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[42]
individuals of European descent, and least common in non-Hispanic Black individuals . This same study
found that another gene variant of PNPLA3, rs6006460, which results in the accumulation of less hepatic fat
than average, was expressed in 10 percent of Black individuals compared to less than 1 percent in White or
Hispanic individuals. Thus, this variant of PNPLA3 may play a role in non-Hispanic Black populations
having a lower observed prevalence of MASLD.

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,
[43]
with the M variant being most common in populations of Hispanic and East Asian ancestry . 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] . A study from 2019 specifically examined Mexican-American individuals and
found that multiple variants of the PNPLA3 gene including rs4823173, rs2896019, and rs228113 were
associated with elevations in ALT and AST, thus highlighting a role for other variants of PNPLA3 .
[46]
Rutledge et al. additionally found that of all the individuals, those with ancestry from Ecuador and Mexico
had the highest outpatient ALT, AST, and FIB-4 values, and these were the same individuals who had the
[45]
highest frequency of the PNPLA3 I148M allele variant . Walker et al. utilized an electronic health records
dataset of more than 27,000 individuals with genetic data from a multiethnic biobank and found that the
PNPLA3 I148M allele variant was associated with increased risk of MASLD and earlier age of MASLD
diagnosis, with both phenomena having the strongest effects within Hispanic individuals . Thus, these
[47]
studies confirm that Hispanic individuals with this variant are significantly vulnerable to MASLD.

A study published in 2019 utilized data from the Hispanic Community Health Study/Study of Hispanic
individuals to investigate the association of MASLD-associated genetic variants and continental ancestry
with suspected MASLD, which was defined by an unexplained increase in levels of aminotransferases and
FIB-4 score . Upon analyzing data from 9,432 Hispanic individuals from Chicago, Bronx, Miami, and San
[48]
Diego, the study found that the PNPLA3 I148M allele was an independent predictor of increased ALT levels
in United States Hispanic individuals. Interestingly, the frequency of the PNPLA3 I148M allele varied within
Hispanic groups of specific nationalities, with Mexican individuals having the highest frequency (51.7%),
followed by South American individuals (50.8%), Central American individuals (47.8%), Puerto Rican
individuals (35.6%), Cuban individuals (28.5%), and lastly Dominican individuals (2.6%). Thus, this
PNPLA3 I148M allele may play a role in explaining why among Hispanic individuals, those with Mexican
ancestry have the highest incidence of MASLD. This same study also found that continental ancestry may
play a role in an individual’s risk for MASLD as well - American ancestry had a positive association with the
level of ALT, whereas African and European ancestry were inversely associated with the level of ALT.

Recent research has also investigated the role of other genes in the high prevalence of MASLD within
Hispanic populations. A study published in 2021 utilized a large multiethnic cohort to determine whether
previously identified genetic variants associated with MASLD within White populations were also
associated with MASLD within other ethnicities . The study analyzed genes including PNPLA3, TM6SF2,
[49]
GATAD2A, GCKR, SUGP1, MBOAT7, and others and found that the highest percentage of replication was
found in Hispanic individuals (43%), followed by Japanese Americans (37%), and Native Hawaiians and
non-Hispanic Black individuals (less than or equal to 10%). A study published in 2020 analyzed genotypes
of the HSD17B13 gene, an enzyme shown to be upregulated in individuals with MASLD, within 9,342
United States Hispanic individuals . This study found that the loss-of-function rs72613567:TA allele was
[50]
associated with lower rates of suspected MASLD and lower FIB-4 scores among Hispanic populations. In