Differential effects of genetic polymorphism on comorbid disease in metabolic dysfunction-associated steatotic liver disease

Yuya Seko; Kanji Yamaguchi; Toshihide Shima; Michihiro Iwaki; Hirokazu Takahashi; Miwa Kawanaka; Saiyu Tanaka; Yasuhide Mitsumoto; Masato Yoneda; Atsushi Nakajima; Takeshi Okanoue; Yoshito Itoh

doi:10.1016/j.cgh.2024.02.031

Differential effects of genetic polymorphism on comorbid disease in metabolic dysfunction-associated steatotic liver disease

Clin Gastroenterol Hepatol. 2024 Apr 9:S1542-3565(24)00311-2. doi: 10.1016/j.cgh.2024.02.031. Online ahead of print.

Authors

Affiliations

¹ Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-chou, Kamigyou-ku, Kyoto, 602-8566, Japan.
² Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, 1-2 Kawazonocho, Suita, 564-0013, Japan.
³ Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
⁴ Liver Center, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
⁵ General Internal Medicine 2, General Medical Center, Kawasaki Medical School, 2-6-1 Nakasange, Kita-ku, Okayama, 700-8505, Japan.
⁶ Center for Digestive and Liver Diseases, Nara City Hospital, 1-50-1 Higashi-kideratyo, Nara, 630-8305, Japan.
⁷ Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, 1-2 Kawazonocho, Suita, 564-0013, Japan. Electronic address: okanoue@suita.saiseikai.or.jp.

PMID: 38604296
DOI: 10.1016/j.cgh.2024.02.031

Abstract

Background & aims: PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567 have been associated with an increased risk of liver-related events (LRE) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we investigated the combined effects of these variants on LRE.

Methods: The longitudinal multicenter cohort study enrolled 1178 patients with biopsy-proven MASLD. We calculated the genetic risk of hepatic fibrosis and LRE according to the impact of these variants.

Results: Patients with genetic fibrosis scores of 2, 3, and 4 or 5 were at greater risk than were patients with scores of 0 or 1, with odds ratios of 2.45 (95% confidence interval [CI] 1.27-4.74), 2.14 (95% CI 1.17-3.94), and 2.54 (95% CI 1.35-4.77), respectively. Multivariate analysis revealed that PNPLA3 and TM6SF2, but not HSD17B13, were significantly associated with LRE development. The hazard ratio (HR) of the genetic high-risk group for LRE was 1.91 (95% CI 1.20-3.04). The higher risk of LRE development in the genetic high-risk group was also seen in patients with F ≥ 3 or FIB-4 index > 2.67. The HRs of the genetic high-risk group for LRE were greater in patients without obesity, without diabetes, and of younger age compared with patients with obesity, with diabetes, or of older age, respectively.

Conclusions: This combination of MASLD-related genetic variants is useful for predicting LRE in Japanese patients with MASLD. The genetic risk according to these variants is useful for LRE risk assessment, especially in patients without metabolic risk factors or in younger patients in Japan.

Keywords: HCC; HSD17B13; MASLD; PNPLA3; TM6SF2.