Influencing factors of hyperuricemia and gene analysis of familial gout among the elderly in Shijing Town, Nan'an City, Fujian Province

doi:10.21203/rs.3.rs-1983374/v1

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Research Article

Influencing factors of hyperuricemia and gene analysis of familial gout among the elderly in Shijing Town, Nan'an City, Fujian Province

https://doi.org/10.21203/rs.3.rs-1983374/v1

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Background

To investigate and analyze the relationship between hyperuricemia and various metabolic diseases and complications in people over 60 years old in Shijing Town, Nan'an City, Fujian Province, as well as the genetic analysis of familial gout attacks.

Methods

A cross-sectional study was conducted on the health examination data of people over 60 years old in Shijing Town, Nan'an City, Fujian Province (total population of 78,500) in 2019 and 2020. The differences between groups of metabolic indicators and complications and the correlation between uric acid and various metabolic indicators were analyzed. And 2 gout attack families were selected and used clinical whole-exome sequencing (including mitochondria) to conduct genome-wide association analysis.

Results

The total prevalence rate of hyperuricemia was 29.04%; albumin, triglyceride, alanine aminotransferase, aspartate aminotransferase, potassium ion, blood urea nitrogen, blood glucose, creatinine, body mass index, hypertension, and fatty liver were higher than those in the non-hyperuricemia group, and the difference was statistically significant (P < 0.05); the high-density lipoprotein in the hyperuricemia group was lower than that in the non-hyperuricemia group blood group, the difference was statistically significant (P < 0.05). There was no significant difference in serum total cholesterol, low-density lipoprotein, total bilirubin, direct bilirubin, sodium ion, diabetes, coronary heart disease, and abnormal electrocardiogram (P > 0.05); serum uric acid level in people over 60 years old It was positively correlated with albumin, triglyceride, low-density lipoprotein, potassium ion, alanine aminotransferase, aspartate aminotransferase, and body mass index levels (P < 0.05), and negatively correlated with HDL level (P < 0.05). P < 0.05); each of SLC4A1 gene, ABCB4 gene, and LRBA gene mutation was detected in the two tested families, and no mutation of SLC2A9 and ABCG2 gene was found.

Conclusions

The prevalence of hyperuricemia in the elderly population in Nan'an City, Fujian Province (29.04%) is significantly higher than the average level of the elderly in my country (13.1%). Compared with the normal population, patients have significantly abnormal metabolism. There is a significant correlation with the abnormal degree of familial hyperuricemia. Hypertension and fatty liver are risk factors for hyperuricemia; the SLC4A1 gene, ABCB4 gene, and LRBA gene may be closely related to the occurrence of familial hyperuricemia.

hyperuricemia

metabolic abnormalities

gout

familial

gene

Hyperuricemia (HUA) is a metabolic disease caused by a disturbance of purine metabolism, which is affected by genetic factors and environmental factors [1]. Gout was once considered a rare disease, and it is most prevalent in Western countries [2]. A systematic review and meta-system analysis showed that the combined prevalence of hyperuricemia was 13.3% in Mainland China from 2000 to 2014 [3]. Hyperuricemia patients often have Abnormal metabolism in the body, prone to obesity, hypertension, hyperlipidemia, type 2 diabetes, and metabolic syndrome [4, 5, 6, 7], leading to coronary heart disease, heart failure, and deep vein thrombosis, There is an increased risk of several cardiovascular diseases, including stroke [8, 9]. In recent years, GWAS has detected multiple susceptibility loci leading to hyperuricemia and gout, such as SLC2A9, SLC22A11, and SLC22A12 gene 1abnormalities that can cause hereditary hypouricemia or enhance uric acid reabsorption [10]; ABCG2, SLC17A1, and SLC17A3 gene abnormalities can reduce renal and intestinal excretion of uric acid [11]. Therefore, genetic variants that induce disorders of uric acid excretion (high reabsorption and low excretion) are the main genetic factors affecting hyperuricemia and gout.

Based on the above background, this study selected Shijing Town, Nan’an City, Fujian Province, as the research area, and the elderly population (over 60 years old) among the fixed residents as the research object. Two gout attack families were selected for genome-wide analysis, aiming to analyze whether various biochemical indicators, complications, or certain gene loci were associated with gout and hyperuricemia.

1. Source of cases

The study investigated the physical examination data of residents over 60 years old from 2019 to 2020 in Shijing Town, Nan'an City, Fujian Province (with a total population of 78,500), screened patients with uric acid > 420 µmol/L, and obtained relevant information on 3 468 people, including high uric acid. There were 1 009 cases of hyperuricemia and 2 459 cases of non-hyperuricemia (NUA).

2. Observation indicators

(1) To compare the biochemical indicators and complications of the two groups of subjects. (2) To analyze the correlation between uric acid and various biochemical indicators. (3) Select 2 families with a gout attack, with more than 3 immediate family members who have a gout attack, and analyze their whole genome.

3. Statistical methods

SPSS 20.0 software was used to analyze and process the data, and descriptive statistical analysis was used for enumeration data; normally distributed measurement data were expressed as Mean ± SD. Approximate t-test; non-normally distributed measurement data are expressed as [M(P25, P75)], and the rank-sum test is used for comparison between groups. The chi-square test was used for categorical data, and the person chi-square test was used for large sample sizes. Correlation analysis was performed using Spearman correlation analysis. P < 0.05 was considered a statistically significant difference.

1 Relationship and correlation analysis between HUA and various metabolic indicators

1.1 Comparison of metabolic index levels between groups

The results showed that in the biochemical indexes of the hyperuricemia group and non-hyperuricemia group, albumin (ALB), triglyceride (TG), high-density lipoprotein (HDL), Alanine transaminase (ALT), aspartate aminotransferase (AST), potassium ion, urea, blood glucose (GLU), creatinine, BMI (Body Mass Index, BMI) The difference was statistically significant (P < 0.05). The differences in serum total cholesterol (TC), low-density lipoprotein (LDL), total bilirubin, direct bilirubin, and sodium ions were all significant. No statistical significance (P > 0.05).

The levels of ALB, TG, ALT, AST, potassium ion, urea, GLU, creatinine, and BMI in the HUA group were higher than those in the NUA group, and the HDL levels were lower than those in the NUA group (P < 0.05, Table 1).

Table 1

Comparison of biochemical indexes between the two groups (n = 3468)
Variables	HUA (P25, P75)	NUA (P25, P75)	Z	P
Total, n	1009	2459
ALB, g/L	44.15(42.50,45.70)	43.90(42.20,45.30)	-2.741	0.006
TC, mmol/L	5.43(4.65,6.23)	5.53(4.81,6.33)	-1.886	0.059
TG, mmol/L	1.51(1.07,2.26)	1.27(0.92,1.80)	-9.438	0.000
LDL, mmol/L	2.92(2.35,3.55)	2.93(2.38,3.50)	-0.728	0.467
HDL, mmol/L	1.36(1.18,1.57)	1.51(1.30,1.75)	-11.321	0.000
ALT, U/L	17.00(13.00,23.00)	15.00(12.00,20.00)	-6.332	0.000
AST, U/L	25.00(21.00,30.00)	24.00(21.00,28.00)	-4.735	0.000
Total bilirubin, µmol/L	10.00(8.00,12.75)	10.20(8.10,12.80)	-0.586	0.558
Direct bilirubin, µmol/L	3.00(2.30,4.10)	3.00(2.30,4.00)	-1.412	0.158
K, mmol/L	4.30(4.06,4.56)	4.25(4.01,4.55)	-3.812	0.000
Na, mmol/L	141.00(139.70,142.20)	141.10(139.80,142.30)	-1.843	0.065
Urea, mmol/L	6.80(5.70,8.07)	6.12(5.14,7.26)	-11.615	0.000
GLU, mmol/L	5.80(5.20,6.80)	5.60(5.00,6.70)	-4.542	0.000
Creatinine, µmol/L	75.00(65.00,87.00)	60.00(52.00,70.00)	-23.940	0.000
BMI	24.61(22.33,27.12)	23.42(21.30,25.92)	-8.494	0.000

P < 0.05 was considered as statistically significance.

1.2 Correlation analysis between HUA and various metabolic indicators

The level of uric acid was positively correlated with ALB, TG, LDL, AST, ALT, potassium ion, GLU, urea, creatinine, and BMI, and negatively correlated with the level of HDL (P < 0.05, Table 2).

Table 2

Correlation Analysis between uric acid level and various biochemical indexes (n = 3468)
Variables	ALB	TG	LDL	HDL	AST	ALT	K	GLU	Urea	Creatinine	BMI
Spearman's rho	0.077	0.236	0.050	-0.251	0.107	0.159	0.092	0.076	0.232	0.508	0.222
P	＜0.01	＜0.01	＜0.01	＜0.01	＜0.01	＜0.01	＜0.01	＜0.01	＜0.01	＜0.01	＜0.01

P< 0.05 was considered as a significant difference.

2. The relationship between HUA and complications

The results showed that between the HUA group and the NUA group, the differences in the prevalence of hypertension and fatty liver were statistically significant (P < 0.05), and the differences in diabetes, coronary heart disease, and abnormal electrocardiogram were not statistically significant (P > 0.05).

The prevalence of hypertension and fatty liver in the HUA group was higher than those in the NUA group (P < 0.05, Table 3).

Table 3

Comparison of complications between the two groups (n = 3468)
Variables	HUA (n = 1009)	NUA (n = 2459)	X²	P
Hypertension, n(%)	603(59.8)	1195(48.6)	36.798	0.000
Diabetes, n(%)	190(18.8)	454(18.5)	0.085	0.771
Coronary heart disease, n(%)	15(1.49)	33(1.34)	0.116	0.733
Fatty liver, n(%)	315(31.2)	502(20.4)	47.050	0.000
abnormal electrocardiogram, n(%)	640(63.4)	1534(62.4)	0.308	0.579

P < 0.05 was considered as statistically significance.

3 Genetic Testing Results

Screening patients with gout attacks from the physical examination population, investigating the incidence of the family, selecting 2 families with ≥ 3 immediate family members who have gout attacks, excluding the history of diabetes, hypertension, and other chronic diseases, excluding the history of smoking and drinking, and no recent use of special drugs. Family 1: The patient, father, and grandfather all suffer from gout, and the patient's mother is verified; Family 2: The patient, sister, and father all suffer from gout, and the patient's mother is verified. The clinical whole-exome sequencing (including mitochondria) detection of the family was carried out, and the results were as follows: no mutation of SLC2A9 and ABCG2 gene was found in the two tested families, and one case of mutation of the SLC4A1 gene, ABCB4 gene, and LRBA gene was detected.

3.1 SLC4A1

After detection and analysis, a heterozygous missense variant was detected in the coding region of the SLC4A1 gene in a subject in family 1. The mother's test result was heterozygous, and the father's test result showed no mutation.

Abnormal SLC4A1 gene can lead to autosomal dominant distal renal tubular acidosis and other diseases. The clinical features of distal renal tubular acidosis include nephrolithiasis, nephrocalcification, primary distal renal tubular acidosis, hypercalciuria, etc. [12–14], but there is no literature report that this variant is directly related to HUA. The population frequency of this variant is relatively high, and the frequency of East Asian populations with this variant included in the gnomAD general population database is 0.000 80. Only 2 computational methods are predicting that this variant could have deleterious effects on a gene or gene product. Distal renal tubular acidosis was partially associated with the clinical presentation of subjects in family 1.

3.2 ABCB4

After detection and analysis, a heterozygous nonsense variant was detected in the coding region of the ABCB4 gene in a subject in family 1. The mother's test result was heterozygous, and the father's test result showed no mutation.

Abnormal ABCB4 gene can lead to autosomal dominant cholecystopathy type 1 and other diseases, and its clinical features include gallstones, cholestasis, liver fibrosis, pancreatitis, cholangitis, jaundice, etc. High-risk factors for the disease include age, females, obesity (especially central obesity), blood lipids, type 2 diabetes, etc. [15–17]. This variant is a rare variant, which is not included in the gnomAD population database and the local population database. It has been reported in the literature that the liver tissue of a proband with familial progressive intrahepatic cholestasis carrying a homozygous nonsense variant (c.2869C > T:p.R957X) was analyzed and found to have reduced or absent levels of RNA and ABCB4 protein [18]; another literature reported that a heterozygous frameshift variant (c.1399_1400ins10:p.Tyr467fs) and a heterozygous nonsense variant (c.3136C > T:p.R1046*) were found in young adults with gallstones, respectively, and speculated that the two variants may be harmful to the function of the ABCB4 protein [18]; the variant detected in this subject is a nonsense variant, which may lead to the loss of protein function. Cholecystopathy is not closely related to the clinical manifestations of the subjects but is a pathogenic variant consistent with a pattern of inheritance.

3.3 LRBA gene

After detection and analysis, a heterozygous nonsense variant was found in the LRBA gene of a subject in family 2, the mother's test result was heterozygous, and the father's test result was not found to be a variant.

Abnormalities in the LRBA gene can cause autosomal recessive immunodeficiency common variant 8 with autoimmunity. The clinical features of the disease include recurrent infections starting in early childhood, especially respiratory infections, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, inflammatory bowel disease, etc. [19–21]. Other clinical features include growth retardation, recurrent sinusitis, recurrent otitis media, recurrent conjunctivitis, bronchiectasis, pneumonia, chronic lung disease, interstitial pneumonia, asthma, autoimmune enteropathy, diarrhea, atrophic Gastritis, colitis, enteritis, arthritis, hypothyroidism, pancytopenia, granuloma, autoimmune deficiency or primary immunodeficiency, etc. [22–25]This variant has not yet been reported in the literature, and the frequency of this variant in the East Asian general population in the gnomAD database is 0.000294. According to ACMG guidelines, this variant is a variant of unknown clinical significance. Only one heterozygous variant was detected in one subject, which was inconsistent with the inheritance pattern of the disease, and type 8, a common variant of immunodeficiency, was only partially associated with the clinical manifestations of the subject.

The prevalence of HUA in mainland China has doubled and steadily increased over the past 20 years, and the rate of gout was rising year by year [3, 26]. The prevalence of metabolic syndrome was exceedingly high among those with gout [27]. This study selected fixed residents in coastal areas with a high incidence of hyperuricemia as the research object. The results showed that the detection rate of hyperuricemia in the surveyed population was 29.09%, and the prevalence of males (45.56%) was higher than that of females. The incidence rate (18.85%) was found, and it was found that uric acid was associated with a variety of abnormal metabolic indicators and complications. At the same time, two gout attack families were selected for gene analysis, and there were mutations in the SLC4A1 gene, ABCB4 gene, and LRBA gene respectively.

In this study, after comparing and analyzing clinical data, it was found that high uric acid may cause changes in liver function, renal function-related index levels, and blood lipid levels, creatinine, and BMI levels were positively correlated, and negatively correlated with HDL levels, suggesting that patients with hyperuricemia may be associated with liver insufficiency, renal insufficiency, dyslipidemia, and obesity, and are also more likely to suffer from hypertension and fatty liver. This phenomenon was also found in other studies [28, 29]. In previous studies, hyperlipidemia was also a risk factor for HUA, and dyslipidemia may cause HUA, especially the elevation of triglycerides and HDL [30]. Although there is evidence that hyperlipidemia and HUA may initiate and exacerbate each other and lead to further deterioration of metabolic status [31], the causal relationship between HUA and dyslipidemia has not been confirmed. In this study, there was no significant correlation between cholesterol, low-density lipoprotein, and uric acid, which may be related to the older age of the study population and some hyperlipidemia patients taking related lipid-lowering drugs.

The main excretion organ of uric acid is the kidney [32], and the renal tubule is an important factor affecting the excretion of uric acid. Primary hyperuricemia and gout are mostly caused by the reduction of uric acid excretion [33]. Renal tubular epithelial cells have a variety of uric acid transporters, and the genetic defects of these uric acid transporters can lead to disorders of purine metabolism, break the original balance of uric acid excretion, increase the reabsorption of uric acid in the renal tubular reabsorption link, and reduce the amount of excretion, resulting in Hyperuricemia [34–36].

In the results of the clinical whole-exome sequencing (including mitochondria) test of the two families in this study, no mutations in SLC2A9 and ABCG2 genes were found, but it cannot be denied that they are related to HUA, and no other genes related to the tested were found. A pathogenic variant or a probable pathogenic variant that is highly correlated with the clinical phenotype and consistent with the inheritance pattern of the disease. Variations in the SLC4A1 gene, ABCB4 gene, and LRBA gene were detected in each case, but the function and mechanism of them and uric acid transport found in GWAS are still unclear.

Hyperuricemia may be related to some liver and kidney functions, abnormal blood lipid metabolism, and obesity, and the causal relationship needs to be confirmed by further research; hyperuricemia patients are more likely to suffer from hypertension and fatty liver. HUA and gout are polygenic hereditary diseases. Many studies have confirmed that SLC2A9 and ABCG2 genes are related to hyperuricemia, while the SLC4A1 gene, ABCB4 gene, and LRBA gene may be closely related to the occurrence of familial hyperuricemia. The correlation and pathogenic mechanism can also be further studied. Therefore, it is necessary to expand the sample size and clarify it by selecting more qualified families and adding genetic testing of other family members in future research, to provide new targets and theories for early screening of gout and new drug development.

HUA: hyperuricemia

NUA: non-hyperuricemia

ALB: albumin

TG: triglyceride

HDL: high-density lipoprotein

ALT: Alanine transaminase

AST: aspartate aminotransferase

GLU: blood glucose

BMI: body mass index

TC: total cholesterol

LDL: low-density lipoprotein

1) Ethics approval and consent to participate

This proposal was reviewed and approved by the Human Ethics Committee of Xiang’an Hospital Of Xiamen University (XAHLL2022007). All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all subjects

2) Consent for publication

Not applicable.

3) Availability of data and materials

The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.

4) Competing interests

The authors declare that they have no competing interests.

5) Funding

The present study was funded by National Natural Science Foundation of China (No.81570772) and Natural Science Foundation of Fujian Province (2020J01018).

6) Authors' contributions

J.D.C., H.Z. and H.Y.T. designed the study and contributed to the formulation and evolution of overarching research goals and aims. H.Y.T., S.T.Z. and H.B.S. prepared the original manuscript, performed the statistical analysis, and participated in most of the study steps. T.Y.W. constructed the manuscript revision. X.J.Y. and T.Y.W. prepared the manuscript and assisted in the study processes. S.T.Z. and X.J.Y. assisted in the data collection and helped in the interpretation of the study. All authors read and approved the final manuscript.

7) Acknowledgments

Not applicable.

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Influencing factors of hyperuricemia and gene analysis of familial gout among the elderly in Shijing Town, Nan'an City, Fujian Province

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