implicated in obesity, hypertension, cancer, or autoimmune diseases.^27
–29 It has been reported that IR may be an important predictor of CVD risk.^30
–32 IR has also been proposed as a principal factor in initiating and perpetuating the pathologic manifestations of MetS,^33,34 and it is associated with inflammatory disease mechanisms.³⁵ Therefore, even though the subjects who did not consume alcohol and had a UA/Cr of ≥6.8 possessed only 1.0 MetS component, high IR would initiate MetS in the future. However, it is possible that high HOMA-IR was due to higher LDL-C and non HDL-C levels than in the other groups. The former explanation is more likely, since the mean LDL-C and non-HDL-C in this group was the highest, but these levels were not particularly high (126.2 and 146.5 mg/dL, respectively). Taken together, the UA/Cr could be a good indicator to identify those who do not consume alcohol but who have high IR. It has been reported that physical activity is inversely associated with HOMA-IR.³⁶ Therefore, it might be advisable for subjects who do not consume alcohol and who have a high UA/Cr to modify their lifestyle habits to lower IR. It has also been reported that moderate drinkers have lower HOMA-IR values³⁷; however, consumption of larger amounts of alcohol was associated with higher risks for stroke incidence and mortality.²⁶

The limitations of the current study were the cross-sectional design, which hindered the determination of a causal relationship. The participants in the current study were middle-aged Japanese subjects; therefore, it remains possible that the relationship between the UA/Cr levels and clinical markers was affected according to ethnicity. Detailed information on diet and beverage intake which may have affected UA levels was not obtained. Finally, our results were calculated from the data of only a fraction of the participants who had undergone annual health examinations; therefore, our findings might not be generalizable to all Japanese individuals.

Conclusions

The UA/Cr might be a good indicator for components of MetS, IR, lipid levels, and liver function in healthy Japanese subjects. Although the UA/Cr value was associated with alcohol intake, IR, LDL-C, and non-HDL-C levels were highest in subjects who did not consume alcohol with a UA/Cr of ≥6.8. Therefore, the UA/Cr might be a useful marker to distinguish subjects who do not consume alcohol with high IR and dyslipidemia.

Footnotes

Acknowledgment

The author thanks the staff at the Health Evaluation and Promotion Center, Tokai University Hachioji Hospital, for their work and help in collecting data.

Author Disclosure Statement

No conflicting financial interests exist.

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