Aims
African Americans (AA) in the United States have a high risk of type 2 diabetes mellitus (T2DM) and suffer from disparities in the prevalence, mortality, and comorbidities of the disease ...compared to other Americans. The present study aimed to shed light on the molecular mechanisms of disease pathogenesis of T2DM among AA in the Washington, DC region.
Methods
We performed TaqMan Low Density Arrays (TLDA) on 24 genes of interest that belong to three categories: metabolic disease and disorders, cancer‐related genes, and neurobehavioural disorders genes. The 18 genes, viz. ARNT, CYP2D6, IL6, INSR, RRAD, SLC2A2 (metabolic disease and disorders), APC, BCL2, CSNK1D, MYC, SOD2, TP53 (Cancer‐related), APBA1, APBB2, APOC1, APOE, GSK3B, and NAE1 (neurobehavioural disorders), were differentially expressed in T2DM participants compared to controls.
Results
Our results suggest that factors including gender, smoking habits, and the severity or lack of control of T2DM (as indicated by HbA1c levels) were significantly associated with differential gene expression. APBA1 was significantly (p‐value <0.05) downregulated in all diabetes participants. Upregulation of APOE and CYP2D6 genes and downregulation of the INSR gene were observed in the majority of diabetes patients.
Conclusions
Tobacco smoking and gender were significantly associated with case‐control differences in expression of the APBA1 and APOE genes (connected with Alzheimer's disease) and the INSR and CYP2D6 (associated with metabolic disorders). The results highlight the need for more effective management of T2DM and for tobacco smoking cessation interventions in this community, and further research on the associations of T2DM with other disease processes, including cancer and neurobehavioral pathways.
The epidemic of type 2 diabetes mellitus (T2DM) is an important global health concern. Our earlier epidemiological investigation in Pakistan prompted us to conduct a molecular investigation to ...decipher the differential genetic pathways of this health condition in relation to non-diabetic controls. Our microarray studies of global gene expression were conducted on the Affymetrix platform using Human Genome U133 Plus 2.0 Array along with Ingenuity Pathway Analysis (
) to associate the affected genes with their canonical pathways. High-throughput qRT-PCR TaqMan Low Density Array (TLDA) was performed to validate the selected differentially expressed genes of our interest, viz.,
, TP53,
and
using a small population validation sample (n = 15 cases and their corresponding matched controls). Overall, our small pilot study revealed a discrete gene expression profile in cases compared to controls. The disease pathways included:
,
,
,
,
,
and
,
,
, and
strongly consistent with the evidence from epidemiological studies. These gene fingerprints could lead to the development of biomarkers for the identification of subgroups at high risk for future disease well ahead of time, before the actual disease becomes visible.
The epidemic of type 2 diabetes mellitus (T2DM) and the possibility of it contributing to the risk of Alzheimer's disease (AD) have become important health concerns worldwide and in Pakistan, where ...the co-occurrence of T2DM and AD is becoming more frequent. To gain insights on this phenomenon, a cross-sectional study was initiated. We recruited and interviewed 820 research participants from four cities in Pakistan: 250 controls, 450 T2DM, 100 AD, and 20 with both diseases. Significant differences between groups were observed for age (
< 0.0001), urban vs. rural locality (
= 0.0472) and residing near industrial areas. The average HbA1c (%) level was 10.68 ± 2.34 in the T2DM group, and females had a lower level than males (
= 0.003). In the AD group, significant relationships existed between education and family history. Overall, the results suggest that T2DM and AD were associated with both socio-demographic and environmental factors in Pakistani participants. Detailed molecular investigations are underway in our laboratory to decipher the differential genetic pathways of the two diseases to address their increasing prevalence in this developing nation.
Our previous gene expression studies in a PCB-exposed cohort of young children in Slovakia revealed that early-life exposures to PCBs and other organochlorine compounds were associated with ...significant alterations across several pathogenetic pathways. The present study was undertaken to further explore the high-throughput qRT-PCR-based gene expression effects by using TaqMan low-density array (TLDA) for selected genes in a sample of 55 children from the cohort. We analyzed the transcriptional changes of 11 genes in relation to PCB and organochlorine pesticide exposure levels (including DDT, DDE, HCH, and HCB), and to BMI and ethnicity in this cohort. The results indicated an overall downregulation of expression of these genes. Maximum downregulation (in fold change) was observed in the
ENTPD3
gene, and the minimum level of downregulation was in
CYP2D6
. As per our multinomial regression model study, downregulation of
LEPR
gene was significantly directly correlated with all the exposure variables. Downregulation of
APC
,
ARNT
,
CYP2D6
,
LEPR
,
LRP12
, and MYC genes was directly correlated with BMI (kg/m
2
) of the individuals. Gender-specific differences in gene expression were observed in
CYP2D6
(
p
-value 0.0001) and
LEPR
(
p
-value 0.028), while downregulation of
CYP2D6
(
p
-value 0.01),
LEPR
(
p
-value 0.02),
LRP12
(
p
-value 0.04), and
MYC
(
p
-value 0.02) genes was consistently observed in Roma children compared to Caucasians. The investigation of such health disparities must be emphasized in future research, together with interventions to reduce the health consequences of PCB exposures. In this context, we emphasize the importance of biomarker-based approaches to future research on genetic susceptibility to the effects of these compounds.
Background
Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Developing countries will have >3 times the prevalence of the developed countries by the year 2050. Our previous ...studies with a Pakistani population have suggested that type 2 diabetes mellitus (T2DM) is strongly associated with impaired cognitive functioning, and genetic pathways showed strong resemblance to known AD patterns. The present case studies investigated two important pathways, i.e., Amyloid Precursor Protein (APP) processing and Lipid Metabolism, using gene expression profiling arrays to compare and contrast AD and T2DM patients from Pakistan.
Method
We performed high‐throughput qRT‐PCR with preconfigured a TaqMan Low Density Profiling Array specific to Human Alzheimer’s Disease (ABI, CAT # 441887) to measure the altered gene expressions and their corresponding pathways (Ingenuity Pathway Analysis, IPA®). Both the T2DM (n = 2; M/F each) and AD (n = 2, M/F each) patients (cases) were recruited from outpatient departments of a regional hospital, and were compared with their respective matched, healthy controls.
Result
Overall, we observed a differential gene expression profile in AD and T2DM participants compared to controls. CYP46A1, MAPT, CAPNS1, GAL, AGER, CAPN1, PSENEN, ST6GAL1, GRIN2B, GRIN2C, GRIN2A, and GAP43 was downregulated in both T2DM and AD patients. ACHE, CHRM3, GRIN2C and GAP43 significantly (p value <0.05) downregulated in all T2DM patients. CDC2, UCHL1, CTSG, CASP3, IDE, NAE1, CDK5R1, IL6, APBB2, GLS are the top 10 common genes that were upregulated in both AD and T2DM groups. The IPA analysis revealed important Canonical Pathways, that included, viz., Amyloid Processing, Neuroinflammation Signaling, ErB4 Signaling, nNOs Signaling. Molecular Mechanisms of Cancer. The top disease and biofunctions included Metabolic Disease, Neurological disease, Organismal Injury and Abnormalities, Psychological Disorders, Cardiovascular Disease, with the top upstream regulators PHLPP2, IL33, APP, CRP, TAC1.
Conclusion
The differential gene expression patterns and associated disease pathways from this pilot study suggest that specific genes and pathways were common to both diseases and may suggest common underlying processes and causes. Information from such biochemical and genetic studies will be crucial to the development of therapeutic targets to treat AD.
Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that is most prevalent in elderly individuals, especially in developed countries, and its prevalence is now ...increasing in developing countries like Pakistan. Objective: Our goal was to characterize key genes and their levels of expression and related molecular transcriptome networks associated with AD pathogenesis in a pilot case-control study in a Pakistani population. Methods: To obtain the spectrum of molecular networks associated with pathogenesis in AD patients in Pakistan (comparing cases and controls), we used high-throughput qRT-PCR (TaqMan Low-Density Array; n = 33 subjects) coupled with Affymetrix Arrays (n = 8) and Ingenuity Pathway Analysis (IPA) to identify signature genes associated with Amyloid processing and disease pathways. Results: We confirmed 16 differentially expressed AD-related genes, including maximum fold changes observed in CAPNS2 and CAPN1. The global gene expression study observed that 61% and 39% of genes were significantly (p-value 0.05) up- and downregulated, respectively, in AD patients compared to healthy controls. The key pathways include, e.g., Amyloid Processing, Neuroinflammation Signaling, and ErbB4 Signaling. The top-scoring networks in Diseases and Disorders Development were Neurological Disease, Organismal Injury and Abnormalities, and Psychological Disorders. Conclusions: Our pilot study offers a non-invasive and efficient way of investigating gene expression patterns by combining TLDA and global gene expression method in AD patients by utilizing whole blood. This provides valuable insights into the expression status of genes related to Amyloid Processing, which could play potential role in future studies to identify sensitive, early biomarkers of AD in general.
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that is most prevalent in elderly individuals, especially in developed countries, and its prevalence is now increasing in ...developing countries like Pakistan.
Our goal was to characterize key genes and their levels of expression and related molecular transcriptome networks associated with AD pathogenesis in a pilot case-control study in a Pakistani population.
To obtain the spectrum of molecular networks associated with pathogenesis in AD patients in Pakistan (comparing cases and controls), we used high-throughput qRT-PCR (TaqMan Low-Density Array;
= 33 subjects) coupled with Affymetrix Arrays (
= 8) and Ingenuity Pathway Analysis (IPA) to identify signature genes associated with Amyloid processing and disease pathways.
We confirmed 16 differentially expressed AD-related genes, including maximum fold changes observed in
and
. The global gene expression study observed that 61% and 39% of genes were significantly (
-value 0.05) up- and downregulated, respectively, in AD patients compared to healthy controls. The key pathways include, e.g.,
,
, and
. The top-scoring networks in Diseases and Disorders Development were
,
, and
.
Our pilot study offers a non-invasive and efficient way of investigating gene expression patterns by combining TLDA and global gene expression method in AD patients by utilizing whole blood. This provides valuable insights into the expression status of genes related to
, which could play potential role in future studies to identify sensitive, early biomarkers of AD in general.
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