Reply
Authors: Fei Wang, Jing Wang, Yaru Li, Jing Yuan, Ping Yao, Sheng Wei, Huan Guo, Xiaomin Zhang, Handong Yang, Tangchun Wu, Meian He
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. We appreciate the comments by Dr. Danford and Dr. Ezaz on our article,1 which discussed three issues regarding the study's design. First, an experimental study has demonstrated the important role of hepatic insulin resistance in the development of gallstone disease (GSD) by increasing the expression of ATP binding cassette subfamily G member 5 and ATP binding cassette subfamily G member 8,2 and epidemiological studies, including the present cohort study,1 have consistently indicated the positive association between GSD and type 2 diabetes (T2D), which is independent of other conventional risk factors.3 Thus, we conducted this study to test whether the causal association between GSD and T2D existed or not. For the pleiotropy of CYP8B1, we further conducted a sensitivity analysis by exclusion of the single‐nucleotide polymorphisms (SNPs) in Cytochrome P450 Family 8 Subfamily B Member 1 when calculation of the genetic risk score (GRS) and the results did not materially change (Table 1). Table 1 - Association of GSD‐Related GRS With GSD and Diabetes Risk Without SNP rs6782601 in CYP8B1 GRS Effect Size on GSD Observed Association With Diabetes Expected Association With Diabetes Observed Association With Diabetes Adjusted for GSD Beta OR (95% CI) P * Beta OR (95% CI) P * OR (95% CI) P † OR (95% CI) P Unweighted GRS 0.147 1.16 (1.11‐1.21) 5.08E‐11 0.017 1.02 (0.98‐1.06) 0.41 1.034 (1.034‐1.034) 0.42 1.01 (0.97‐1.05) 0.59 Weighted GRS 0.995 2.70 (2.03‐3.60) 1.20E‐11 0.162 1.18 (0.90‐1.54) 0.24 1.257 (1.257‐1.257) 0.63 1.13 (0.86‐1.48) 0.09 *Adjusted for age, sex, marital, education, smoking, drinking, physical activity, hypertension, hyperlipidemia, CHD, stroke, and BMI.†P value for difference between expected and observed association with diabetes.Abbreviations: BMI, body mass index; CHD, coronary heart disease; CI, confidence interval; OR, odds ratio. Second, considering the limited number of genome‐wide association studies (GWAS) conducted especially in Asian populations, we selected SNPs mainly based on the findings from GWAS conducted in Europeans. Large‐scale genome‐wide transancestry meta‐analysis indicated that there was directional consistency of weak disease risk alleles across ancestry groups for diseases such as T2D4 and hypertension.5 Analogously, we selected eight SNPs in the corresponding gene found in Europeans to construct the instrumental variable. Corresponding proxy SNPs were selected by the criteria of minor allele frequency >0.01 and the smallest P value in the same gene. As the authors indicated, overfitting might potentially exist. However, even with potentially overfitting data, we did not detect a causal association between GSD and T2D risk. Finding more GSD‐related loci specific to an Asian population to construct the GRS was warranted. Third, we agreed with the authors that one should be cautious in drawing conclusions about the null causal associations of GSD with T2D, as we discussed in the “Strengths and Limitations” of our original article.1 Although our article investigated this issue, the small contribution of the GRS to the variation of GSD risk and the relatively small sample size in the Mendelian randomization analysis limited us from drawing any solid conclusion. Further large‐scale studies with more loci identified are warranted to examine the causal associations.