Delineating miR-126-3p, miR-223-3p, and miR-320a expression patterns with body mass index and insulin resistance in South African adults living with HIV

People living with human immunodeficiency virus (PLWH) have increased risk of weight gain, overweight, and obesity, and subsequent cardiometabolic diseases (CMDs). MicroRNAs (miRNAs) are emerging biomarkers for diabetes and obesity due to their regulatory roles in pathophysiological pathways leading to these conditions. In non-HIV populations, microRNAs (miR-126-3p, −223-3p, and -320a) have been associated with CMD risk. To examine the expression patterns of targeted miRNAs (miR-126-3p, −223-3p, and -320a) with overweight/obesity status in PLWH in South Africa. This cross-sectional study included ≥18-years-old PLWH, from 17 HIV clinics that provided antiretroviral care in the Western Cape between 2014 and 2015. Body mass index (BMI) <25 kg/m 2 is defined as normal/underweight, BMI between ≥25 kg/m 2 and < 30 kg/m 2 is defined as overweight, and BMI ≥30 kg/m 2 is defined as obesity. Whole blood miRNAs were isolated and quantified by reverse transcription polymerase chain reaction with small nucleolar RNA, C/D box 84 (SNOR D48) endogenous control used for normalisation. Statistical analyses used R software, with p -value<0.05 characterising significant results. Overall, all three target miRNAs were significantly but weakly correlated with fasting glucose (all, p < 0.046), fasting insulin (all, p < 0.015), and homeostatic model assessment-estimated insulin resistance (all, p < 0.002). Furthermore, miR-126-3p and − 223-3p were significantly correlated with 2-h insulin (both, p < 0.029) and alanine transaminase (both, p < 0.021). There were no significant differences in target miRNAs expression by BMI categories. Age and gender-adjusted regression analysis found no significant associations between the target miRNAs and CMD risk profiles. The expression patterns evaluated in this study appear to have weak associations with fasting glucose and cannot differentiate overweight/obesity status in PLWH. While not promising markers for overweight/obesity in PLWH, these findings remain exploratory, and further investigation is warranted. • This study is the first in Sub-Saharan Africa to examine the expression of miR-126-3p, miR-223-3p, and miR-320a in relation to overweight and obesity among people living with human immunodeficiency virus (PLWH), addressing an important evidence gap as these metabolic-associated miRNAs have not been previously evaluated in this high-risk population. PLWH face an increased risk of cardiovascular and cardiometabolic conditions, including diabetes and obesity, due to the combined effects of chronic inflammation, metabolic disruptions caused by antiretroviral therapy, and traditional lifestyle-related factors such as poor diet and physical inactivity. • The findings showed that all three miRNAs were weakly but significantly correlated with fasting glucose, fasting insulin, and HOMA-IR (all, p -value < 0.05 ), while miR-126-3p and miR-223-3p also correlated with 2-h insulin (both, p < 0.029 ) and alanine transaminase (both, p < 0.021 ), suggesting limited involvement in glucose regulation and liver-associated pathways. However, miRNA expression did not differ across BMI categories, and age- and sex-adjusted analyses revealed no significant associations between the target miRNAs and broader cardiometabolic disease risk profiles. • Overall, the results indicate that these miRNAs are not effective markers for distinguishing overweight or obesity in PLWH, yet they provide valuable insight into how metabolic-associated miRNAs may function differently in this population compared with general cohorts, underscoring the need for further investigation.