Association of <b><i>PNPLA3</i></b> I148M with Liver Disease Biomarkers in Latinos

Abstract

Introduction. Liver disease accounts for approximately 2 million deaths per year worldwide. The majority of liver diseases are due to complications of cirrhosis, viral hepatitis, and hepatocellular carcinoma. Increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may indicate liver disease. Moreover, there are additional noninvasive liver fibrosis indices that help to estimate liver damage, including AST to ALT ratio, AST to platelet ratio index (APRI), fibrosis-4 (FIB-4) score, and nonalcoholic fatty liver disease (NAFLD) fibrosis score. The aims of the present study were to (1) perform an association analysis of the patatin-like phospholipase domain containing 3 (PNPLA3) I148M (rs738409) variant with ALT, AST, and various liver fibrosis indices, and (2) determine whether there are gender related-differences in these associations. Methods. We obtained demographic, anthropometric, and metabolic phenotypes from Latino adult participants (n = 503, 64% female, 36.4 ± 0.5 years) from the Arizona Insulin Resistance (AIR) registry. SNP genotyping of I148M was performed using the TaqMan allelic discrimination assay. We used linear regression for the association analyses of the genotypes with ALT, AST, and the various liver fibrosis indices. We included genotype, age, body mass index (BMI), and alcohol status in the linear regression model. Results. The variant I148M was in Hardy-Weinberg equilibrium, with genotype distribution: non-risk CC = 118, heterozygous CG = 246, and risk GG = 139. The G allele was significantly associated with increased ALT and AST levels (p = 7.8 x 10-7 and p = 9.7 x 10-6, respectively). Moreover, we showed that the G allele was significantly associated with higher APRI (p = 3.7 x 10-7) and FIB-4 score (p = 4.1 x 10-3). When we analyzed the data by gender, we observed similar significant trends for ALT, AST, and APRI (all, p &lt; 0.01). In females, the G allele was significantly associated with increased FIB-4 score (p = 6.9 x 10-3), which was not observed in the males (p &gt; 0.05). There was no association of the I148M variant with AST/ALT ratio nor NAFLD risk score, whether analyzed in all adults or by gender. Discussion/Conclusion. Our findings provide additional evidence of an association of PNPLA3 I148M with several liver disease biomarkers in male and female Latinos residing in the Southwest of the United States.

Impact of the PNPLA3 genotype on the risk of hepatocellular carcinoma after hepatitis C virus eradication

“…Our Kaplan‐Meier curves show that the PNPLA3 GG genotype increased de novo HCC in our female patients. Recent studies including Caucasian, African, and Latino patients have shown similar results: women with the PNPLA3 G‐allele had a significantly higher probability of steatosis or fibrosis than did men 26–28 . Although the mechanism remains unclear, the main hypothesis for this finding is that the effect of PNPLA3 may be amplified by an interaction with female sex hormones 29 .…”

“…In fact, despite steatosis having been proven to be a risk factor for HCC G-allele had a significantly higher probability of steatosis or fibrosis than did men. [26][27][28] Although the mechanism remains unclear, the main hypothesis for this finding is that the effect of PNPLA3 may be amplified by an interaction with female sex hormones. 29 In a study of CHC patients who achieved SVR before or after the application of a DAA, Miki et al reported that the PNPLA3 CG/GG genotype increased de novo HCC in the absence of metabolic disorders associated with HCC, such as obesity and diabetes.…”

Racial and ethnic disparities in metabolic dysfunction-associated steatotic liver disease

“…The PNPLA3 I148M allele is found most commonly in Hispaniic individuals, then European individuals, and then non-Hispanic Black individuals [42,43] Within Hispanic populations, the PNPLA3 I148M allele is associiated with elevated levels of AST, ALT, FIB-4 score, and increased risk of MASLD [44][45][46][47][48] The frequency of the PNPLA3 I148M allele varies among Hispanicc groups, with Mexican individuals having the highest frequency, followed by South Americans, Central Americans, Puerto Ricans, Cubans, and lastly Dominicans [48] Within Hispanic populations, low plasma concentrations of very long chain n-3 polyunsaturated fatty acids and very long chain saturated fatty acids are rongly associated with advanced liver fibrosis [51,52] There is a positive association between exposures including arsenic and mercury and risk of MASLD, with the highest exposure seen among Mexican Americans and those of Hispanic ethnicity [58,59] Behavioral risk factors, including high-fat, high-carbohydrate diet and sedentary behavior, are risk factors for all populations to develop MASLD,regardless of race and ethnicity polymorphisms associated with MASLD risk and progression. The most notable single nucleotide polymorphism (SNP) associated with MASLD is the gene that codes for PNPLA3.…”

“…The 1,000 Genomes Project Study, published in 2015, utilized whole-genome sequencing in 2,504 individuals from 26 populations and found that the distribution of the PNPLA3 I148M allele varies globally, with the M variant being most common in populations of Hispanic and East Asian ancestry [43] . Multiple studies support that the PNPLA3 I148M allele (rs738409) variant is associated with increased levels of ALT, AST, and FIB-4 score in Hispanic individuals, including a study of 503 Hispanic adult participants from the Arizona Insulin Resistance (AIR) registry and a study published in 2023 of 8,739 adult Hispanic participants from the BioMe biobank [44,45] .…”

Research of <i>PNPLA3</i> I148M Gene Polymorphism in Patients with Non-Alcoholic Fatty Liver Disease, with Liver Cirrhosis and with Hepatocellular Carcinoma

“…Развитие НАЖБП исследователи связывают с рядом однонуклеотидных полиморфизмов, в частности выявлена связь полиморфизма гена PNPLA3 (patatin like phospholipase domain containing 3) p.I148M (rs738409 C>G) с развитием стеатоза [4]. Более частое развитие ГЦР также может указывать на вероятную связь полиморфизма гена PNPLA3 и ГЦР на фоне НАЖБП [5]. Особое внимание обращается на носительство минорного аллеля G как на фактор риска развития агрессивных форм течения НАЖБП [6].…”