Impact of NAFLD-related SNPs on the carotid atherosclerosis development; a five-year prospective observational study

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 (GCKR, NCAN, and PNPLA3) 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 NCAN (rs2228603) T allele was associated with a lower incidence rate of carotid atherosclerosis (4.7 % in NCAN CT/TT genotype vs. 13.9 % in CC genotype; p = 0.04), and NCAN T allele carriers exhibited a favorable lipid profile. These associations were not altered by either recruiting area or obese. The GCKR T allele and PNPLA3 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.