Elevated Serum Low-Density Lipoproteins-Cholesterol Levels and B1B2/B2B2 CETP Genotype Are Positively Associated with Nonalcoholic Fatty Liver Disease in Women with Gallstone Disease

Abstract

Background:

Nonalcoholic fatty liver disease (NAFLD) is generated by the interaction between environmental and genetic factors, and the presence of metabolic alterations. Since Taq1B cholesteryl ester transfer protein (CETP) polymorphism is associated with abnormal serum lipid values, it could be related to NAFLD. The aim of this study was to determine the role of the Taq1B CETP polymorphism with serum lipids, anthropometric variables, and the extent of steatosis in Mexican-mestizo women with gallstone disease (GD).

Methods:

Sixty-two women were enrolled in this cross-sectional study. Serum lipids were determined by dry chemistry. The Taq1B CETP polymorphism was determined by allelic discrimination. CETP serum levels were measured by enzyme-linked immunosorbent assay, and the extent of steatosis with a biopsy staining with Oil-Red-O.

Results:

Subjects with the B1B2/B2B2 genotype had higher percentage of degree of steatosis than those with B1B1 (11.95% vs. 2.19%, P = 0.008). The B1B2/B2B2 genotype (odds ratio [OR] 3.90 [confidence interval {CI} 95% 1.891–8.536], P = 0.04) and an elevated low-density lipoproteins (LDL)-cholesterol (OR 3.54 [CI 95% 1.042–2.058, P = 0.039) significantly increase the risk for NAFLD.

Conclusions:

This study provides evidence that the B1B2/B2B2 genotype of CETP and the elevated LDL-cholesterol serum levels increase the risk of NAFLD in women with GD.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is defined by a significant lipid accumulation in liver tissue in the absence of chronic alcohol consumption or another cause of liver disease.¹ This term includes a spectrum ranging from triglyceride (TG) accumulation in hepatocytes to hepatic steatosis with inflammation, fibrosis, and cirrhosis.² Moreover, it is the most common hepatic alteration in western world that affects 24% of global population and 45% of Hispanics.^3,4

The etiology of NAFLD is due to the interaction of environmental factors, genetic predisposition, and the presence of metabolic alterations such as dyslipidemias,^5

–8 which represent an abnormal lipid metabolism that promotes an increase of circulating free fatty acids and its accumulation as TG in the liver that are present in up to 80% of patients with NAFLD.⁹

Recent studies have pointed out that proteins that modulate lipoprotein metabolism might be important for the study of NAFLD similar to the cholesteryl ester transfer protein (CETP) that modifies lipoproteins composition by transferring cholesterol esters and TG among high-density lipoproteins cholesterol (HDL-cholesterol), low-density lipoproteins cholesterol (LDL-cholesterol) and very low-density lipoproteins cholesterol (VLDL-cholesterol). Therefore, serum CETP levels and single nucleotide polymorphisms (SNPs) in the gene that encodes it could be decisive in this pathology.^10,11

In this regard, the Taq1B CETP polymorphism, which is a transition from guanine (B1 allele) to adenine (B2 allele) at nucleotide 277 of the first intron,^12,13 has been associated with abnormal serum lipid values and could be also related to NAFLD.^11,14 Thus, we hypothesize that the Taq1B CETP polymorphism is associated with serum lipids, anthropometric variables, and the extent of steatosis in Mexican-mestizo women with gallstone disease (GD).

Materials and Methods

Study subjects

In this cross-sectional study, women from West Mexico were recruited from July 2016 to December 2017. A general medical screening by the medical personal was performed in subjects who attended the general surgery service and were diagnosed with GD through a biliary ultrasound who were scheduled for laparoscopic cholecystectomy surgery.

The inclusion criteria were mestizo women aged 18–60 years with a body mass index (BMI) ≥18.5 kg/m². Subjects were excluded if they had type 2 diabetes mellitus, liver, kidney, or pancreatic disease, or if they ingested oral contraceptives or any type of lipid lowering medication in the last year. Women who used drugs, tobacco, or ingested a significant amount of alcohol (>14 g/day) during the past year were also excluded.¹⁵ Pregnant or breastfeeding women were also excluded, as well as women with incomplete data. The selection of the participants was done through convenience sampling.

Anthropometric measurements

Anthropometric parameters were measured after 8–10 hr of fasting. Measurements were performed with light clothes and without shoes. Height measurement was determined using a stadiometer with a precision of 1 mm (Rochester Clinical Research, Inc., New York, NY). Waist circumference was measured according to International Society for the Advancement of Kinanthropometry method¹⁶ using a 2-mm measuring tape (Lufkin Executive^® Thinline, New Brighton, MN). Tetrapolar body electrical bioimpedance was used to assess body composition (InBody 370; Biospace Co., Seoul, Korea). BMI was calculated as weight in kilograms divided by height in meters squared (kg/m²).

Biochemical measurements

Blood samples were taken after 8–10 hr of fasting and then centrifuged to obtain the serum. Determinations of TG, total cholesterol, HDL-cholesterol, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase were carried out by dry chemistry using a Vitros 250 Analyzer (Ortho-Clinical Diagnostics, Johnson & Johnson Services Inc., Rochester, NY). LDL-cholesterol was calculated using the Friedewald formula as long as TG levels were <400 mg/mL.¹⁷ The cutoff points used to define alterations in lipid profile were: hypertriglyceridemia >150 mg/dL, hypercholesterolemia >200 mg/dL, low HDL-cholesterol <50 mg/dL, and elevated LDL-cholesterol >100 mg/dL.¹⁸ Serum CETP levels were measured by enzyme-linked immunosorbent assay with the kit STA-614 (Cell Biolabs, Inc., San Diego, CA).

Liver histology

During laparoscopic cholecystectomy, 1 cm² of liver tissue was taken ensuring hemostasis of the biopsied tissue. Then, the tissue was immediately transferred to the Histopathology Service of the Institution for analysis. The histological diagnosis was made by staining the liver biopsy with Oil-Red-O. Hepatic steatosis was defined as intrahepatic fat accumulation >5% of the hepatocytes (Supplementary Fig. S1).¹⁹ Once the tissue was analyzed, the main pathologist reported the data as well as a second pathologist considering that in case of having different diagnoses, the opinion of a third pathologist would be requested to decide the most appropriate diagnosis.

DNA extraction and genotyping

Genomic DNA was extracted from peripheral leukocytes using the High Pure PCR Template Preparation Kit (Roche Diagnostics, Indianapolis, IN). The Taq1B CETP polymorphism (rs708272) was determined by allelic discrimination using TaqMan^® probes (Drug Metabolism Assay, Applied Biosystems, Foster City, CA) in a LightCycler^® 96 Real-Time PCR System (Roche Diagnostics, Mannheim, Germany) under the following conditions: 95°C for 10 min, 40 cycles of denaturation at 95°C for 15 sec, and annealing/extension at 60°C for 1 min. The accuracy of Taq1B CETP genotyping was verified using positive controls of DNA samples corresponding to the three possible genotypes and negative controls in each 96-well plate assay. As a quality control measure, 20% of the samples were tested in duplicate, and the same result was obtained.

Statistical analysis

The sample size was calculated using a formula designed for studies where two means are compared,²⁰ based on data obtained from a study from Austria, where the mean and standard deviation for serum CETP levels were analyzed in subjects with genotype B1B1 versus B1B2/B2B2 (1.74 ± 0.73 vs. 1.46 ± 0.64 μg/mL, respectively) giving a total “n” of 18 subjects. The statistical power was of 80% and a level of confidence of 95%.²¹ The Shapiro–Wilk test was used to analyze normal distribution of the variables. Crude means between groups were compared using the Student's t-test or Mann–Whitney U test, as appropriate. The Hardy–Weinberg equilibrium was calculated using the chi-squared test. Subjects with one or two B2 allele were grouped together. Statistical analyses were done using the SPSS version 20.0 software (IBM Corp., Armonk, NY), and a P value <0.05 was considered statistically significant.

Ethical guidelines

Subjects were informed about the research procedures, and those who agreed to participate signed an informed consent. Besides, this study was approved by the Ethics Committee of our institute (Register No. 24/HCJIM-JAL/2016). All procedures were conducted in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki).²²

Results

Population description

Seventy-one patients were recruited, 9 were excluded because they were men; therefore, 62 subjects were included in this investigation (Fig. 1), with an average age of 38.60 ± 14.98 years. The anthropometric variables, serum lipids, CETP serum levels, and percentage of degree of steatosis is described in Table 1.

FIG. 1.

Flow diagram of study subjects.

Table 1.

Quantitative Variables in the Study Subjects and By Study Groups

Variables	All subjects (n = 62)	B1B1 (n = 18)	B1B2/B2B2 (n = 44)	P
Demographic and anthropometric variables
Age (years)	38.60 ± 14.98	37.65 ± 13.20	39.18 ± 15.44	0.723
BMI (kg/m²)	28.45 ± 5.90	27.73 ± 4.51	29.03 ± 6.40	0.466
WC (cm)	92.32 ± 11.84	90.86 ± 9.10	93.62 ± 12.77	0.482
Body fat (%)	39.88 ± 8.71	39.41 ± 9.61	40.66 ± 8.29	0.635
Biochemical variables
TG (mg/dL)	120.46 ± 53.04	128.68 ± 63.43	116.58 ± 47.96	0.458
TC (mg/dL)	172.32 ± 43.21	172.12 ± 31.36	172.41 ± 48.23	0.983
LDL (mg/dL)	104.90 ± 34.30	102.37 ± 25.90	106.08 ± 37.92	0.725
HDL (mg/dL)	37.36 ± 8.66	37 ± 5.98	37.52 ± 9.75	0.843
ALT (U/L)	37.45 ± 19.41	38.06 ± 10.63	37.29 ± 14.75	0.954
GGT (U/L)	59.45 ± 19.40	60.59 ± 15.56	59.57 ± 12.09	0.963
AST (U/L)	28.61 ± 15.62	25.12 ± 11.74	9.57 ± 17.39	0.522
CETP (μg/mL)	6.07 ± 3.82	5.58 ± 3.58	7.11 ± 3.48	0.262
Histopathological variables
Liver fat (%)	9.06 ± 17.91	2.19 ± 3.78	11.95 ± 20.61	0.008
NAFLD, n (%)	21 (38.9)	5 (28)	24 (53)	0.049

Statistically significant p-values are in bold.

Values are shown as mean ± SD. NAFLD was defined as hepatic steatosis (intrahepatic fat accumulation >5% of the hepatocytes) without chronic alcohol consumption.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; B1B1, wild homozygote for allele B1; B1B2/B2B2, heterozygous and homozygous for allele B2; BMI, body mass index; CETP, cholesteryl ester transfer protein; GGT, gamma-glutamyl transferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NAFLD, nonalcoholic fatty liver disease; SD, standard deviation; TC, total cholesterol; TG, triglycerides; WC, waist circumference.

The most prevalent dyslipidemia was low HDL-cholesterol (94%, n = 58) followed by elevated LDL-cholesterol (52%, n = 32), hypertriglyceridemia (28%, n = 17), and hypercholesterolemia (26%, n = 16). Likewise, the 38.9% (n = 21) had NAFLD.

Characteristics of study population according to Taq1B CETP Polymorphism

The B1B1 genotype was present in 31% (n = 19) of the study population, B1B2 in 44.9% (n = 28), and B2B2 in 24.1% (n = 15). When comparing the expected and observed genotypic frequencies, no significant differences were observed. This population was in Hardy–Weinberg equilibrium (P = 0.536). The allele frequency detected for the B1 allele was 53.2%, whereas for the B2 allele was 46.8%.

Comparisons were made between the groups with wild-type genotype B1B1 versus the group with polymorphic genotype B1B2/B2B2. Regarding to serum lipids and anthropometric characteristics, there were no significant differences between genotypes. Moreover, it was found that subjects with B1B2/B2B2 genotype had a higher percentage of degree of steatosis (P = 0.008). In addition, a higher prevalence of NAFLD was observed in this last group (P = 0.049) (Table 1).

Risk factors for NAFLD

To determine the risk variables associated with NAFLD an odds ratio (OR) was performed. It was observed that B1B2/B2B2 genotype (OR 3.90 [confidence interval {CI} 95% 1.891–8.536], P = 0.04) and elevated LDL-cholesterol (OR 3.54 [CI 95% 1.042–2.058], P = 0.039) significantly increases the risk to develop NAFLD. Likewise, a multivariable linear regression analysis was conducted, and it was demonstrated that 18% of the liver steatosis could be explained by the presence of high LDL-cholesterol and the B2B2 genotype (Table 2).

Table 2.

Linear Regression Model for Risk Factors Associated With Liver Steatosis (n = 62)

Model 1. Variables	B	ANOVA, P	R	R²
Elevated LDL	21.20
B1B2/B2B2 Taq1B CETP genotype	3.748	0.019	0.481	0.180

Statistically significant p-values are in bold.

ANOVA, analysis of variance; B, nonstandardized coefficient; B1B2/B2B2, heterozygous and homozygous polymorphic for allele B2; R, correlation coefficient; R ², determination coefficient.

Discussion

GD is one of the most prevalent gastrointestinal diseases, with a frequency in Western countries of 8.9% in men and 26.7% in women.^23,24 It has been widely described that GD mostly affects women due to hormonal factors, since estrogens increase the secretion of bile cholesterol, which causes a supersaturation of the bile and a greater formation of gallstones.²⁵ Therefore, only women were included in this investigation.

In contrast, NAFLD is a complex disease consequence of the dysfunction of several metabolic pathways. Few studies had suggested the association of NAFLD and GD because both entities share risk factors such as an altered lipid metabolism (uptake and storage, biosynthesis, and excretion).^26,27 This study found that Taq1B CETP polymorphism and elevated LDL-cholesterol are significant risk factors for NAFLD in women with GD.

It is noteworthy that in this research, 39% of patients with GD also had NAFLD. Similarly, a study with 161 subjects from Italy reported that 33.8% of NAFLD patients also had gallbladder stones.²⁸

As it was expected, low HDL-cholesterol and elevated LDL-cholesterol were highly prevalent in the study subjects; this is in agreement with studies carried out in Mexican population, where emphasizes that both dyslipidemias are the most prevalent in this population.^29,30 These data also match to those reported in a prospective cross-sectional study made in 50 patients from Pakistan, where they described a median for serum LDL-cholesterol of 118.40 (23.96) mg/dL and 29.54 (8.406) mg/dL for HDL-cholesterol in patients with GD.³¹

Moreover, in this study, higher serum CETP levels were found compared with other populations. In this sense, an average of 3.0 ± 0.83 μg/mL has been reported in Canadian population, 2.50 ± 0.67 μg/mL in subjects from Europe and 2.54 ± 0.60 μg/mL in Asian population.^32

–35 However, this could be explained in part, the fact that 90% of the study subjects had low HDL-cholesterol levels because it has been well established that CETP levels and its activity are inversely associated with serum HDL-cholesterol values.^{36

–45}

Related to Taq1B CETP polymorphism, our results are in agreement with an Iranian study that analyzed the distribution of genotypes in 200 subjects with metabolic syndrome, being the B1B2 genotype was the most prevalent with 55%, whereas for the genotypes B1B1 and B2B2 they found 31% and 14%, respectively.¹³ Our B1 and B2 allele distribution was 53.2% and 46.8%, respectively. This coincides with what was recently published in 215 Mexican subjects, where an allelic frequency of 51.6% for B1 and 48.4% for B2 was described.⁴⁶ Likewise, these data are in agreement with a study conducted in 480 women from the state of Guerrero, Mexico, where they reported a frequency of 49.3% for B1 and 50.7% for B2.⁴⁷

No differences were found in relation to lipid profile and anthropometry; however, a higher prevalence of NAFLD was found in subjects with the B1B2/B2B2 genotype, which to our knowledge has not been previously reported. Nevertheless, it is necessary to point out that other polymorphisms in CETP have been described, such as rs1800777, which has been associated with steatosis and lobular inflammation.⁴⁸ Subsequent statistical analyses confirmed that this genotype, in addition to elevated LDL-cholesterol, are risk factors for NAFLD.

Although Taq1B SNP is an intronic variant, it has been described in various populations, including Caucasians, that is in linkage disequilibrium with the −629 C/A SNP, a genetic variant located in the CETP promoter region, which has a negative effect in its transcriptional activity, it causes a repression of the expression up to 45%. Therefore, it has been concluded that B2 allele is associated with a better lipid profile. Although it has been suggested that B2 allele effect is beneficial as it has been associated with lower CETP serum levels and better lipid profile,^49

–52 this is still controversial since recent evidence has suggested that the effect could be modulated by numerous factors such as diet, physical activity, and the presence of co-morbidities and genetics.^14,46

In this regard, a meta-analysis found that the B2/B2 genotype is associated with a lower concentration/mass of CETP as well as a decrease in the activity, and with elevated levels of HDL-cholesterol, ApoA-1.¹² In fact, for each B2 allele inherited, carriers of the Taq1B variant had lower mean CETP mass (−9.7%; 95% CI −11.7% to −7.8%), lower mean CETP activity (−8.6%; 95% CI −13.0% to −4.1%) than B1/B1 carriers.¹² At this point, even though the main role of CETP described is at the circulatory level, mediating the transfer of lipids between plasmatic lipoproteins, it also acts locally in the hepatocyte.^53
–55

Thus, reducing CETP activity in the liver may be related to the development of NAFLD. According to in vivo studies conducted on diet-induced obese mice have shown that reducing CETP activity modified the control of several steps in liver metabolism: increased TG content, increased inflammation, and worsened insulin resistance.⁵³ Besides, other studies have shown that CETP transgenic expression reduces liver TG content by promoting lipid oxidation and VLDL-TG production in chow-fed female mice⁵⁴ and improve insulin sensitivity in high-fat diet mice.⁵⁵ Therefore, these studies suggested that the effects of CETP inhibition/restriction may be metabolically context dependent.⁵³ Thus, the Taq1B variant could contribute considerably to NAFLD when other environmental factors, such as insulin resistance, hypoadiponectinemia, reduced antioxidant intake,⁵⁶ overweight, obesity, or GD, are present.

It is an interesting finding that the group with the risk genotype (BIB2/B2B2) had a greater number of subjects with NAFLD compared with B1B1 despite the fact that higher CETP values in the B1B2/B2B2 group were not statistically significant, possibly if a greater number of subjects were included, differences in CETP serum protein values and in the lipid profile in the study groups would be observed in future studies. Likewise, it would also be interesting to quantify CETP liver protein values, to corroborate the negative correlation found by Palmisano et al of CETP and liver fat.⁵⁴

These data reinforce what is recently postulated about B2 allele could be considered as risky in subjects exposed to inadequate environmental factors, the presence of co-morbidities and, as found in this study, it could also be related to increased liver fat. However, more studies are needed with a larger population measuring CETP expression levels in liver tissue and its activity in serum, and the −629 C/A CETP SNP should also be measured in future research in this population. Likewise, other metabolic disturbances should be considered to clarify how the polymorphism increases the risk for NAFLD, and it would also be important to measure plasma lipoprotein subfractions. A limitation of this research is that other features of NASH could not be determined, such as inflammation and fibrosis.

Conclusions

This study suggests that the B1B2/B2B2 genotype of CETP and elevated LDL-cholesterol levels increase the risk for developing NAFLD in women with GD. These findings highlight the importance of the determination of genetic variants in the clinic practice.

Footnotes

Acknowledgments

The authors cordially thank the Universidad de Guadalajara, the Hospital Civil de Guadalajara “Dr. Juan I. Menchaca,” and the subjects who participated in this study.

Authors' Contributions

M.P.R., W.C.P., and J.J.R.V. collected, processed, and analyzed the data. E.M.N.M. and R.A.F.T. performed the statistical analysis. M.M.G., S.C.R.R., and B.R.M. were involved in planning and supervised the study. E.M.L. designed the study and implementation of the research, to the analysis of the results and article preparation. All authors read and approved the final article.

Availability of Data and Materials

The data sets used and/or analyzed during this study are available from the corresponding author on reasonable request.

Author Disclosure Statement

The authors declare that they have no competing interests.

Funding Information

This study was supported by the National Council of Science and Technology (CONACYT-PS-Salud-202540). The funding source was not involved in the study design, data collection, data analysis, interpretation, writing of the article, or decision to submit the article for publication.

Supplementary Material

Supplementary Figure S1

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