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View the Exact Pathogenesis Has Not Been Fully Understood, Board of Tougaloo College Mao et al. BMC Genomics 2011, 12(Suppl 5):S12 http://www.biomedcentral.com/1471-2164/12/S5/S12 RESEARCH Open Access Transcriptomic profiles of peripheral white blood cells in type II diabetes and racial differences in expression profiles Jinghe Mao1*, Junmei Ai2, Xinchun Zhou3, Ming Shenwu1, Manuel Ong Jr4, Marketta Blue5, Jasmine T Washington1, Xiaonan Wang6, Youping Deng6,7* From BIOCOMP 2010. The 2010 International Conference on Bioinformatics and Computational Biology Las Vegas, NV, USA. 12-15 July 2010 Abstract Background: Along with obesity, physical inactivity, and family history of metabolic disorders, African American ethnicity is a risk factor for type 2 diabetes (T2D) in the United States. However, little is known about the differences in gene expression and transcriptomic profiles of blood in T2D between African Americans (AA) and Caucasians (CAU), and microarray analysis of peripheral white blood cells (WBCs) from these two ethnic groups will facilitate our understanding of the underlying molecular mechanism in T2D and identify genetic biomarkers responsible for the disparities. Results: A whole human genome oligomicroarray of peripheral WBCs was performed on 144 samples obtained from 84 patients with T2D (44 AA and 40 CAU) and 60 healthy controls (28 AA and 32 CAU). The results showed that 30 genes had significant difference in expression between patients and controls (a fold change of <-1.4 or >1.4 with a P value <0.05). These known genes were mainly clustered in three functional categories: immune responses, lipid metabolism, and organismal injury/abnormaly. Transcriptomic analysis also showed that 574 genes were differentially expressed in AA diseased versus AA control, compared to 200 genes in CAU subjects. Pathway study revealed that “Communication between innate and adaptive immune cells"/"Primary immunodeficiency signaling” are significantly down-regulated in AA patients and “Interferon signaling"/"Complement System” are significantly down-regulated in CAU patients. Conclusions: These newly identified genetic markers in WBCs provide valuable information about the pathophysiology of T2D and can be used for diagnosis and pharmaceutical drug design. Our results also found that AA and CAU patients with T2D express genes and pathways differently. Background factors[1,2]. African American (AA) is the ethnicity with Type 2 diabetes (T2D) is the most common form dia- thehighestincidenceandmortalityrateofT2D. betes, and it accounts for more than 90% of all diag- According to 2010 statistics of adults aged 20 years or nosed diabetic cases [1]. It is a heterogeneous and older, 15.7 million non-Hispanicwhiteshavediabetes multi-factorial disease. Although the exact pathogenesis (10.2% of the ethnic group), compared to 4.9 million has not been fully understood, older age, family history, non-Hispanic blacks (18.7%). After adjusting for popula- physical inactivity and race/ethnicity are important risk tion age differences, AAs are 1.8 times as likely to have diabetes as CAUs at similar ages [3-5]. In addition, obe- sity and immune/inflammatory processes contribute to * Correspondence: [email protected]; [email protected] 1Department of Biology, Tougaloo College, Tougaloo, MS 39174, USA the onset of T2D [6-9]. For example, elevated levels of 6Wuhan University of Science and Technology, Wuhan, Hubei 430081, P.R. circulating IL-1b, IL-6, TNFa, and acute phase proteins China in T2D have been extensively described in several Full list of author information is available at the end of the article © 2011 Mao et al. licensee BioMed Central Ltd This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mao et al. BMC Genomics 2011, 12(Suppl 5):S12 Page 2 of 8 http://www.biomedcentral.com/1471-2164/12/S5/S12 studies. That may reflect the activation of innate ethnicity differences were not shown). As compared to immune cells by excessive levels of nutrient concentra- all controls (mixed), the patients group was 4.5 years tion, including glucose and free fatty acids. In turn, both older, had significantly higher body mass index (BMI), IL-6 and IL-1b act on the liver to produce a characteris- blood TG, and fasting glucose, and had lower high den- tic dyslipidemia in metabolic syndrome, one which man- sity apolipoprotein (HDL). There were no differences in ifests as increased very low density lipoprotein (VLDL) low density apolipoproteins (LDL) and total cholesterols and decreased high density lipoprotein (HDL) [10,11]. (Table 1) between controls and T2D patients. IL-6 and tumor necrosis factor TNFa also participate in the impairment of insulin signaling in adipocytes [12]. Identification of differentially expressed genes between Many clinical and epidemiological studies have been all T2D patients and healthy controls done to elucidate environmental contribution to T2D Whole human genome (4 × 44K) oligo-microarrays of [13-15]. Microarray analysis will allow us to study peripheral WBCs from 60 healthy subjects and 84 T2D genetic contribution and patterns of altered gene expres- subjects were performed. Of 41,000 probes available on sion related to T2D. Thus far, human skeletal muscles, the Agilent arrays, we identified 30 genes that were dif- liver, adipose tissues, and pancreatic b-cells [16-22] have ferentially expressed (a fold change of <-1.4 or >1.4 with been chosen for gene expression assay in T2D. These a P value <0.05). Six known genes were up-regulated, studies have yielded important insights into the patho- including erythroid associated factor (ERAF), delta-ami- genesis of T2D and its relationship to obesity. For exam- nolevulinate synthase 2 (ALAS2), oxysterol binding pro- ple, adipose tissue gene expression has been found to tein 2 (OSBP2), carbonic anhydrase I (CA1), serine/ show more differences between T2D and healthy control threonine/tyrosine kinase 1 (STYK1), and Zinc finger than muscle tissue gene expression. Many genes are protein 2 (ZIC2). Sixteen known genes were down-regu- inflammatory and metabolically important [23]. Because lated, including G0/G1 switch 2 (GOS2); telomerase- it is difficult to obtain permission from a clinic to use associated protein 1 (TEP1); prostaglandin-endoperoxide tissue samples such as liver, adipose, and muscle for synthase 2 (PTGS2); interleukin 4 (IL4); interleukin 8 genetic studies, the peripheral blood could be a conveni- (IL8); interferon alpha-inducible protein 27 (IFI27); ent source of cells for this study. To date, only one interferon-induced protein with tetratricopeptide repeats microarray study of human peripheral blood has been 3(IFIT3); interferon-induced protein with tetratricopep- reported by Grayson et al [24]. Their finding indicated tide repeats 2 (IFIT2); tumor necrosis factor alpha- that genes differentially expressed in T2D have key roles induced protein 6T (NFAIP6); radical S-adenosyl in T-cell activation and signaling, but this study used a methionine domain containing 2 (RSAD2); apolipopro- limited sample size (n = 6) andlackedethnicityinfor- tein B mRNA editing enzyme, catalytic polypeptide-like mation. In this study, we measured the up/down regula- 3A (APOBEC3A); ATP/GTP binding protein-like 4 tion of some T2D-related genes using white blood cells (ABGL4); ATP-binding cassette sub-family A transporter from T2D patients, and we compared the gene expres- (ABCA1); epithelial stromal interaction 1 isoform 2 sion profiles between two ethnic groups. The informa- (EPSTI1); Ephrin type-A receptor 6 (EPHA6); and leu- tion obtained from our study would provide further cine rich repeat neuronal protein 3 (LRRN3). Most of understanding of the pathogenesis of T2D and the dis- these genes belonged to three functional categories: parities in expression profiles between AA and CAU. Results Table 1 The clinical characteristics of the study subjects Characteristics of studied subjects Normal controls Diabetic This study comprised a balanced distribution of the stu- (n = 60) (n = 84) died subjects in gender and ethnicity: among 60 con- Age, yr (mean ± SD) 58.5 ± 16.1 63 ± 13 trols, 28 were AA including 14 females and 14 males, Sex (female/male) 28/32 45/39 and 32 were CAU including 14 females and 20 males. Race 32 Caucasian 40 Caucasian Among84patientswithT2D,44wereAAincluding22 28 African American 44 African American females and 22 males, and 40 were CAU including 23 Body mass index (kg/m2) 30.1 ± 7.3 34.2 ± 8.4** females and 17 males. As compared to AA, CAU had a Triacylglycerol (mg/dL) 134 ± 76.9 186 ± 113.8** significantly higher level of blood triglycerides (TG) in HDL cholesterol (mg/dL) 56.6 ± 17.5 49.1 ± 15.4** both the controls (106 ± 54.3 mg/dl in AA vs. 153 ± LDL cholesterol (mg/dL) 112 ± 44.8 109.8 ± 36.5 77.8 mg/dl in CAU, p = 0.0009), and the patients (157 ± Total cholesterol (mg/dL) 197 ± 44.8 195 ± 46.8 128 mg/dl in AA vs. 207 ± 98.3 mg/dl in CAU, p = Glucose (mg/dL) 88.8 ± 10.8 142.7 ± 56.8*** 0.037). There were no significant differences in other Data are mean ± SD. Statistical analyses were performed using the Student’s studied clinical parameters between two races (data for t-Test. **p < 0.05 ***p < 0.001, values are based on differences from controls. Mao et al. BMC Genomics 2011, 12(Suppl 5):S12 Page 3 of 8 http://www.biomedcentral.com/1471-2164/12/S5/S12 immune and inflammatory responses, such as IL-4, IL-8, Using the tool of Ingenuity Canonical Pathways Analy- TNFAIP6,andPTGS2; lipid and glucose metabolism, sis, the differentially expressed genes in two ethnic such as ABCA1, OSBP2,andGOS2;andorganismal groups were clustered into various pathways. The top injury and abnormalities, such as APOBEC3A. Thus, 10 down-regulated and up-regulated pathways were these genes might be the genetic signatures for T2D.
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