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Variations in Mitochondrial Respiration Differ in IL-1ß/IL-10 Ratio Based Subgroups in Autism Spectrum Disorders.

ABSTRACT: Autism spectrum disorder (ASD)7 is associated with multiple physiological abnormalities, including immune dysregulation, and mitochondrial dysfunction. However, an association between these two commonly reported abnormalities in ASD has not been studied in depth. This study assessed the association between previously identified alterations in cytokine profiles by ASD peripheral blood monocytes (PBMo) and mitochondrial dysfunction. In 112 ASD and 38 non-ASD subjects, cytokine production was assessed by culturing purified PBMo overnight with stimuli of innate immunity. Parameters of mitochondrial respiration including proton-leak respiration (PLR), ATP-linked respiration (ALR), maximal respiratory capacity (MRC), and reserve capacity (RC) were measured in peripheral blood mononuclear cells (PBMCs). The ASD samples were analyzed by subgrouping them into high, normal, and low IL-1ß/IL-10 ratio groups, which was previously shown to be associated with changes in behaviors and PBMo miRNA expression. MRC, RC, and RC/PLR, a marker of electron transport chain (ETC) efficiency, were higher in ASD PBMCs than controls. The expected positive associations between PLR and ALR were found in control non-ASD PBMCs, but not in ASD PBMCs. Higher MRC, RC, RC/PLR in ASD PBMCs were secondary to higher levels of these parameters in the high and normal IL-1ß/IL-10 ratio ASD subgroups than controls. Associations between mitochondrial parameters and monocyte cytokine profiles differed markedly across the IL-1ß/IL-10 ratio based ASD subgroups, rendering such associations less evident when ASD samples as a whole were compared to non-ASD controls. Our results indicate for the first time, an association between PBMC mitochondrial function and PBMo cytokine profiles in ASD subjects. This relationship differs across the IL-1ß/IL-10 ratio based ASD subgroups. Changes in mitochondrial function are likely due to adaptive changes or mitochondrial dysfunction, resulting from chronic oxidative stress. These results may indicate alteration in molecular pathways affecting both the immune system and mitochondrial function in some ASD subjects.

SUBMITTER: Jyonouchi H

PROVIDER: S-EPMC6391925 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDespite the global increase in the prevalence of autism spectrum disorders (ASD), relevant research studies are lacking in Brunei Darussalam. Various studies have shown a significant association between a lowered 2D:4D ratio (ratio of second digit/index finger to the fourth digit/ring finger) and ASD, making it one of the potential phenotypic biomarkers for early detection of autism, which is important for early intervention and management.ObjectiveThe objective of this study is to explore the association between 2D:4D ratio and ASD in Brunei Darussalam, as a potential tool to complement early ASD diagnosis.MethodsWe conducted a case-control study comprising 28 ASD and 62 typically developing (TD) children in the case and control group, respectively (age range: 3-11 years old; median age: 6 years old). Median 2D:4D ratios were measured, compared and analysed between the two groups. Logistic regression models were used to explore potential associations between the median 2D:4D ratio and ASD in respective gender, for both left and right hands, independently.ResultsOur study shows that the median 2D:4D ratio of left hand in ASD males is significantly lower than those in TD males, after adjusting for ethnicity and age [Odds Ratio (OR) = 0.57 (95% Confidence Interval (CI): 0.31-0.96); p = 0.044]. For females, there is no association of ASD with the median left hand 2D:4D ratio [OR = 3.09 (95% CI: 0.98-19.86); p = 0.144] or the median right hand 2D:4D ratio [OR = 1.23 (95% CI: 0.42-3.88); p = 0.702]. Our study also shows a significant positive correlation and/or a reduced asymmetry between the average 2D:4D ratio of left hands and right hands in ASD males (Pearson's correlation (r) = 0.48; 95% CI: 0.076-0.75, p = 0.023).ConclusionsThere is significant association between a lowered median 2D:4D ratio of the left hand (in males only) and ASD diagnosis. Once validated in a larger sample size, a lowered median 2D:4D ratio on the left hand may be a potential tool to complement ASD diagnosis for males in our study population. There is no association between the median 2D:4D ratio (left or right hands) and ASD in females, which could be due to the small female sample size and/or the possibility of different aetiology for ASD in females. Reduced asymmetry between the average 2D:4D ratio of left and right hands observed in ASD males only (not in ASD females) also suggests the importance of considering gender-specific biomarkers for ASD diagnosis.

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Variations in Mitochondrial Respiration Differ in IL-1ß/IL-10 Ratio Based Subgroups in Autism Spectrum Disorders.

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