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YANG Jing Li, HUANG Jun Jun, CHENG Ning, ZHANG De Sheng, LIU Si Min, HUANG Wen Ya, LI Na, HUANG Pei Yao, DING Jiao, LIU Nian, BAO Kai Fang, DING Jie, CHEN Xiao Liang, ZHENG Tong Zhang, BAI Ya Na. Sex-specific and Dose-response Relationship between the Incidence of Gallstones and Components of the Metabolic Syndrome in Jinchang Cohort: A Prospective Study[J]. Biomedical and Environmental Sciences, 2020, 33(8): 633-638. doi: 10.3967/bes2020.084
Citation: YANG Jing Li, HUANG Jun Jun, CHENG Ning, ZHANG De Sheng, LIU Si Min, HUANG Wen Ya, LI Na, HUANG Pei Yao, DING Jiao, LIU Nian, BAO Kai Fang, DING Jie, CHEN Xiao Liang, ZHENG Tong Zhang, BAI Ya Na. Sex-specific and Dose-response Relationship between the Incidence of Gallstones and Components of the Metabolic Syndrome in Jinchang Cohort: A Prospective Study[J]. Biomedical and Environmental Sciences, 2020, 33(8): 633-638. doi: 10.3967/bes2020.084

Sex-specific and Dose-response Relationship between the Incidence of Gallstones and Components of the Metabolic Syndrome in Jinchang Cohort: A Prospective Study

doi: 10.3967/bes2020.084
Funds:  This work was supported by the Belt and Road Special Project of Lanzhou University [No.2018ldbrzd008]; the Natural Science Foundation of China [No.81673248]; and the National Major Infectious Disease Project-Follow-up Study of High-risk Population Cohort of Liver Cancer in Gansu Province [No.2018ZX10732202]
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  • Author Bio:

    YANG Jing Li, female, born in 1994, PHD, majoring in environmental epidemiology

  • Corresponding author: BAI Ya Na, Professor, Tel: 86-931-8915526; E-mail: baiyana@lzu.edu.cn
  • Received Date: 2019-08-30
  • Accepted Date: 2020-05-29
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  • [1] Lammer F, Gurusamy K, Ko CW, et al. Gallstones. Nat Revi Dis Primers, 2016; 2, 16024−40. doi:  10.1038/nrdp.2016.24
    [2] Sherling DH, Perumareddi P, Hennekens CH. Metabolic syndrome. J Cardiovas Phar Ther, 2017; 22, 365−7. doi:  10.1177/1074248416686187
    [3] Lao XQ, Zhang YH, Wong MC, et al. The prevalence of metabolic syndrome and cardiovascular risk factors in adults in southern China. BMC Public Health, 2012; 12, 64−71. doi:  10.1186/1471-2458-12-64
    [4] Zhou HC, Lai YX, Shan ZY, et al. Effectiveness of different waist circumference cut-off values in predicting metabolic syndrome prevalence and risk factors in adults in China. Biomed Environ Sci, 2014; 27, 325−34.
    [5] Rochlani Y, Pothineni NV, Mehta JL. Metabolic syndrome: does it differ between women and men? Cardiovas Drug Ther, 2015; 29, 329−38. doi:  10.1007/s10557-015-6593-6
    [6] Chen L, Qiao QH, Zhang SC, et al. Metabolic syndrome and gallstone disease. World J Gastroentero, 2012; 18, 4215−20. doi:  10.3748/wjg.v18.i31.4215
    [7] Bai Y, Yang A, Pu H, et al. Cohort profile: the China metal-exposed workers cohort study (Jinchang cohort). Inter J Epidemiol, 2017; 46, 1095−6e.
    [8] Lin IC, Yang YW, Wu MF, et al. The association of metabolic syndrome and its factors with gallstone disease. BMC Fam Pract, 2014; 15, 138−43. doi:  10.1186/1471-2296-15-138
    [9] Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation, 2009; 120, 1640−5. doi:  10.1161/CIRCULATIONAHA.109.192644
    [10] Stinton LM, Myers RP, Shaffer EA. Epidemiology of gallstones. Gastroenterol Clin North America, 2010; 39, 157−69, vii. doi:  10.1016/j.gtc.2010.02.003
    [11] Madura JA, Loomis RC, Harris RA, et al. Relationship of obesity to bile lithogenicity in man. Ann Surg, 1979; 189, 106−11. doi:  10.1097/00000658-197901000-00020
    [12] Shaffer EA, Small DM. Biliary lipid secretion in cholesterol gallstone disease. The effect of cholecystectomy and obesity. J Clin Invest, 1977; 59, 828−40. doi:  10.1172/JCI108705
    [13] Mathus-vliegen EM, Van Ierland-Leeuwen ML, et al. Determinants of gallbladder kinetics in obesity. Dig Dis Sci, 2004; 49, 9−16. doi:  10.1023/B:DDAS.0000011595.39555.c0
    [14] Han T, Zhang D, Fu Z, et al. Retinol-binding protein 4 as a risk factor for cholesterol gallstone formation. Mol Cell Biochem, 2013; 377, 219−27. doi:  10.1007/s11010-013-1587-9
    [15] Wang RC, Li GD, Zhang JL, et al. Clinical study on gallstones associated with metabolic syndrome based on turbidity toxicity theory. World J Integr Tradit West Med, 2019; 14, 695−9.
    [16] Guo S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol, 2014; 220, T1−t23. doi:  10.1530/JOE-13-0584
    [17] Liew PL, Wang W, Lee YC, et al. Gallbladder disease among obese patients in Taiwan. Obes Surg, 2007; 17, 383−90. doi:  10.1007/s11695-007-9068-4
    [18] Kovacs P, Kurtz U, Wittettenburg H. Hepatic insulin resistance ties cholesterol gallstone formation and the metabolic syndrome. Annals Hepatol, 2008; 7, 262−4. doi:  10.1016/S1665-2681(19)31861-7
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Sex-specific and Dose-response Relationship between the Incidence of Gallstones and Components of the Metabolic Syndrome in Jinchang Cohort: A Prospective Study

doi: 10.3967/bes2020.084
Funds:  This work was supported by the Belt and Road Special Project of Lanzhou University [No.2018ldbrzd008]; the Natural Science Foundation of China [No.81673248]; and the National Major Infectious Disease Project-Follow-up Study of High-risk Population Cohort of Liver Cancer in Gansu Province [No.2018ZX10732202]
  • Author Bio:

  • Corresponding author: BAI Ya Na, Professor, Tel: 86-931-8915526; E-mail: baiyana@lzu.edu.cn
YANG Jing Li, HUANG Jun Jun, CHENG Ning, ZHANG De Sheng, LIU Si Min, HUANG Wen Ya, LI Na, HUANG Pei Yao, DING Jiao, LIU Nian, BAO Kai Fang, DING Jie, CHEN Xiao Liang, ZHENG Tong Zhang, BAI Ya Na. Sex-specific and Dose-response Relationship between the Incidence of Gallstones and Components of the Metabolic Syndrome in Jinchang Cohort: A Prospective Study[J]. Biomedical and Environmental Sciences, 2020, 33(8): 633-638. doi: 10.3967/bes2020.084
Citation: YANG Jing Li, HUANG Jun Jun, CHENG Ning, ZHANG De Sheng, LIU Si Min, HUANG Wen Ya, LI Na, HUANG Pei Yao, DING Jiao, LIU Nian, BAO Kai Fang, DING Jie, CHEN Xiao Liang, ZHENG Tong Zhang, BAI Ya Na. Sex-specific and Dose-response Relationship between the Incidence of Gallstones and Components of the Metabolic Syndrome in Jinchang Cohort: A Prospective Study[J]. Biomedical and Environmental Sciences, 2020, 33(8): 633-638. doi: 10.3967/bes2020.084
  • Gallstones is a very common gastrointestinal disease, involving the formation of masses in the gall bladder or biliary tract, due to abnormally high concentrations of cholesterol or bilirubin in the bile[1]. There is a 10%–20% prevalence of gallstones worldwide, and > 20% of patients with gallstones show clinical symptoms, implying a substantial disease burden[1]. Metabolic syndrome (MS) comprises a series of cardiovascular risk factors, including obesity, abnormal lipid metabolism, high blood glucose or insulin resistance, and hypertension[2]. The prevalence of MS in China increased from 0–10% in 2002[3] to 24.2% in 2014[4]. The prevalence of MS ranges from 10% to 84% across the world, with nearly 30% of people in the United States and one in four in Europe having this syndrome[5].

    The association between gallstones and MS has been a focus of some studies recently. MS is known to be strongly associated with lifestyle, and if MS is proved to be related to gallstone, we may reduce the prevalence of gallstones through lifestyle interventions, and form the basis of primary prevention by lifestyle changes[6]. Many previous studies tried to clarify this association, but they might be carried out without sufficient evidence. First, some studies were conducted with cross-sectional designs. As we all know, cross-sectional designs may be insufficient to capture the direct links between MS and gallstones. Second, most of these studies did not exclude people with cholecystectomy. However, those people should be excluded due to a history of gallstones at baseline in the cohort. In addition, those people with cholecystectomy for other reasons will hardly develop gallstones, so they also should be excluded in order to prevent them from assigning to the control group mistakenly, which may cause a large bias. Third, the associations of gallstones with MS as a whole were evaluated, but not those with specific components of MS. Last but not least, most studies did not explore potential sex differences. Thus, there is a need for more appropriate study design and statistical methods to be adopted to assess these associations. Consequently, we aimed to conduct a prospective study using Jinchang Cohort, to determine the dose-response relationships between gallstones and MS and its components, and explore the potentially sex differences.

    This study used the Jinchang Cohort, established in June 2011, whose design and methods have been previously described in detail[7]. Because waist circumference (WC) data were collected from December 2012, this study included participants who entered the cohort after December 2012, making a total of 21,716. After excluding 620 individuals with missing data regarding the MS, 9,097 who were lost to follow-up, 976 with gallstones at baseline, and 477 who had undergone cholecystectomy, data from 10,419 participants remained to be analyzed in the present study.

    Cox regression analysis was used to determine the relationships of MS as a whole, specific components of the MS, and the number of components of the MS present, with the incidence of gallstones. Because the incidence of gallstones and the related risk factors differed between the sexes, HRs (95% CIs) were calculated separately for men and women. Two models were used in the analysis: Model 1 was unadjusted, whereas Model 2 was adjusted for age, smoking status, alcohol intake status, physical exercise, and mean monthly income. We also investigated the dose-response relationship between components of the MS and risk of gallstones using the stratified analysis method and the restricted cubic splines function (RCS). Statistical analysis of the data was performed using SPSS 20.0 (IBM Inc., Armonk, NY, USA) and SAS 9.4 (SAS Institute Inc. Cary, NC, USA) software, and graphic rendering using R 3.6.1.

    A total of 10,419 participants were included in this study, of whom 59.7% (6,223) were men and 40.3% (4,196) were women. Their mean age was 46.86 ± 13.74 years (Table 1). The adjusted HRs (95% CI) for gallstones were 7.92 (95% CI: 3.38–18.57) for women (Ptrend < 0.05) and 5.01 (95% CI: 2.65–9.48) for total population (Ptrend < 0.05) when five component of the MS were present, but this was not significant in men (Ptrend > 0.05) (Table 2). Indeed, many studies conducted around the world have found that MS has a greater impact on the risk of gallstones in women than in men [8]. The mechanism for this may involve sex hormones, because estrogen enhances hepatic synthesis and secretion of cholesterol, and progesterone can reduce the secretion of bile salts and affect gall bladder emptying, which leads to a higher incidence of gallstones[9].

    VariableAll participants (n = 10,419)
    Age (years), mean ± SD46.86 ± 13.74
    Gender, n (%)
     men6,223 (59.7)
     women4,196 (40.3)
    Average monthly income (yuan), n (%)
     < 1,000414 (4.0)
     1,000–1,9994,300 (41.3)
     2,000–4,9995,503 (52.8)
     ≥ 5,000202 (1.9)
    Smoking, n (%)
     yes4,499 (43.2)
     no5,920 (56.8)
    Drinking, n (%)
     yes2,392 (23.0)
     no8,027 (77.0)
    Physical exercise, n (%)
     yes8,608 (82.6)
     no1,811 (17.4)
    WC (cm), mean ± SD84.31 ± 10.34
    TG (mmol/L), mean ± SD1.91 ± 1.40
    HDL-C (mmol/L), mean ± SD1.37 ± 0.35
    SBP (mmHg), mean ± SD124.26 ± 20.12
    DBP (mmHg), mean ± SD78.38 ± 12.56
    FPG (mmol/L), mean ± SD5.30 ± 1.41
    Note. WC, Waist circumference; TG, Triglyceride; HDL-C, High density lipoprotein cholesterol; SBP, Systolic blood pressure; DBP, Diastolic blood pressure; FPG, Fasting plasma glucose; SD, standard deviation.

    Table 1.  The characteristics of participants in Jinchang cohort at baseline (2012–2013)

    No. of components Model 1*Model 2#
    HR (95% CI)PHR (95% CI)P
    Mennormal1.00 (Ref)1.00 (Ref)
    11.12 (0.50−2.52)0.7791.22 (0.54−2.77)0.630
    20.91 (0.40−2.05)0.8191.00 (0.44−2.28)0.995
    30.74 (0.32−1.70)0.4730.82 (0.35−1.92)0.641
    40.66 (0.25−1.74)0.4000.73 (0.28−1.95)0.533
    50.77 (0.20−2.95)0.7040.89 (0.23−3.46)0.871
    Ptrend> 0.05> 0.05
    Womennormal1.00 (Ref)---1.00 (Ref)---
    13.32 (1.47−7.51)0.0042.78 (1.22−6.33)0.015
    24.02 (1.82−8.90)0.0013.16 (1.41−7.08)0.005
    34.41 (1.99−9.79)< 0.0013.06 (1.36−6.92)0.007
    45.60 (2.49−12.56)< 0.0013.73 (1.63−8.55)0.002
    511.11 (4.82−25.61)< 0.0017.92 (3.38−18.57)< 0.001
    Ptrend< 0.05< 0.05
    Totalnormal1.00 (Ref)1.00 (Ref)
    12.13 (1.21−3.77)0.0092.21 (1.25−3.93)0.007
    22.17 (1.24−3.79)0.0072.25 (1.28−3.96)0.005
    32.11 (1.20−3.70)0.0102.16 (1.22−3.84)0.009
    42.53 (1.41−4.53)0.0022.53 (1.39−4.60)0.002
    54.94 (2.65−9.23)< 0.0015.01 (2.65−9.48)< 0.001
    Ptrend< 0.05< 0.05
      Note. *Model 1 was unadjusted for the confounding factors;
    #Model 2 was adjusted for age, smoking status, alcohol intake status, physical exercise, and mean monthly income. HR, Hazard ratio; CI, Confidence interval.

    Table 2.  HRs and 95% CIs for gallstones with the number of metabolic syndrome components in Jinchang cohort

    We found a nonlinear dose-response relationship between the risk of gallstones and WC across the cohort as a whole and in women specifically (Table 3 and Figure 1). In a previous survey conducted in China, the prevalence of obesity was 25%, and the author thought the more serious the obesity was, the higher the incidence of gallstones[10]. Studies have shown that obesity has been associated with more cholesterol. Cholesterol is excessively secreted from the liver into the bile due to the upregulation of HMG-CoA reductase activity among obese people[11]. In addition, reduced bile acid and phospholipid production in obese people may lead to more lithogenic bile. Furthermore, studies have found gallbladder capacity and residual volumes are higher in obese women, and their gallbladder motility is lower[12]. The above may explain the present finding.

    Figure 1.  The dose-response relationship between metabolic syndrome components and the hazard risk of gallstones among women in Jinchang cohort.

    IndexsMenWomenTotal population
    HR (95% CI)PHR (95% CI)PHR (95% CI)P
    WC (cm)< 70*________1.00 (Ref)1.00 (Ref)
    70–1.00 (Ref)2.06 (0.50−8.52)0.3182.74 (0.67−11.27)0.162
    80–1.19 (0.56−2.49)0.6553.83 (0.93−15.69)0.0635.23 (1.29−21.25)0.021
    90–1.34 (0.63−2.78)0.4376.84 (1.64−28.53)0.0087.48 (1.82−30.70)0.005
    ≥ 1000.98 (0.37−2.55)0.978________2.84 (0.60−13.57)0.191
    Ptrend0.910< 0.001< 0.001
    TG (mmol/L)< 1.41.00 (Ref)1.00 (Ref)1.00 (Ref)
    1.4–1.13 (0.60−2.12)0.7151.17 (0.77−1.77)0.4741.24 (0.88−1.76)0.218
    1.7–0.73 (0.32−1.67)0.4591.04 (0.64−1.69)0.8671.06 (0.70−1.60)0.780
    2.0–2.02 (1.09−3.77)0.0271.41 (0.88−2.26)0.1581.75 (1.20−2.54)0.040
    ≥ 2.30.83 (0.47−1.48)0.4231.37 (0.94−2.00)0.1001.29 (0.94−1.76)0.116
    Ptrend0.9420.0790.045
    HDL-C (mmol/L)< 0.81.00 (Ref)1.00 (Ref)1.00 (Ref)
    0.8–3.15 (0.39−25.65)0.2830.87 (0.29−2.59)0.8031.08 (0.44−2.67)0.872
    0.9–1.53 (0.18−13.09)0.6990.45 (0.16−1.24)0.1240.67 (0.27−1.64)0.375
    1.0–2.92 (0.38−22.23)0.3010.35 (0.13−0.90)0.0290.78 (0.34−1.78)0.557
    ≥ 1.11.89 (0.26−13.67)0.5290.28 (0.13−0.64)0.0030.56 (0.26−1.19)0.131
    Ptrend0.634< 0.0010.005
    SBP (mmHg)< 1001.00 (Ref)1.00 (Ref)1.00 (Ref)
    1001.28 (0.37−4.24)0.7122.29 (0.81−6.50)0.1182.07 (0.94−4.55)0.072
    1201.18 (0.36−3.88)0.7892.26 (0.82−6.26)0.1172.17 (1.00−4.69)0.050
    1400.55 (0.15−2.03)0.3722.73 (0.97−7.68)0.0572.13 (0.96−4.72)0.063
    ≥ 1600.93 (0.24−3.53)0.9115.44 (1.91−15.50)0.0023.79 (1.68−8.53)0.001
    Ptrend0.149< 0.0010.001
    DBP (mmHg)< 701.00 (Ref)1.00 (Ref)1.00 (Ref)
    701.09 (0.62−1.91)0.7741.23 (0.78−1.94)0.3841.22 (0.85−1.74)0.274
    800.35 (0.17−0.72)0.0051.26 (0.80−1.99)0.3270.90 (0.61−1.31)0.568
    900.63 (0.31−1.28)0.2031.65 (1.01−2.69)0.0451.25 (0.84−1.86)0.275
    ≥ 1000.40 (0.16−1.01)0.0521.70 (0.99−2.91)0.8481.21 (0.76−1.90)0.423
    Ptrend0.0050.0200.553
    FPG (mmol/L)< 4.51.00 (Ref)1.00 (Ref)1.00 (Ref)
    4.52.03 (0.78−5.27)0.1481.30 (0.66−2.56)0.4481.49 (0.86−2.59)0.157
    5.01.71 (0.65−4.57)0.2891.09 (0.55−2.16)0.8011.23 (0.70−2.14)0.481
    6.01.32 (0.45−3.91)0.6121.16 (0.56−2.37)0.6901.17 (0.64−2.13)0.605
    ≥ 6.01.21 (0.42−3.48)0.7281.50 (0.75−2.98)0.2521.43 (0.81−2.55)0.221
    Ptrend0.3450.3250.808
      Note. #Model 2 was adjusted for age, smoking status, alcohol intake status, physical exercise, and mean monthly income. *In the male population, no gallstones occurred when the waist circumference was less than 70 cm. In the female population, no gallstones occurred when the waist circumference was more than 100 cm.

    Table 3.  HRs and 95% CIs for gallstones with components of the metabolic syndrome in Jinchang cohort#

    In the present study, there was a positive linear dose-response relationship between the risk of gallstones and TG concentrations in total population and in women specifically (Table 3 and Figure 1). However, it is thought that the relationship between TG and gallstones is more complex. Some reports have suggested that supersaturated fatty acids may be produced in obese people with high TG concentrations, but it may also be that a high triglyceride concentration itself can reduce gall bladder contraction, which predisposes towards gallstone development[13]. Therefore, the relationship between gallstones and triglyceride must be confirmed in further studies.

    There was a negative linear dose-response relationship between the risk of gallstones and HDL-C in total population and in women specifically (Table 3 and Figure 1). Studies conducted in many western countries have shown that low HDL-C is associated with a high incidence of gallstones, which may be the result of the associations between low HDL-C and insulin resistance, and insulin resistance and gallstones[14]. Wang et al.[15] found that HDL-C concentration affects the treatment of gallstones; specifically, the higher the HDL-C concentration is, the more likely gallstones are to be treated successfully. HDL-C is mainly synthesized in the liver, which can help cholesterol that is from peripheral sources transported to the liver and metabolized into bile, in which form it is expelled from the body.

    Several studies have shown that hypertension is positively correlated with gallstones. Here, we show that this correlation is mainly the result of SBP, and that there is a positive linear dose-response relationship between the risk of gallstones and SBP in total population and in women specifically, but not in men (Table 3 and Figure 1). Insulin resistance might underpin this relationship between hypertension and gallstones[16], because it is associated with a higher rate of biliary cholesterol secretion, which promotes gallstone formation. Other studies have shown that a lower frequency of defecation is a risk factor for gallstones, and patients with hypertension may have more sympathetic nerve activity, which may inhibit defecation[17].

    Although in recent years many studies have demonstrated relationships between diabetes and gallstones, and multiple studies have shown associations between blood glucose or insulin resistance and gallstones, the present prospective study has shown a positive linear dose-response relationship between gallstones and FPG only in women (Figure 1). Hyperglycemia may promote gallstone formation through a few mechanisms. Firstly, hyperglycemia in rats is associated with the upregulation of foxo1, which promotes the excretion of cholesterol in bile[18]. Alternatively, hyperglycemia may be associated with an inhibition of bile secretion, impaired gall bladder contraction and motor function, and altered crystal nucleation and mucus secretion into the bile[6].

    In summary, metabolic syndrome is associated with a higher risk of gallstones with potential heterogeneities by sexes, and the risk of gallstones increased with the number of metabolic syndrome components. In addition, there was a dose-response relationship between WC, TG, HDL-C, SBP, FPG, and the risk of gallstones in women, but not in men. The findings emphasize the probable role of metabolic syndrome for gallstones, and call for more studies on the risk of gallstones in a sex-specific manner.

    We thank all study participants and staff of the Worker’s Hospital of the JNMC for their generous work, and the interviewers from the Department of Epidemiology and Health Statistics, School of Public Health, Lanzhou University. The authors also thank YANG Ai Min (Hong Kong Institute of Diabetes and Obesity, the Chinese University of Hong Kong) for his help in the data analysis.

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