Page 60 - Read Online

Gulati et al. Metab Target Organ Damage 2024;4:9 https://dx.doi.org/10.20517/mtod.2023.45 Page 9 of 17

addition, the study found that the rs72613567:TA allele was associated with lower rates of suspected
MASLD in Hispanic individuals with the PNPLA3 I148M allele. Rutledge et al. also investigated the role of
HSD17B13 in MASLD in Hispanic populations and found a similar trend where HSD17B13 variants which
[45]
were predicted to have loss-of-function were associated with reduced ALT, AST, and FIB-4 levels . In fact,
this study found that the same Hispanic individuals who had the highest outpatient ALT, AST, and FIB-4
levels and were found to have the highest frequency of the PNPLA3 G allele variant also had the lowest
frequency of the HSD17B13 variants predicted to have loss-of-function. The study concluded that the
HSD17B13 loss-of-function variants mitigated the increase in ALT that came about with the PNPLA3 G
allele, thus further supporting the protective role of HSD17B13 in Hispanic individuals with MASLD.

Studies investigating lipid profiles in Hispanic populations with MASLD
Recent genetic studies have dived into other potential genetic explanations for the higher incidence of
MASLD within Hispanic populations. A study published in 2021, which analyzed plasma fatty acid
concentrations in 116 Hispanic subjects from South Texas, found that low plasma concentrations of very
long-chain n-3 polyunsaturated fatty acids and very-long-chain saturated fatty acids were strongly
[51]
associated with advanced liver fibrosis in this population . This finding was supported by a separate
targeted lipidomic profiling study published in 2022 in Hispanic individuals and non-Hispanic White
individuals with biopsy-confirmed MASLD . The authors reported that MASLD is associated with
[52]
diminished long-chain polyunsaturated fatty acids in Hispanic populations, along with lower lipoxygenase
and higher soluble epoxide hydrolase activities in Hispanic individuals compared to non-Hispanic White
individuals. Another study published in 2021 compared untargeted plasma metabolomics profiles for
primary metabolism, complex lipids, choline, and related compounds between a group of Hispanic and
[53]
White subjects . This study found that independent of obesity, Hispanic individuals had higher plasma
triglycerides, acylcarnitines, and free fatty acids. In addition, MASLD progression was associated with
higher free fatty acids and lysophospholipids, greater hepatic triglyceride content, and higher plasma
triglyceride concentrations in Hispanic individuals, thus suggesting more significant alterations in lipid
metabolism in Hispanic individuals with MASLD progression. These studies each contribute to our current
understanding of genetic factors associated with a higher risk of MASLD presence and severity.

Genetic studies investigating MASLD in pediatric populations
Recent research has also been conducted investigating genetic variants in pediatric populations with
MASLD, and how these may vary among different ethnicities/races. A GWAS including 624,297 SNPs was
performed in 234 Hispanic children (up to 18 years of age) with biopsy-proven MASLD in the Nonalcoholic
Steatohepatitis Clinical Research Network Studies. The study found 10 SNPs associated with BMI z score,
including 1 within CAMK1D which plays a role in liver gluconeogenesis. In addition, 9 novel variants were
identified and associated with insulin resistance - 6 associated with HOMA-IR and 3 associated with
HbA1c . Other studies have investigated whether genetic variant trends found in adults are also seen in
[54]
children. The rs626283 polymorphism in the MBOAT7 gene has been associated with MASLD in adults,
which is believed to be due to increased intrahepatic triglyceride content and inflammation. A study
published in 2018 investigated this association within a multiethnic cohort of obese children and
adolescents and found that this rs626283 variant in the MBOAT7 gene was associated with MASLD in non-
Hispanic White obese children and adolescents but not among Hispanic and Black children and youth, thus
showing genetic variation at the pediatric level that does not exist at the adult level .
[55]

Studies have also started investigating the association between certain hormones and antibodies with
MASLD in Hispanic pediatric populations. Since previous studies had found an association between
elevated thyroid-stimulating hormone (TSH) levels and MASLD in non-Hispanic White children, a study
was published in 2020 that investigated the association between elevated TSH and MASLD in Hispanic