Skip to main content
Download PDF

Association between the LRP5 rs556442 gene polymorphism and the risks of NAFLD and CHD in a Chinese Han population

BMC Gastroenterology volume 22, Article number: 305 (2022) Cite this article

Abstract

Background

Multiple studies have demonstrated the involvement of low-density lipoprotein receptor-related protein 5 (LRP5) in metabolism-related diseases. This study explored the relationship between the LRP5 rs556442 gene polymorphism and the risks of non-alcoholic fatty liver disease (NAFLD) and coronary heart disease (CHD) in a Chinese Han population.

Methods

This retrospective case–control study included 247 patients with NAFLD, 200 patients with CHD, 118 patients with both NAFLD and CHD, and 339 healthy controls from June 2018 to June 2019 at Qingdao Municipal Hospital. Basic information and clinical characteristics were collected for all subjects. The genotype and allele frequency of LRP5 rs556442 were determined.

Results

The genotype distributions of LRP5 rs556442 differed significantly between the CHD and NAFLD + CHD groups (P < 0.05). The LRP5 rs556442 GG genotype markedly promoted the risk of NAFLD in CHD patients [odds ratio (OR) = 2.857, 95% confidence interval (CI): 1.196–6.824, P = 0.018). After adjustment for sex, age, and body mass index (BMI), this association remained significant (OR = 3.252, 95% CI: 1.306–8.102, P = 0.011). In addition, the LRP5 rs556442 AA + AG genotype was associated with an increased BMI in obese NAFLD patients (OR = 1.526, 95% CI: 1.004–2.319, P = 0.048). However, after adjustment for sex and age, this association was no longer significant (OR = 1.504, 95% CI: 0.991–2.282, P = 0.055).

Conclusions

This study found that the LRP5 rs556442 GG genotype increased the risk of NAFLD in CHD patients and AA + AG genotype may be associated with an increased BMI in obese NAFLD patients among a Chinese Han population.

Trial registration ChiCTR, ChiCTR1800015426. Registered 28 March 2018—Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=26239.

Peer Review reports

Background

NAFLD is the most prevalent chronic liver disease and may progress to NAFLD-associated cirrhosis [1]. NAFLD cases are usually classified as lean NAFLD or obese NAFLD based on the BMI value of 25 kg/m2 [2]. The recent studies suggested that the prevalence of NAFLD in Asia is about 29.62% [3, 4]. In addition, an increasing number of adolescents are being diagnosed with NAFLD, with an estimated prevalence rates ranging from 3–18% [3, 5]. A sedentary lifestyle, poor diet, and metabolism-related diseases are the main reasons for the elevated morbidity of NAFLD, and NAFLD is currently the main condition requiring liver transplantation [6, 7]. At present, no targeted drug is available for the treatment of NAFLD, and the primary means to improve the symptoms of NAFLD are weight loss and improvement of insulin resistance through lifestyle, medication, or endoscopic/surgical interventions [1, 8, 9].

CHD is the main cause of myocardial ischemia, which is closely correlated with the occurrence of major adverse cardiovascular events [10]. CHD has become the main cause of death in patients with NAFLD, and a prospective cohort study found that NAFLD is tightly related to CHD and an independent risk factor for CHD [11, 12]. An imaging study also detected a strong relationship between CHD and NAFLD [13]. In a prospective cohort study by Wong et al., the prevalence of NAFLD among patients with CHD was 58.2% [14]. Arslan et al. also demonstrated a correlation between NAFLD and CHD [15]. NAFLD and CHD are interrelated through complex pathophysiological mechanisms [16]. As genetic factors have been recognized to play important roles in precision medicine, some common risk genes have been reported for these two diseases, including TRIB1 rs17321515, ADIPOQ rs266729, PNPLA3 rs738409, and LEPR rs1137100 [17,18,19,20,21,22,23].

LRP5 is located on chromosome 11, and the rs556442 variant is present in the 15th exon of the LRP5 gene [24]. LRP5 is expressed in various tissues, including the liver and pancreatic β-cells [25, 26], participates in the process of adipogenesis by down-regulating adipogenic transcription factors, and also regulates the process of glucose-induced insulin secretion and cholesterol metabolism [27]. Montazeri-Najafabady et al. reported that the LRP5 rs556442 polymorphism increases the risk of insulin resistance in Iranian adolescents and emphasized that the A allele played a key role in the increase in total cholesterol (TC) levels in the study population [28, 29]. In 2019, Adabi et al. showed that the LRP5 rs556442 variant could affect the basal metabolic rate [30]. It is well known that hypercholesterolemia, insulin resistance, and obesity all contribute to NAFLD and play important roles in the occurrence and development of CHD. In view of the known functional characteristics of LRP5 rs556442, it is reasonable to presume that LRP5 rs556442 may influence the risks of NAFLD and CHD, but no available study has proven this. This study aimed to explore the correlation between LRP5 rs556442 and the risks of NAFLD and CHD in a Chinese Han population, and to investigate the effect of the LRP5 rs556442 A allele specifically on metabolism-related parameters.

Methods

Research subjects

In this retrospective case–control study, all subjects were treated from June 2018 to June 2019 in Qingdao Municipal Hospital. NAFLD was diagnosed according to the Guidelines of Prevention and Treatment for Nonalcoholic Fatty Liver Disease: a 2018 update [31]. Patients with NAFLD were recruited from the department of Infectious Disease and Gastroenterology in Qingdao Municipal Hospital. NAFLD was diagnosed based on basic features such as an enhanced anterior field echo (bright liver), attenuation of distant field echo, and an unclear intrahepatic duct structure observed on abdominal ultrasound. Patients with alcoholic liver disease, viral liver disease, autoimmune liver disease, drug-induced liver disease, and other related liver diseases were excluded from this study. CHD was diagnosed based on the 2015 Chinese Society of Cardiology (CSC) guidelines for the diagnosis and management of patients with ST-segment elevation myocardial infarction, and patients were diagnosed with CHD when coronary angiography showed stenosis more than 50% in any of the main coronary arteries. Patients with both NAFLD and CHD (NAFLD + CHD) met both the criteria for diagnosis of both NAFLD and CHD. Patients with CHD or NAFLD + CHD were recruited from the department of Cardiology in Qingdao Municipal Hospital. Healthy controls were recruited from the Health Management Center in Qingdao Municipal Hospital. NAFLD was assessed by a hepatologist, and CHD was assessed by a cardiologist, all of whom were blinded to the study aims and patient details. A total of 339 healthy controls, 247 patients with NAFLD, 200 with CHD, and 118 with both NAFLD and CHD were included. All participants were of Chinese Han ethnicity. This study was approved by the ethics committee of Qingdao Municipal Hospital and performed in accordance with the Declaration of Helsinki and its amendments [32].

Biochemical analyses

Blood samples were collected from participants after 12 h of overnight fasting. The levels of biochemical parameters such as high-density lipoprotein (HDL), aspartate aminotransferase (AST), fasting plasma glucose (FPG), TC, alanine aminotransferase (ALT), triglycerides (TG), low-density lipoprotein (LDL), alkaline phosphatase (ALP), total bilirubin (TB), and γ-glutamyl transpeptidase (GGT) were measured in the laboratory medicine department. All basic information for the participants was retrieved from a questionnaire.

Genomic DNA extraction and genotyping

For the genotyping, genomic DNA of blood samples was extracted using a commercial kit (TIANGEN, Beijing, China). Polymerase chain reaction (PCR) amplification for LRP5 rs556442 was performed used the primers S: 5′-ACGTTGGATGTACTGAAATCACTGTCCCTC-3′; AS: 5′-ACGTTGGATGAACAAGCACTTCGGTCATCC-3′, and the procedure previous described by Chen et al. [33]. After PCR amplification, the PCR products were treated with alkaline phosphatase before single-base extension reaction and resin purification. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry was applied to analyze the spectral chip after sampling, and the MassARRAY TYPER 4.0 software was used to analyzed the raw data.

Statistical analysis

Statistical analyses were performed using SPSS 23.0 software (SPSS, Inc., USA). Hardy–Weinberg equilibrium was applied to confirm balance of genotype frequencies among the groups. Genotype distribution, allele frequency, and sex were compared among groups using the χ2 test. Data for variables that followed a normal distribution are expressed as mean ± standard deviation (SD), and data for variables that did not are expressed as quartiles. If the data were normally distributed and F test showed equal variance, differences in continuous variables between two groups were identified using t tests. Otherwise, the Wilcoxon test was used. Also, if the data were normally distributed and F test showed equal variance, the differences in continuous variables in two of the four groups were identified using Student–Newman–Keuls test. Otherwise, the Kruskal–Wallis test was used. OR and 95% CI values were calculated by the binary logistic regression model. P < 0.05 was considered as the statistic difference.

Results

Characteristics of subjects in this study

Data for 904 individuals were analyzed in this retrospective study, including 247 patients with NAFLD (139 males and 108 females), 200 patients with CHD (127 males and 73 females), 118 patients with both NAFLD and CHD (81 males and 37 females), and 339 healthy controls (188 males and 151 females). The age and gender of NAFLD patients did not differ from those of the control individuals. The levels of FPG, TC, ALT, AST, ALT/AST, GGT, and ALP as well as BMI in NAFLD patients were elevated compared with those of the control group, while the levels of TB and HDL in NAFLD patients were markedly decreased compared with those of controls (all P < 0.05). The levels of ALT, GGT, FPG, AST, and ALP in addition to the age and BMI of CHD patients were elevated compared with those of the controls, while the levels of LDL and HDL were lower in the CHD patients than in the controls (all P < 0.05). The proportion of male patients in the NAFLD + CHD patients was higher than that in the controls (P < 0.05). Additionally, the levels of FPG, ALT, GGT, and ALP as well as the age and BMI of the NAFLD + CHD patients were higher than that in controls, while the levels of HDL and LDL in NAFLD + CHD patients were inferior to that in controls (all P < 0.05). The proportion of male patients in NAFLD group was higher than that in the NAFLD + CHD group (P < 0.05). Age and FPG concentration were higher in NAFLD + CHD patients than in NAFLD patients, whereas BMI, the ALT/AST ratio, and the concentrations of TC, HDL, and LDL were lower in the NAFLD + CHD patients than in the NAFLD patients (all P < 0.05). No significant differences in gender and age were observed between the NAFLD + CHD patients and the CHD patients (both P > 0.05), and only the TG level in the NAFLD + CHD patients was elevated compared with that in CHD patients (P < 0.05) (Table 1).

Table 1 Clinical characteristics in the NAFLD, CHD, NAFLD + CHD, and control groups
Full size table

Distribution of LRP5 rs556442 genotype and allele frequency

The genotype distributions of LRP5 rs556442 among the four groups conformed to Hardy–Weinberg equilibrium, no significant differences of genotype distributions of LRP5 rs556442 were found in NAFLD group, CHD group, NAFLD + CHD group, and Control group (all P > 0.05). In the CHD group, the genotype distribution of LRP5 rs556442 was significantly different from that in the NAFLD + CHD group (P < 0.05), but the difference of allele frequency distribution of LRP5 rs556442 was not significant between CHD and NAFLD + CHD groups (P > 0.05). No significant differences in allele frequency and genotype distribution of LRP5 rs556442 were found between NAFLD patients and controls, CHD patients and controls, NAFLD + CHD patients and healthy controls, NAFLD patients and NAFLD + CHD patients, or lean NAFLD patients and obese NAFLD patients (Table 2). Binary logistic regression analysis suggested a significant association between the LRP5 rs556442 GG genotype and the risk of NAFLD in CHD patients (OR = 2.857, 95% CI: 1.196–6.824, P = 0.018), and this association remained significant after adjustment for age, sex, and BMI (OR = 3.252, 95% CI: 1.306–8.102, P = 0.011; Table 3).

Table 2 Distributions of LRP5 rs556442 genotypes and allele frequencies in the four groupsa
Full size table
Table 3 Correlations of genotypes with risks of NAFLD and CHD in the study groups
Full size table

Association between LRP5 rs556442 A allele and clinical parameters in each group

Among all study participants and among NAFLD patients, LRP5 rs556442 A allele carriers possessed an elevated BMI compared to non-carriers (both P < 0.05). In addition, no significant differences in other indicators were observed between carriers and non-carriers in these groups. LRP5 rs556442 A allele carriers had an elevated AST level compared to non-carriers among NAFLD + CHD patients (P < 0.05), but the differences in other indicators were not significant between carriers and non-carriers in this group (Table 4). In addition, no significant differences in clinical parameters were observed between the carriers and non-carriers of A allele among CHD patients or controls. NAFLD cases were divided into lean NAFLD and obese NAFLD according to BMI. Binary logistic regression analysis showed that the LRP5 rs556442 AA + AG genotype was associated with the increased BMI in obese NAFLD patients (OR = 1.526, 95% CI: 1.004–2.319, P = 0.048). However, this association was not significant after adjustment for sex and age (OR = 1.504, 95% CI: 0.991–2.282, P = 0.055; Table 5).

Table 4 Clinical characteristics of LRP5 rs556442 A allele carriers and non-carriers in the study population
Full size table
Table 5 Associations between AA + AG genotype and BMI in all study participants and in NAFLD patients by binary logistic regression analysis
Full size table

Discussion

Accumulated studies have proven that the LRP5 rs556442 polymorphism tightly associated with the risk of multiple metabolic related diseases, but the correlation between LRP5 rs556442 and the risks of NAFLD and CHD in a Chinese Han population remain unclear. This study investigated the relationship between the LRP5 rs556442 gene polymorphism and the risks of non-alcoholic fatty liver disease (NAFLD) and coronary heart disease (CHD) in a Chinese Han population. The results showed that LRP5 rs556442 GG genotype markedly promoted the risk of NAFLD in CHD patients, and the AA + AG genotype may be associated with an increased BMI in obese NAFLD patients among a Chinese Han population.

Previous studies have suggested that NAFLD and CHD are interrelated through a variety of pathophysiological mechanisms and share common risk factors, such as genetic mutations, dyslipidemia, hyperuricemia, hyperglycemia, hypertension, insulin resistance, and obesity [16, 34]. LRP5 participates in lipid and glucose metabolism, and genetic polymorphism of LRP5 has been identified as contributing factor for metabolic disorders, which are determinants of cardiovascular disease and also closely associated with NAFLD [27, 35]. In this study, the relationship of the LRP5 rs556442 polymorphism with the risks of NAFLD and CHD were explored in a Chinese Han population for the first time. The results of this study show that the distribution of LRP5 rs556442 differed significantly between patients with only CHD and those with both NAFLD and CHD, and that the LRP5 rs556442 GG genotype contributed to the risk of NAFLD in CHD patients. In addition, LRP5 rs556442 AA + AG genotype correlated with the risk of obese NAFLD, but this association was not significant after adjustment for sex and age.

LRP5 is one of the LDL cholesterol receptors and is widely expressed in various tissues. LRP5 is known to participate in adipogenesis by down-regulating adipogenic transcription factors and also to regulate insulin secretion and cholesterol metabolism [25,26,27, 36]. In 2006, Guo et al. explored the effects of LRP5 gene polymorphisms on obesity in a Caucasian population, and they found that intronic variants in the LRP5 gene were significantly related to the risk for obesity [37]. In 2019, Adabi et al. conducted a cross-sectional study in Iranian postmenopausal women to explore the effect of the LRP5 rs556442 polymorphism on basal metabolic rate and obesity. They found that among obese women, AG and AA genotype carriers had a lower basal metabolic rate than GG genotype carriers, and a lower basal metabolic rate will further aggravate obesity. Therefore, the AA/AG genotype was regarded as a risk factor for obesity in these patients [30]. In the present study, the LRP5 rs556442 AA + AG genotype was associated with an increased BMI in all study participants and in obese NAFLD patients of the Chinese Han population, and these findings are consistent with the previous studies.

Prior research has shown that hepatic steatosis can contribute to the progression of CHD through increased inflammation in the local environment and endothelial dysfunction [38]. In the present study, CHD patients with the LRP5 rs556442 GG genotype had an increased risk of developing NAFLD, which indicates that detection of the LRP5 rs556442 GG genotype should be included in NAFLD screening efforts in CHD patients. No relationships between LRP5 rs556442 and the risks of NAFLD, CHD, or the combination of NAFLD and CHD were found in this study. However, the pathogenesis of both NAFLD and CHD is complex and dependent on the combined actions of multiple factors. Therefore, single risk factors such as the LRP5 rs556442 polymorphism may be masked by the influence of other factors. Although the present study did not find any significant associations between the LRP5 rs556442 polymorphism and these diseases, the role of LRP5 rs556442 in NAFLD, CHD, and NAFLD + CHD patients remains to be confirmed. In addition, the strong linkage disequilibrium between LRP5 rs556442 and other polymorphisms may affect the effect of LRP5 rs556442 on the risk of NAFLD, CHD, and NAFLD + CHD. Therefore, further studies should also explore these issues.

Serum AST is mainly produced in the liver and heart. When liver cells and cardiomyocytes are injured, AST in the cytoplasm can enter the blood, leading to an increase in the serum AST concentration. Therefore, a high serum AST level in clinical practice is usually related to liver cell or cardiomyocyte injury [39,40,41]. In this study, the LRP5 rs556442 A allele carriers among NAFLD + CHD patients had elevated serum AST levels compared to the non-carriers, which suggests that LRP5 rs556442 A allele carriers with NAFLD and CHD might be more prone to hepatocyte or cardiomyocyte damage. In addition, the levels of LDL in the CHD group and NAFLD + CHD group were inferior to that in the controls in present study, and this phenomenon might have been caused by the use of lipid-lowing drugs by patients with CHD and NAFLD + CHD.

The main strength of this study was the finding that the LRP5 rs556442 GG genotype could increase the risk of NAFLD in CHD patients, which suggests that LRP5 rs556442 genotype can potentially be considered for screening purposes in the future if further research confirms these findings in other populations as well. The findings of this study provide insight for a new method to predict the risk of NAFLD in patients with CHD. This study also has several limitations. All patients with NAFLD were diagnosed by ultrasound rather than liver biopsy; therefore, diagnostic error may exist in this research. Also, the number of participants in this study was relatively small, which may affect the results. Finally, all of the participants were Chinese Han, and thus, the association of LRP5 rs556442 with the risks of NAFLD, CHD, and the combination of NAFLD + CHD need to be verified in other ethnicities.

Conclusions

This study explored the associations between the LRP5 rs556442 polymorphism and the risks of NAFLD, CHD, and the combination of NAFLD + CHD in Chinese Han patients. The distributions of LRP5 rs556442 genotypes differed between the CHD and NAFLD + CHD groups, and the LRP5 rs556442 GG genotype increased the risk of NAFLD in CHD patients. In addition, the LRP5 rs556442 AA + AG genotype was associated with an increased BMI in obese NAFLD patients, but this association was not statistically significant after adjustment for sex and age. Further studies are needed to verify the association of LRP5 rs556442 polymorphism and the risks of NAFLD, CHD, and combined NAFLD + CHD in other countries and ethnicities, and the underlying mechanism by which LRP5 rs556442 affecting the risk of NAFLD in patients with CHD needs to be clarified. Overall, the findings of this study provide insight for a new method to predict the risk of NAFLD in patients with CHD.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Abbreviations

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

BMI:

Body mass index

BMR:

Basal metabolic rate

CHD:

Coronary heart disease

CI:

Confidence interval

CSC:

Chinese Society of Cardiology

FPG:

Fasting blood glucose

GGT:

γ-Glutamyl transpeptidase

HDL:

High density lipoprotein

LDL:

Low density lipoprotein

LRP5:

Low-density lipoprotein receptor-related protein 5

NAFL:

Nonalcoholic simple fatty liver

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

OR:

Odds ratio

SD:

Standard deviation

TBIL:

Total bilirubin

TC:

Total cholesterol

TG:

Triglycerides

References

  1. Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic steatohepatitis: a review. JAMA. 2020;323(12):1175–83.

    Article  CAS  PubMed  Google Scholar 

  2. Fan JG, Kim SU, Wong VW. New trends on obesity and NAFLD in Asia. J Hepatol. 2017;67(4):862–73.

    Article  PubMed  Google Scholar 

  3. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84.

    Article  PubMed  Google Scholar 

  4. Li J, Zou B, Yeo YH, Feng Y, Xie X, Lee DH, Fujii H, Wu Y, Kam LY, Ji F, et al. Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999–2019: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2019;4(5):389–98.

    Article  PubMed  Google Scholar 

  5. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhao CW, Gao YH, Song WX, Liu B, Ding L, Dong N, Qi X. An update on the emerging role of resistin on the pathogenesis of osteoarthritis. Mediat Inflamm. 2019;2019:1532164.

    Google Scholar 

  7. Ahadi M, Molooghi K, Masoudifar N, Beheshti Namdar A, Vossoughinia H, Farzanehfar M. A review of non-alcoholic fatty liver disease in non-obese and lean individuals. J Gastroenterol Hepatol. 2021;36(6):1497–507.

    Article  PubMed  Google Scholar 

  8. Brunner KT, Henneberg CJ, Wilechansky RM, Long MT. Nonalcoholic fatty liver disease and obesity treatment. Curr Obes Rep. 2019;8(3):220–8.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Cai H, Qin YL, Shi ZY, Chen JH, Zeng MJ, Zhou W, Chen RQ, Chen ZY. Effects of alternate-day fasting on body weight and dyslipidaemia in patients with non-alcoholic fatty liver disease: a randomised controlled trial. BMC Gastroenterol. 2019;19(1):219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Malakar AK, Choudhury D, Halder B, Paul P, Uddin A, Chakraborty S. A review on coronary artery disease, its risk factors, and therapeutics. J Cell Physiol. 2019;234(10):16812–23.

    Article  CAS  PubMed  Google Scholar 

  11. Assy N, Djibre A, Farah R, Grosovski M, Marmor A. Presence of coronary plaques in patients with nonalcoholic fatty liver disease. Radiology. 2010;254(2):393–400.

    Article  PubMed  Google Scholar 

  12. Arslan U, Yenerçağ M. Relationship between non-alcoholic fatty liver disease and coronary heart disease. World J Clin Cases. 2020;8(20):4688–99.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Patil R, Sood GK. Non-alcoholic fatty liver disease and cardiovascular risk. World J Gastrointest Pathophysiol. 2017;8(2):51–8.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wong VW, Wong GL, Yeung JC, Fung CY, Chan JK, Chang ZH, Kwan CT, Lam HW, Limquiaco J, Chim AM, et al. Long-term clinical outcomes after fatty liver screening in patients undergoing coronary angiogram: a prospective cohort study. Hepatology. 2016;63(3):754–63.

    Article  PubMed  Google Scholar 

  15. Arslan U, Türkoğlu S, Balcioğlu S, Tavil Y, Karakan T, Cengel A. Association between nonalcoholic fatty liver disease and coronary artery disease. Coron Artery Dis. 2007;18(6):433–6.

    Article  PubMed  Google Scholar 

  16. Stahl EP, Dhindsa DS, Lee SK, Sandesara PB, Chalasani NP, Sperling LS. Nonalcoholic fatty liver disease and the heart: JACC state-of-the-art review. J Am Coll Cardiol. 2019;73(8):948–63.

    Article  PubMed  Google Scholar 

  17. Wang L, Jing J, Fu Q, Tang X, Su L, Wu S, Li G, Zhou L. Association study of genetic variants at newly identified lipid gene TRIB1 with coronary heart disease in Chinese Han population. Lipids Health Dis. 2015;14:46.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Liu Q, Xue F, Meng J, Liu SS, Chen LZ, Gao H, Geng N, Jin WW, Xin YN, Xuan SY. TRIB1 rs17321515 and rs2954029 gene polymorphisms increase the risk of non-alcoholic fatty liver disease in Chinese Han population. Lipids Health Dis. 2019;18(1):61.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Smetnev S, Klimushina M, Kutsenko V, Kiseleva A, Gumanova N, Kots A, Skirko O, Ershova A, Yarovaya E, Metelskaya V, et al. Associations of SNPs of the ADIPOQ Gene with Serum Adiponectin Levels, Unstable Angina, and Coronary Artery Disease. Biomolecules. 2019;9(10):537.

    Article  PubMed Central  Google Scholar 

  20. Liu M, Liu S, Shang M, Liu X, Wang Y, Li Q, Mambiya M, Yang L, Zhang Q, Zhang K, et al. Association between ADIPOQ G276T and C11377G polymorphisms and the risk of non-alcoholic fatty liver disease: an updated meta-analysis. Mol Genet Genomic Med. 2019;7(5):e624.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Posadas-Sánchez R, López-Uribe ÁR, Posadas-Romero C, Pérez-Hernández N, Rodríguez-Pérez JM, Ocampo-Arcos WA, Fragoso JM, Cardoso-Saldaña G, Vargas-Alarcón G. Association of the I148M/PNPLA3 (rs738409) polymorphism with premature coronary artery disease, fatty liver, and insulin resistance in type 2 diabetic patients and healthy controls. The GEA study. Immunobiology. 2017;222(10):960–6.

    Article  PubMed  Google Scholar 

  22. Zain SM, Mohamed Z, Mahadeva S, Cheah PL, Rampal S, Chin KF, Mahfudz AS, Basu RC, Tan HL, Mohamed R. Impact of leptin receptor gene variants on risk of non-alcoholic fatty liver disease and its interaction with adiponutrin gene. J Gastroenterol Hepatol. 2013;28(5):873–9.

    Article  CAS  PubMed  Google Scholar 

  23. Shi R, Zhang M, Wang W, Song X, Liu H, Tian R, Yang F, Ding M, Lv S. Effect of interactions between LEPR polymorphisms and smoking on coronary artery disease susceptibility. Int J Clin Exp Pathol. 2017;10(9):9753–9.

    PubMed  PubMed Central  Google Scholar 

  24. Koay MA, Woon PY, Zhang Y, Miles LJ, Duncan EL, Ralston SH, Compston JE, Cooper C, Keen R, Langdahl BL, et al. Influence of LRP5 polymorphisms on normal variation in BMD. J Bone Miner Res. 2004;19(10):1619–27.

    Article  CAS  PubMed  Google Scholar 

  25. Figueroa DJ, Hess JF, Ky B, Brown SD, Sandig V, Hermanowski-Vosatka A, Twells RC, Todd JA, Austin CP. Expression of the type I diabetes-associated gene LRP5 in macrophages, vitamin A system cells, and the Islets of Langerhans suggests multiple potential roles in diabetes. J Histochem Cytochem. 2000;48(10):1357–68.

    Article  CAS  PubMed  Google Scholar 

  26. Kim DH, Inagaki Y, Suzuki T, Ioka RX, Yoshioka SZ, Magoori K, Kang MJ, Cho Y, Nakano AZ, Liu Q, et al. A new low density lipoprotein receptor related protein, LRP5, is expressed in hepatocytes and adrenal cortex, and recognizes apolipoprotein E. J Biochem. 1998;124(6):1072–6.

    Article  CAS  PubMed  Google Scholar 

  27. Fujino T, Asaba H, Kang MJ, Ikeda Y, Sone H, Takada S, Kim DH, Ioka RX, Ono M, Tomoyori H, et al. Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proc Natl Acad Sci U S A. 2003;100(1):229–34.

    Article  CAS  PubMed  Google Scholar 

  28. Montazeri-Najafabady N, Dabbaghmanesh MH, Omrani GR, Saki F, Bakhshayeshkaram M. Polymorphism in LRP5 (rs556442) is associated with higher TG levels in Iranian children. Ann Hum Biol. 2017;44(4):373–8.

    Article  PubMed  Google Scholar 

  29. Montazeri-Nafafabady N, Dabbaghmanesh MH, Mohamadian Amiri R, Bakhshayeshkaram M, Ranjbar Omrani G. Influence of LRP5 (rs556442) polymorphism on insulin resistance in healthy Iranian children and adolescents. Turk J Med Sci. 2019;49(2):490–6.

    Article  PubMed  Google Scholar 

  30. Adabi E, Omidfar A, Farahani NA, Faghihi F. Asghar Malek Hosseini SA, Maghbooli Z, Shirvani A. The association of LRP5 (rs556442) polymorphism with body composition and obesity in postmenopausal women. Diabetes Metab Syndr. 2019;13(4):2381–5.

    Article  PubMed  Google Scholar 

  31. National Workshop on Fatty L, Alcoholic Liver Disease CSoHCMA, Fatty Liver Expert Committee CMDA: [Guidelines of prevention and treatment for nonalcoholic fatty liver disease: a 2018 update]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese Journal of Hepatology 2018;26(3):195–203.

  32. Rickham PP. Human experimentation. Code of ethics of the world medical association. Declaration of Helsinki. Br Med J. 1964;2(5402):177.

    Article  CAS  PubMed  Google Scholar 

  33. Chen LZ, Ding HY, Liu SS, Liu Q, Jiang XJ, Xin YN, Xuan SY. Combining I148M and E167K variants to improve risk prediction for nonalcoholic fatty liver disease in Qingdao Han population, China. Lipids Health Dis. 2019;18(1):45.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66(6):1138–53.

    Article  PubMed  Google Scholar 

  35. Wong CR, Lim JK. The association between nonalcoholic fatty liver disease and cardiovascular disease outcomes. Clin Liver Dis (Hoboken). 2018;12(2):39–44.

    Article  Google Scholar 

  36. You HF, Zhao JZ, Zhai YJ, Yin L, Pang C, Luo XP, Zhang M, Wang JJ, Li LL, Wang Y, et al. Association between low-density lipoprotein receptor-related protein 5 polymorphisms and type 2 diabetes mellitus in Han Chinese: a case-control study. Biomed Environ Sci. 2015;28(7):510–7.

    CAS  PubMed  Google Scholar 

  37. Guo YF, Xiong DH, Shen H, Zhao LJ, Xiao P, Guo Y, Wang W, Yang TL, Recker RR, Deng HW. Polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study. J Med Genet. 2006;43(10):798–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Meyersohn NM, Mayrhofer T, Corey KE, Bittner DO, Staziaki PV, Szilveszter B, Hallett T, Lu MT, Puchner SB, Simon TG, et al. Association of hepatic steatosis with major adverse cardiovascular events, independent of coronary artery disease. Clin Gastroenterol Hepatol. 2021;19(7):1480–8.

    Article  PubMed  Google Scholar 

  39. Vanderlinde RE, Rej R, Fasce CF Jr. Enzyme determinations: criticisms of some recent reports. Clin Chem. 1973;19(2):282–4.

    Article  CAS  PubMed  Google Scholar 

  40. Liu X, Hamnvik OP, Chamberland JP, Petrou M, Gong H, Christophi CA, Christiani DC, Kales SN, Mantzoros CS. Circulating alanine transaminase (ALT) and γ-glutamyl transferase (GGT), but not fetuin-A, are associated with metabolic risk factors, at baseline and at two-year follow-up: the prospective Cyprus Metabolism Study. Metabolism. 2014;63(6):773–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Otto-Ślusarczyk D, Graboń W, Mielczarek-Puta M. Aspartate aminotransferase–key enzyme in the human systemic metabolism. Postepy Hig Med Dosw. 2016;70:219–30.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Jie Zhang for the assistance in this study.

Funding

This study was supported by a grant from the National Natural Science Foundation of China (No. 32171277) and the Medical and Health Technology Development Project of Shandong Province (No. 202111000637).

Author information

Authors and Affiliations

  1. Department of Infectious Disease, Qingdao Municipal Hospital, 1 Jiaozhou Road, Qingdao, 266011, Shandong Province, China

    Dongli Han & Yongning Xin

  2. Health Management Center, Qingdao Central Hospital, Qingdao, China

    Haiying Zhang

  3. Clinical Research Center, Qingdao Municipal Hospital, Qingdao, China

    Shousheng Liu, Likun Zhuang & Zhenzhen Zhao

  4. Second Department of General Surgery, Qingdao Municipal Hospital, 1 Jiaozhou Road, Qingdao, 266011, Shandong Province, China

    Hongguang Ding

  5. Digestive Disease Key Laboratory of Qingdao, Qingdao, China

    Yongning Xin

  6. Department of Gastroenterology, Zhumadian Central Hospital, Zhumadian, China

    Dongli Han

Authors
  1. Dongli Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haiying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shousheng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Likun Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhenzhen Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongguang Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yongning Xin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HDL and ZHY collected, analyzed, and interpreted data and drafted the article; LSS, ZLK, and ZZZ collected, analyzed, and interpreted data; and XYN and DHG designed the study and revised the article. All authors have read and approved the manuscript.

Corresponding authors

Correspondence to Hongguang Ding or Yongning Xin.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Qingdao Municipal Hospital and all methods were performed in accordance with the principles of the Helsinki declaration and its appendices. The written informed consent was signed by all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Han, D., Zhang, H., Liu, S. et al. Association between the LRP5 rs556442 gene polymorphism and the risks of NAFLD and CHD in a Chinese Han population. BMC Gastroenterol 22, 305 (2022). https://doi.org/10.1186/s12876-022-02385-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12876-022-02385-9

Keywords

BMC Gastroenterology

ISSN: 1471-230X

Contact us