Date of Award

12-2023

Degree Type

Thesis

Degree Name

MPhil in Biological and Biomedical Sciences

First Advisor

Dr Syeda Sadia Fatima

Second Advisor

Ms. Sabah Farhat

Department

Biological and Biomedical Sciences

Abstract

Introduction: Obesity is a well-established trigger for metabolic diseases, contributing to increased morbidity rates. Epigenetic modifications, including DNA methylation at specific CpG sites, are of considerable interest in understanding the heightened susceptibility to these diseases. Our study aims to assess the methylation profiles of genes associated with satiety, specifically FTO, POMC, Leptin, and Ghrelin, in metabolically healthy and unhealthy individuals to explore their potential roles in metabolic and cardiovascular disorders.
Methods: Ethical approval and informed consent were obtained for a study involving 228 participants from the general population at Aga Khan University. General characteristics and biochemical assessments were conducted, followed by DNA isolation from buffy coat using a Qiagen Kit. Primers for FTO, POMC, Leptin, and Ghrelin were designed using the UCSC genome browser. Bisulphite treatment was applied to extracted DNA, and gene amplification was carried out through MS-PCR using Promega GoTaq® Green Master Mix. Gel electrophoresis was employed to analyze the amplified products. Methylation percentages were calculated using densitometry, and risk scores for metabolic and cardiovascular disorders were determined using MetS severity Z score and FRS score.
Results: The study comprised subjects with an average age of 33.14 ± 0.82 SEM, of which 64.9% were female and 35.1% were male. Among them, 99 subjects were diagnosed with Metabolic Syndrome. In the unhealthy group, FTO, POMC, and Leptin promoters showed methylation levels exceeding 40% compared to the healthy group (p< 0.001). Ghrelin, on the other hand, remained unaffected and physiologically active across all groups. After adjusting for age, BMI, and gender, FTO, Leptin, and POMC methylation exhibited a moderate correlation with LDL levels (p>< 0.001, r=0.4) and VLDL levels (p=0.001, r=0.4). The FRS score displayed weak but independent correlations with fasting blood glucose levels (p>< 0.001, r=0.2) and HbA1c (p>< 0.001, r=0.2). MetS Severity Z-score demonstrated strong independent correlations with fasting blood glucose (p>< 0.001, r=0.9) and moderate correlations with > triglyceride levels (p< 0.001, r=0.4) and VLDL levels (p>< 0.001, r=0.4). Out of the participants, 25 individuals were identified as at high risk for cardiovascular disease, while 12 were categorized as having moderate risk, irrespective of their BMI. Notably, impaired fasting blood glucose was a common factor among all high-risk subjects. Conclusion: Methylation at the POMC, FTO, and Leptin gene loci may play a role in regulating glucose metabolism and influencing cardiovascular risk in the Pakistani population. Further investigation into monitoring fasting blood glucose levels as a potential indicator for cardiovascular risk assessment, particularly in South Asian individuals, could shed light on the causal relationship across different weight groups.>< 0.001, r=0.4) and VLDL levels (p< 0.001, r=0.4).>< 0.001, r=0.4) Out of the participants, 25 individuals were identified as at high risk for cardiovascular disease, while 12 were categorized as having moderate risk, irrespective of their BMI. Notably, impaired fasting blood glucose was a common factor among all high-risk subjects.
Conclusion: Methylation at the POMC, FTO, and Leptin gene loci may play a role in regulating glucose metabolism and influencing cardiovascular risk in the Pakistani population. Further investigation into monitoring fasting blood glucose levels as a potential indicator for cardiovascular risk assessment, particularly in South Asian individuals, could shed light on the causal relationship across different weight groups.

First Page

1

Last Page

62

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