Introduction
Overweight and obesity have become a major public health challenge worldwide and have negative effects on various aspects of health and well-being [1]. The association of obesity/overweight (as measured by calculating factors such as body mass index [BMI], waist-to-hip ratio [WHR], or waist-to-height ratio [WHtR]), with the development of cardiovascular diseases including hypertension, diabetes, and hepatobiliary disorders has been reported in various studies [2–4]. Obesity is a known risk factor for gallstone disease (GSD). In Iran, the overall prevalence of obesity was reported to be about 22.3%, and the prevalence of overweight and obesity in northern Iran were 29.9% and 22.5%, respectively [7, 8]. Since the prevalence of obesity is high in northern Iran and no study has yet examined the relationship of obesity and overweight components with GSD in northern Iran, the present study aims to investigate the relationship between anthropometric indices and GSD in the PERSIAN Guilan Cohort Study (PGCS) population. 

Methods
This cross-sectional study that was conducted on the PGCS population (n=10,520) was carried out in other studies in 2024 [17, 18]. Individuals aged 35-70 years who resided in Guilan were included in the study, and deaf, blind, or disabled people who were unable to visit the cohort center, as well as patients with cognitive disorders such as dementia and mental retardation, were excluded from the study. Demographic and anthropometric information including age, gender, marital status, education level, occupation, residence, wealth status index (WSI), metabolic equivalent of task (MET), cigarette use, hookah use, drug use, alcohol use, BMI, WHR and WHtR were recorded. The WHtR index was evaluated in two groups: <0.5 and ≥0.5, based on the World Health Organization (WHO) definition [19].

Statistical analysis
Chi-square test was used to examine the relationship between obesity indices (as a qualitative variable) and GSD. The association between obesity indices (as a quantitative variable) and GSD was examined using simple logistic regression and multiple logistic regression analyses. The results of these analyses were presented using odds ratios (OR) at 95% confidence intervals (95% CI). A receiver operating characteristic (ROC) curve was also plotted to obtain the area under the curve (AUC), which is a criterion for evaluating the power of obesity indices in predicting GSD. To determine the optimal cutoff point, Youden’s index was used, which maximizes the specificity and sensitivity. Data were analyzed in SPSS software, version 16 and MedCalc software, version 19.4.1 and the significance level was set at 0.05.

Results
Participants’ demographic and clinical characteristics
The mean age of the participants was 51.52±8.90 years. Of the 10,520 individuals, 5,633(53.5%) were female, 9,527(90.6%) were married, 5,739(54.6%) were employed, and 4,613(43.8%) were urban residents. The mean years of education in the participants was 63.6±4.52 years; 1738(16.5%) were illiterate, 3312(31.5%) had primary education, 4832(45.9%) had high school education/diploma, and 638(6.1%) had university education. The mean BMI of the participants was 28.14±5.09 kg/m2; 141(1.3%) were underweight, 2746(26.1%) had normal weight, 4198(39.9%) were overweight, and 3435(32.7%) were obese. Moreover, 2,584 people (24.6%) were cigarette smokers, 1,515(14.4%) were hookah users, 726(6.9%) were substance users, and 1,395(13.3%) were alcohol users.

Association between obesity indices (as a qualitative variable) and GSD
Overall, the prevalence of GSD in underweight-normal, overweight, and obese individuals was 1.21, 1.62 and 3.32%, respectively. Overall, the incidence of GSD increased with increasing BMI (P<0.001). In women, a significant association was found (P<0.001), while in men there was no significant association between BMI and GSD (P=0.477). In terms of WHR, the overall prevalence of GSD was significantly higher in obese people than in non-obese people (21.2% vs. 0.97 %, P=0.004). In terms of WHtR, the overall prevalence of GSD was significantly higher in people with WHtR≥0.5 than in people with WHtR <0.5 (20.2% vs. 0.85, P=0.003).

Association between obesity indices (as a quantitative variable) and GSD
In the unadjusted model, the odds of GSD increased with increasing BMI in all participants (OR=1.08, 95% CI, 1.06%, 1.10%), such that for every one-unit increase in participants’ BMI, the odds of having GSD increased by 8%. This association remained significant after adjustment for some demographic variables (OR=1.05, 95% CI, 1.03%, 1.08%). In women, a statistically significant association was observed between BMI and GSD in univariate (OR=1.06, 95% CI, 1.03%, 1.09%) and multivariate (OR=1.06, 95% CI, 1.03%, 1.08%) analyses. In men, there were no significant associations between BMI and GSD in univariate or multivariate analyses (P>0.05).

The power of obesity indices in predicting GSD
Overall, the AUC was 0.630 (95% CI, 0.621%, 0.639%), 0.598 (95% CI, 0.589%, 0.608%) and 0.672 (95% CI, 0.663%, 0.681%) for BMI, WHR and WHtR indices, respectively. The cut-off point based on Youden’s J index for BMI was 29.48 (sensitivity: 57.6 and specificity: 63.7); for WHR was 0.96 (sensitivity: 67.3 and specificity: 51.3); and for WHtR was 0.61 (sensitivity: 76 and specificity: 51.7). According to the method proposed by DeLong et al., the power of WHtR in predicting GSD was significantly higher than that of BMI and WHR (P<0.001).

Conclusion
According to the results of this study, obese people showed the highest prevalence of GSD and the risk of developing GSD increased with increasing BMI, WHR, and WHtR, which indicates the impact of weight gain and obesity on the risk of developing physical and health problems. The power of WHtR was shown to be higher than that of BMI and WHR for predicting the risk of developing GSD. These results suggest that maintaining a healthy weight and controlling overweight and obesity can help prevent physical and health problems associated with GSD. However, to more accurately assess the impact of BMI, WHR, and WHtR on physical and health problems, further research is needed to examine other factors associated with these problems.

Ethical Considerations
Compliance with ethical guidelines
This study was approved by the Ethics Committees of the Guilan University of Medical Sciences, Rasht, Iran [Code: IR.GUMS.REC.1402.029]. Informed consent was obtained from all individual participants.

Funding
This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors.

Authors' contributions
Conceptualization, methodology, resources, supervision, and writing: Ahmad Alizadeh, Farahnaz Joukar, and Fariborz Mansour-Ghanaei; Investigation, and funding acquisition All authors. 

Conflicts of interest
The authors declared no conflict of interests.

Acknowledgements
The authors would like to express their special gratitude to all the staff of the Gastrointestinal and Liver Diseases Research Center in Rasht, Iran for their cooperation.


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