Impact of NAFLD-related SNPs on the Carotid Atherosclerosis Development; a Five-year Prospective Observational Study

Overview

Journal Atheroscler Plus

Date 2025 Jan 13

PMID 39802653

Authors

Hiroaki Ikezaki

Ryoko Nakashima

Yuji Matsumoto

Azusa Ohta

Sho Yamasaki

Satoshi Hiramine

Koji Takayama

Eiichi Ogawa

Masayuki Murata

Norihiro Furusyo

Jun Hayashi

Nobuyuki Shimono

Ernst J Schaefer

Affiliations

Soon will be listed here.

Abstract

Background And Aims: The prevalence of metabolic dysfunction associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), has become a significant public health concern with an increased atherosclerotic cardiovascular disease risk. This study investigates the impact of NAFLD-related single nucleotide polymorphisms (SNPs) on carotid atherosclerosis development in a Japanese population without diabetes, dyslipidemia, and hypertension.

Methods: The prospective observational study, part of the Kyushu and Okinawa Population Study (KOPS), included 945 participants (median age 55 [47, 63]) without carotid atherosclerosis, increased alcohol intake, diabetes, dyslipidemia, hypertension, or chronic hepatitis at baseline. NAFLD-related SNPs (, , ) were genotyped, and carotid intima-media thickness (cIMT) was measured using ultrasonography. Univariate and multivariate regression analyses were performed to assess the association of NAFLD-related SNPs on newly developed carotid atherosclerosis over five years.

Results: After five years, 125 (13.2 %) participants developed carotid atherosclerosis. The (rs2228603) T allele was associated with a lower incidence rate of carotid atherosclerosis (4.7 % in CT/TT genotype vs. 13.9 % in CC genotype; p = 0.04), and T allele carriers exhibited a favorable lipid profile. These associations were not altered by either recruiting area or obese. The T allele and C allele were associated with low carotid atherosclerosis development rates but were not significant.

Conclusions: Our results suggested that some NAFLD-related SNPs may influence atherosclerosis through lipid metabolism among Japanese individuals without metabolic syndrome.

References

Ikezaki H, Furusyo N, Nakashima R, Umemoto M, Yamamoto K, Matsumoto Y . Kyushu and Okinawa Population Study (KOPS): a large prospective cohort study in Japan. BMJ Open. 2021; 11(12):e053763. PMC: 8693098. DOI: 10.1136/bmjopen-2021-053763. View

Duell P, Welty F, Miller M, Chait A, Hammond G, Ahmad Z . Nonalcoholic Fatty Liver Disease and Cardiovascular Risk: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol. 2022; 42(6):e168-e185. DOI: 10.1161/ATV.0000000000000153. View

Gorden A, Yang R, Yerges-Armstrong L, Ryan K, Speliotes E, Borecki I . Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity. Hum Hered. 2013; 75(1):34-43. PMC: 3864002. DOI: 10.1159/000346195. View

Lin H, Wong G, Whatling C, Chan A, Leung H, Tse C . Association of genetic variations with NAFLD in lean individuals. Liver Int. 2021; 42(1):149-160. DOI: 10.1111/liv.15078. View

Wu M, Yuan C, Lu L, An B, Xuan S, Xin Y . Role of NCAN rs2228603 polymorphism in the incidence of nonalcoholic fatty liver disease: a case-control study. Lipids Health Dis. 2016; 15(1):207. PMC: 5124242. DOI: 10.1186/s12944-016-0367-4. View

Deng G, Yin R, Guan Y, Liu C, Zheng P, Wei B . Association of the SNPs and gene-gene and gene-environment interactions with serum lipid levels. Aging (Albany NY). 2020; 12(12):11893-11913. PMC: 7343441. DOI: 10.18632/aging.103361. View

Oniki K, Saruwatari J, Izuka T, Kajiwara A, Morita K, Sakata M . Influence of the PNPLA3 rs738409 Polymorphism on Non-Alcoholic Fatty Liver Disease and Renal Function among Normal Weight Subjects. PLoS One. 2015; 10(7):e0132640. PMC: 4511733. DOI: 10.1371/journal.pone.0132640. View

Saeed A, Feofanova E, Yu B, Sun W, Virani S, Nambi V . Remnant-Like Particle Cholesterol, Low-Density Lipoprotein Triglycerides, and Incident Cardiovascular Disease. J Am Coll Cardiol. 2018; 72(2):156-169. PMC: 6051722. DOI: 10.1016/j.jacc.2018.04.050. View

Krawczyk M, Liebe R, Lammert F . Toward Genetic Prediction of Nonalcoholic Fatty Liver Disease Trajectories: PNPLA3 and Beyond. Gastroenterology. 2020; 158(7):1865-1880.e1. DOI: 10.1053/j.gastro.2020.01.053. View

10.

Rinella M, Lazarus J, Ratziu V, Francque S, Sanyal A, Kanwal F . A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023; 79(6):1542-1556. DOI: 10.1016/j.jhep.2023.06.003. View

11.

Petta S, Valenti L, Marchesini G, Di Marco V, Licata A, Camma C . PNPLA3 GG genotype and carotid atherosclerosis in patients with non-alcoholic fatty liver disease. PLoS One. 2013; 8(9):e74089. PMC: 3775795. DOI: 10.1371/journal.pone.0074089. View

12.

Cichon S, Muhleisen T, Degenhardt F, Mattheisen M, Miro X, Strohmaier J . Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder. Am J Hum Genet. 2011; 88(3):372-81. PMC: 3059436. DOI: 10.1016/j.ajhg.2011.01.017. View

13.

Schaefer E, Ikezaki H, Diffenderfer M, Lim E, Liu C, Hoogeveen R . Atherosclerotic cardiovascular disease risk and small dense low-density lipoprotein cholesterol in men, women, African Americans and non-African Americans: The pooling project. Atherosclerosis. 2023; 367:15-23. DOI: 10.1016/j.atherosclerosis.2023.01.015. View

14.

Nischalke H, Lutz P, Kramer B, Sohne J, Muller T, Rosendahl J . A common polymorphism in the NCAN gene is associated with hepatocellular carcinoma in alcoholic liver disease. J Hepatol. 2014; 61(5):1073-9. DOI: 10.1016/j.jhep.2014.06.006. View

15.

Ikezaki H, Furusyo N, Yokota Y, Ai M, Asztalos B, Murata M . Small Dense Low-Density Lipoprotein Cholesterol and Carotid Intimal Medial Thickness Progression. J Atheroscler Thromb. 2020; 27(10):1108-1122. PMC: 7585909. DOI: 10.5551/jat.54130. View

16.

Riazi K, Azhari H, Charette J, Underwood F, King J, Afshar E . The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022; 7(9):851-861. DOI: 10.1016/S2468-1253(22)00165-0. View

17.

Escarceller M, Estivill X, Sumoy L . Cloning of the novel gene TM6SF1 reveals conservation of clusters of paralogous genes between human chromosomes 15q24-->q26 and 19p13.3-->p12. Cytogenet Cell Genet. 2000; 90(3-4):255-60. DOI: 10.1159/000056784. View

18.

Speliotes E, Yerges-Armstrong L, Wu J, Hernaez R, Kim L, Palmer C . Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011; 7(3):e1001324. PMC: 3053321. DOI: 10.1371/journal.pgen.1001324. View

19.

Holmen O, Zhang H, Fan Y, Hovelson D, Schmidt E, Zhou W . Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet. 2014; 46(4):345-51. PMC: 4169222. DOI: 10.1038/ng.2926. View

20.

Yanase T, Nasu S, Mukuta Y, Shimizu Y, Nishihara T, Okabe T . Evaluation of a new carotid intima-media thickness measurement by B-mode ultrasonography using an innovative measurement software, intimascope. Am J Hypertens. 2006; 19(12):1206-12. DOI: 10.1016/j.amjhyper.2006.05.010. View