Hostname: page-component-669899f699-2mbcq Total loading time: 0 Render date: 2025-04-25T06:41:37.429Z Has data issue: false hasContentIssue false
  • English
  • Français

PUFA and intrahepatic cholestasis of pregnancy: a two-sample Mendelian randomisation analysis

Published online by Cambridge University Press:  23 October 2024

Qiong Li Open the ORCID record for Qiong Li [Opens in a new window] ,
Xinchun Xu ,
Chenyang Zhao ,
Yonghong Wang ,
Xiaohu Chen ,
Miao Liu  and
Chaoyan Yue
Qiong Li
Affiliation:
Department of Obstetrics and Gynecology, The First People’s Hospital of Chenzhou, Chenzhou, People’s Republic of China
Xinchun Xu
Affiliation:
Department of Ultrasound, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, People’s Republic of China
Chenyang Zhao
Affiliation:
Department of Obstetrics and Gynecology, The First People’s Hospital of Chenzhou, Chenzhou, People’s Republic of China
Yonghong Wang
Affiliation:
Department of Obstetrics and Gynecology, The First People’s Hospital of Chenzhou, Chenzhou, People’s Republic of China
Xiaohu Chen
Affiliation:
Obstetrics and Gynecology Hospital of Fudan University, Shanghai, People’s Republic of China
Miao Liu*
Affiliation:
Department of Obstetrics and Gynecology, The First People’s Hospital of Chenzhou, Chenzhou, People’s Republic of China
Chaoyan Yue*
Affiliation:
Obstetrics and Gynecology Hospital of Fudan University, Shanghai, People’s Republic of China
*
*Corresponding authors: Miao Liu, email liumiao3567@163.com; Chaoyan Yue, email 20111250007@fudan.edu.cn
*Corresponding authors: Miao Liu, email liumiao3567@163.com; Chaoyan Yue, email 20111250007@fudan.edu.cn
Get access Rights & Permissions [Opens in a new window]

Abstract

This study aimed to explore the potential causal association between PUFA and the risk of intrahepatic cholestasis of pregnancy (ICP) using Mendelian randomisation (MR) analysis. A two-sample MR analysis was conducted utilising large-scale European-based genome-wide association studies summary databases. The primary MR analysis was carried out using the inverse variance-weighted (IVW) method, complemented by other methods such as MR-egger, weighted-median and weighted mode. Sensitivity analysis was also performed to validate the robustness of the findings. Results indicated a 31 % reduced risk of ICP for every 1 standard deviation (sd) increase in n-3 fatty acids levels (OR = 0·69, 95 % CI: 0·54, 0·89, P = 0·004) and in the ratio of n-3 fatty acids to total fatty acids (OR = 0·69, 95 % CI: 0·53, 0·91, P = 0·008). Conversely, there was a 51 % increased risk of ICP for every 1 sd increase in the ratio of n-6 fatty acids to n-3 fatty acids (OR = 1·51, 95 % CI: 1·20, 1·91, P < 0·001) and a 138 % increased risk for every 1 sd increase in the ratio of linoleic fatty acids to total fatty acids (OR = 2·38, 95 % CI: 1·55, 3·66, P < 0·001). The findings suggest that n-3 fatty acids may have a protective effect against the risk of ICP, while n-6 fatty acids and linoleic fatty acids could be potential risk factors for ICP. The supplementation of n-3 fatty acids, as opposed to n-6 fatty acids, could be a promising strategy for the prevention and management of ICP.

Keywords

PUFAIntrahepatic cholestasis of pregnancyMendelian randomisation analysis
Type
Research Article
Information
British Journal of Nutrition , Volume 132 , Issue 8 , 28 October 2024 , pp. 1022 - 1029
Check for updates
Copyright
© The Author(s), 2024. Published by Cambridge University Press on behalf of The Nutrition Society

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

Footnotes

†

These authors contribute equally to the research.

References

Williamson, C & Geenes, V (2014) Intrahepatic cholestasis of pregnancy. Obstet Gynecol 124, 120–133.CrossRefGoogle ScholarPubMed
Floreani, A, Caroli, D, Lazzari, R, et al. (2013) Intrahepatic cholestasis of pregnancy: new insights into its pathogenesis. J Maternal-Fetal Neonatal Med: Offic J Eur Assoc Perinatal Med, Fed Asia Oceania Perinatal Soc, Int Soc Perinatal Obstet 26, 1410–1415.CrossRefGoogle ScholarPubMed
Menżyk, T, Bator, M, Derra, A, et al. (2018) The role of metabolic disorders in the pathogenesis of intrahepatic cholestasis of pregnancy. Clin Exp Hepatol 4, 217–223.CrossRefGoogle ScholarPubMed
Downie, LE, Ng, SM, Lindsley, KB, et al. (2019) n-3 and n-6 polyunsaturated fatty acids for dry eye disease. Cochrane Database Syst Rev 2019 issue 12, CD011016.Google Scholar
Oh, DY, Talukdar, S, Bae, EJ, et al. (2010) GPR120 is an n-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698.CrossRefGoogle Scholar
Skulas-Ray, AC, Wilson, PWF, Harris, WS, et al. (2019) n-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association. Circulation 140, e673–e691.CrossRefGoogle ScholarPubMed
Jaca, A, Durão, S & Harbron, J (2020) n-3 fatty acids for the primary and secondary prevention of cardiovascular disease. S Afr Med J = Suid-Afrikaanse tydskrif vir geneeskunde 110, 1158–1159.Google ScholarPubMed
Calder, PC (2017) n-3 fatty acids and inflammatory processes: from molecules to man. Biochem Soc Trans 45, 1105–1115.CrossRefGoogle ScholarPubMed
Park, C, Choi, JE, Jin, Y, et al. (2019) Eicosapentaenoic acid and docosahexaenoic acid, but not α-linolenic acid, decreased low-density lipoprotein cholesterol synergistically with estrogen via regulation of cholesterol synthesis and clearance in ovariectomized rats. Nutr Res (New York, NY) 66, 13–21.CrossRefGoogle Scholar
Wu, Y, Ding, Y, Tanaka, Y, et al. (2014) Risk factors contributing to type 2 diabetes and recent advances in the treatment and prevention. Int J Med Sci 11, 1185–1200.CrossRefGoogle ScholarPubMed
Yan, JH, Guan, BJ, Gao, HY, et al. (2018) n-3 polyunsaturated fatty acid supplementation and non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Medicine 97, e12271.CrossRefGoogle ScholarPubMed
Dong, R, Ye, N, Zhao, S, et al. (2021) Studies on novel diagnostic and predictive biomarkers of intrahepatic cholestasis of pregnancy through metabolomics and proteomics. Front Immunol 12, 733225.CrossRefGoogle ScholarPubMed
Hu, YY, Liu, JC & Xing, AY (2015) Oxidative stress markers in intrahepatic cholestasis of pregnancy: a prospective controlled study. Eur Rev Med Pharmacol Sci 19, 3181–3186.Google ScholarPubMed
Davey Smith, G & Hemani, G (2014) Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 23, R89–98.CrossRefGoogle ScholarPubMed
Dixon, PH, Levine, AP, Cebola, I, et al. (2022) GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements. Nat Commun 13, 4840.CrossRefGoogle ScholarPubMed
Yavorska, OO & Burgess, S (2017) MendelianRandomization: an R package for performing Mendelian randomization analyses using summarized data. Int J Epidemiol 46, 1734–1739.CrossRefGoogle Scholar
Burgess, S & Thompson, SG (2017) Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol 32, 377–389.CrossRefGoogle ScholarPubMed
Bowden, J, Davey Smith, G, Haycock, PC, et al. (2016) Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol 40, 304–314.CrossRefGoogle ScholarPubMed
Zagkos, L, Dib, MJ, Pinto, R, et al. (2022) Associations of genetically predicted fatty acid levels across the phenome: a Mendelian randomisation study. PLoS Med 19, e1004141.CrossRefGoogle ScholarPubMed
Khalili, L, Valdes-Ramos, R & Harbige, LS (2021) Effect of n-3 (n-3) polyunsaturated fatty acid supplementation on metabolic and inflammatory biomarkers and body weight in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of RCTs. Metabolites 11, 742.CrossRefGoogle ScholarPubMed
Rivellese, AA, De Natale, C & Lilli, S (2002) Type of dietary fat and insulin resistance. Ann NY Acad Sci 967, 329–335.CrossRefGoogle ScholarPubMed
Acharya, P & Talahalli, RR (2019) Aging and hyperglycemia intensify dyslipidemia-induced oxidative stress and inflammation in rats: assessment of restorative potentials of ALA and EPA + DHA. Inflammation 42, 946–952.CrossRefGoogle ScholarPubMed
Jin, WY, Lin, SL, Hou, RL, et al. (2016) Associations between maternal lipid profile and pregnancy complications and perinatal outcomes: a population-based study from China. BMC Pregnancy Childbirth 16, 60.CrossRefGoogle ScholarPubMed
Ide, K, Koshizaka, M, Tokuyama, H, et al. (2018) n-3 polyunsaturated fatty acids improve lipoprotein particle size and concentration in Japanese patients with type 2 diabetes and hypertriglyceridemia: a pilot study. Lipids Health Dis 17, 51.CrossRefGoogle ScholarPubMed
Serhan, CN, Clish, CB, Brannon, J, et al. (2000) Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from n-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J Exp Med 192, 1197–1204.CrossRefGoogle ScholarPubMed
Isobe, Y, Arita, M, Iwamoto, R, et al. (2013) Stereochemical assignment and anti-inflammatory properties of the n-3 lipid mediator resolvin E3. J Biochem 153, 355–360.CrossRefGoogle Scholar
Serhan, CN, Hong, S, Gronert, K, et al. (2002) Resolvins: a family of bioactive products of n-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med 196, 1025–1037.CrossRefGoogle ScholarPubMed
Kasbi Chadli, F, Nazih, H, Krempf, M, et al. (2013) n 3 fatty acids promote macrophage reverse cholesterol transport in hamster fed high fat diet. PloS one 8, e61109.CrossRefGoogle ScholarPubMed
Zhao, J, Nishiumi, S, Tagawa, R, et al. (2020) Adrenic acid induces oxidative stress in hepatocytes. Biochem Biophys Res Commun 532, 620–625.CrossRefGoogle ScholarPubMed
Horas, HNS, Nishiumi, S, Kawano, Y, et al. (2017) Adrenic acid as an inflammation enhancer in non-alcoholic fatty liver disease. Arch Biochem Biophys 623–624, 64–75.CrossRefGoogle Scholar
Simopoulos, AP (2016) An increase in the n-6/n-3 fatty acid ratio increases the risk for obesity. Nutrients 8, 128.CrossRefGoogle Scholar
Puri, P, Wiest, MM, Cheung, O, et al. (2009) The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology 50, 1827–1838.CrossRefGoogle ScholarPubMed
Kirpich, IA, Feng, W, Wang, Y, et al. (2013) Ethanol and dietary unsaturated fat (corn oil/linoleic acid enriched) cause intestinal inflammation and impaired intestinal barrier defense in mice chronically fed alcohol. Alcohol (Fayetteville, NY) 47, 257–264.CrossRefGoogle ScholarPubMed
Warner, DR, Warner, JB, Hardesty, JE, et al. (2019) Decreased ω-6:ω-3 PUFA ratio attenuates ethanol-induced alterations in intestinal homeostasis, microbiota, and liver injury. J Lipid Res 60, 2034–2049.CrossRefGoogle ScholarPubMed
Zhou, Y, Khan, H, Xiao, J, et al. (2021) Effects of arachidonic acid metabolites on cardiovascular health and disease. Int J Mol Sci 22, 12029.CrossRefGoogle ScholarPubMed
Simopoulos, AP (2000) Human requirement for n-3 polyunsaturated fatty acids. Poultr Sci 79, 961–970.CrossRefGoogle ScholarPubMed
Ozler, A, Ucmak, D, Evsen, MS, et al. (2014) Immune mechanisms and the role of oxidative stress in intrahepatic cholestasis of pregnancy. Central-Eur J Immunol 39, 198–202.CrossRefGoogle ScholarPubMed
Licinio, J, Kling, MA & Hauser, P (1998) Cytokines and brain function: relevance to interferon-α-induced mood and cognitive changes. Semin Oncol 25, 30–38.Google ScholarPubMed