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. 2023 Jun 7:14:1160312.
doi: 10.3389/fimmu.2023.1160312. eCollection 2023.

Lipids, lipid-lowering agents, and inflammatory bowel disease: a Mendelian randomization study

Heqing Tao  1 , Zhou Yu  2 , Yongqiang Dong  3 , Ligang Liu  4 , Liang Peng  1 , Xueqing Chen  1
Affiliations

Lipids, lipid-lowering agents, and inflammatory bowel disease: a Mendelian randomization study

Heqing Tao et al. Front Immunol. .

Abstract

Background: To assess the causal role of lipid traits and lipid-lowering agents in inflammatory bowel disease (IBD).

Methods: Univariable mendelian randomization (MR) and multivariable MR (MVMR) analyses were conducted to evaluate the causal association between low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and IBD. Drug-targeted MR analyzed the effects of lipid-lowering drugs on IBD, and network MR was used to analyze potential mediation effects.

Results: The levels of HDL-C had an inverse relationship with the risk of Crohn's disease (CD, OR: 0.85, 95% CI: 0.73-0.98, P = 0.024). In MVMR, the inverse relationships were found in all three outcomes. Drug-targeted MR analyses showed that with one-SD LDL-C decrease predicted by variants at or near proprotein convertase subtilisin/kexin type 9 (PCSK9), the OR values of people diagnosed with IBD, ulcerative colitis (UC) and CD were 1.75 (95%CI: 1.13-2.69, P = 0.011), 2.1 (95%CI: 1.28-3.42, P = 0.003) and 2.24 (95%CI: 1.11-4.5, P = 0.024), respectively. With one-SD LDL-C decrease predicted by variants at or near cholesteryl ester transfer protein (CETP), the OR value of people diagnosed with CD was 0.12 (95%CI: 0.03-0.51, P = 0.004). Network-MR showed that HDL-C mediated the causal pathway from variants at or near CETP to CD.

Conclusion: Our study suggested a causal association between HDL-C and IBD, UC and CD. Genetically proxied inhibition of PCSK9 increased the risk of IBD, UC and CD, while inhibition of CETP decreased the risk of CD. Further studies are needed to clarify the long-term effect of lipid-lowering drugs on the gastrointestinal disorders.

Keywords: CTEP 2; Mendelian randomization; PCSK9; inflammatory bowel disease; lipid-lowering; lipids.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Overview of the study design. GWAS, genome-wide association study; IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn’s disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; IVW, inverse-variance weighted; RAPS, MR robust adjusted profile score; HMGCR, 3-Hydroxy-3-Methylglutaryl-CoA Reductase; NPC1L1, NPC1 Like Intracellular Cholesterol Transporter 1; PCSK9, Proprotein convertase subtilisin/kexin type 9; APOB, Apolipoprotein B; CETP, Cholesteryl ester transfer protein; GLGC, Global Lipid Genetics Consortium; MR, Mendelian randomization.
Figure 2
Figure 2
Univariable Mendelian randomization results using different methods. (A) IBD; (B) UC; (C) CD. IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn’s disease; SNP N, number of single nucleotide polymorphisms; OR, odds ratio; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; IVW, inverse-variance weighted; RAPS, MR robust adjusted profile score.
Figure 3
Figure 3
(A) Multivariable Mendelian randomization results using the inverse-variance weighted method. (B) Network-MR diagram of CETP and CD. IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn’s disease; SNP N, number of single nucleotide polymorphisms; OR, odds ratio; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; CETP, Cholesteryl ester transfer protein, →, causal association; – – – –, no causal association.
Figure 4
Figure 4
Drug target Mendelian randomization results. IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn’s disease; SNP N, number of single nucleotide polymorphisms; OR, odds ratio; CI, confidence interval; HMGCR, 3-Hydroxy-3-Methylglutaryl-CoA Reductase; NPC1L1, NPC1 Like Intracellular Cholesterol Transporter 1; PCSK9, Proprotein convertase subtilisin/kexin type 9; APOB, Apolipoprotein B; CETP, Cholesteryl ester transfer protein.
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References

    1. Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. . Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet (2017) 390:2769–78. doi: 10.1016/s0140-6736(17)32448-0 - DOI - PubMed
    1. Sappati Biyyani RS, Putka BS, Mullen KD. Dyslipidemia and lipoprotein profiles in patients with inflammatory bowel disease. J Clin Lipidol (2010) 4:478–82. doi: 10.1016/j.jacl.2010.08.021 - DOI - PubMed
    1. Koutroumpakis E, Ramos-Rivers C, Regueiro M, Hashash JG, Barrie A, Swoger J, et al. . Association between long-term lipid profiles and disease severity in a Large cohort of patients with inflammatory bowel disease. Dig Dis Sci (2016) 61:865–71. doi: 10.1007/s10620-015-3932-1 - DOI - PubMed
    1. Liu Z, Tang H, Liang H, Bai X, Zhang H, Yang H, et al. . Dyslipidaemia is associated with severe disease activity and poor prognosis in ulcerative colitis: a retrospective cohort study in China. Nutrients (2022) 14. doi: 10.3390/nu14153040 - DOI - PMC - PubMed
    1. Voutilainen M, Hutri-Kähönen N, Tossavainen P, Sipponen T, Pitkänen N, Laitinen T, et al. . Low childhood high density lipoprotein cholesterol levels and subsequent risk for chronic inflammatory bowel disease. Dig Liver Dis (2018) 50:348–52. doi: 10.1016/j.dld.2018.01.121 - DOI - PubMed

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Grants and funding

This study was supported in part by a grant from the Guangdong Natural Science Foundation(2018A030313970) and (2021A1515110491) managed by LP and HT, National Natural Science Foundation of the P.R. China (81900521) and Programs for Science and Technology Development of Henan province (SBJ202003033) managed by YD. The funders of the study had no role in the study design, data collection, analysis, interpretation, writing of the report, or decision to submit for publication.