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Synergistic role of inflammation and insulin resistance as coronary artery disease risk factors in African Americans and Caucasians.

ABSTRACT: The separate roles of inflammation and insulin resistance (IR) in the pathogenesis of cardiovascular disease (CVD) are well recognized. We investigated whether presence of inflammation would modify coronary artery disease (CAD) risk prediction in subjects with or without IR. Insulin, glucose, CRP and fibrinogen levels were determined in 317 Caucasians and 222 African Americans undergoing diagnostic coronary angiography. Extent of CAD was defined by a composite score (0-75). The overall prevalence of IR (HOMA-IR>or=3.0) in Caucasians and African Americans was 32.5% and 22.9%, respectively (P<0.05). The degree of CAD (composite score) was higher in subjects with IR (20.7 vs. 14.5, P=0.014 and 20.1 vs. 13.1, P=0.031 for Caucasians and African Americans, respectively), and in a multiple regression model IR was an independent predictor for CAD in both groups. In both ethnic groups, subjects with a combination of IR and high CRP (>or=3mg/l) had significantly higher composite score compared to those with no IR and low CRP (<3mg/l) (21.2 vs. 13.9, P<0.05 and 20.9 vs. 10.2, P<0.05 for Caucasians and African Americans, respectively). Similarly, the composite score was significantly higher in subjects with IR and high fibrinogen (>or=340 mg/dl) compared to those with no IR and low fibrinogen. In conclusion, elevated levels of inflammatory markers were positively associated with IR. Further, a combination of IR and inflammation resulted in a higher degree of CAD in both Caucasians and African Americans. The results suggest that inflammation may potentiate the cardiovascular risk factor role of IR.

SUBMITTER: Anuurad E

PROVIDER: S-EPMC2700183 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Synergistic role of inflammation and insulin resistance as coronary artery disease risk factors in African Americans and Caucasians.

Anuurad Erdembileg E Tracy Russell P RP Pearson Thomas A TA Kim Kyoungmi K Berglund Lars L

Atherosclerosis 20081206 1

The separate roles of inflammation and insulin resistance (IR) in the pathogenesis of cardiovascular disease (CVD) are well recognized. We investigated whether presence of inflammation would modify coronary artery disease (CAD) risk prediction in subjects with or without IR. Insulin, glucose, CRP and fibrinogen levels were determined in 317 Caucasians and 222 African Americans undergoing diagnostic coronary angiography. Extent of CAD was defined by a composite score (0-75). The overall prevalenc ...[more]

PMID: 19135196

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Project description:BACKGROUND:Rare coding variants ABI3_rs616338-T and PLCG2_rs72824905-G were identified as risk or protective factors, respectively, for Alzheimer's disease (AD). METHODS:We tested the association of these variants with five neurodegenerative diseases in Caucasian case-control cohorts: 2742 AD, 231 progressive supranuclear palsy (PSP), 838 Parkinson's disease (PD), 306 dementia with Lewy bodies (DLB) and 150 multiple system atrophy (MSA) vs. 3351 controls; and in an African-American AD case-control cohort (181 AD, 331 controls). 1479 AD and 1491 controls were non-overlapping with a prior report. RESULTS:Using Fisher's exact test, there was significant association of both ABI3_rs616338-T (OR?=?1.41, p?=?0.044) and PLCG2_rs72824905-G (OR?=?0.56, p?=?0.008) with AD. These OR estimates were maintained in the non-overlapping replication AD-control analysis, albeit at reduced significance (ABI3_rs616338-T OR?=?1.44, p?=?0.12; PLCG2_rs72824905-G OR?=?0.66, p?=?0.19). None of the other cohorts showed significant associations that were concordant with those for AD, although the DLB cohort had suggestive findings (Fisher's test: ABI3_rs616338-T OR?=?1.79, p?=?0.097; PLCG2_rs72824905-G OR?=?0.32, p?=?0.124). PLCG2_rs72824905-G showed suggestive association with pathologically-confirmed MSA (OR?=?2.39, p?=?0.050) and PSP (OR?=?1.97, p?=?0.061), although in the opposite direction of that for AD. We assessed RNA sequencing data from 238 temporal cortex (TCX) and 224 cerebellum (CER) samples from AD, PSP and control patients and identified co-expression networks, enriched in microglial genes and immune response GO terms, and which harbor PLCG2 and/or ABI3. These networks had higher expression in AD, but not in PSP TCX, compared to controls. This expression association did not survive adjustment for brain cell type population changes. CONCLUSIONS:We validated the associations previously reported with ABI3_rs616338-T and PLCG2_rs72824905-G in a Caucasian AD case-control cohort, and observed a similar direction of effect in DLB. Conversely, PLCG2_rs72824905-G showed suggestive associations with PSP and MSA in the opposite direction. We identified microglial gene-enriched co-expression networks with significantly higher levels in AD TCX, but not in PSP, a primary tauopathy. This co-expression network association appears to be driven by microglial cell population changes in a brain region affected by AD pathology. Although these findings require replication in larger cohorts, they suggest distinct effects of the microglial genes, ABI3 and PLCG2 in neurodegenerative diseases that harbor significant vs. low/no amyloid ß pathology.

Project description:BackgroundAfrican Americans have a high risk for type 2 diabetes (T2D) and insulin resistance. Studies among other population groups have identified DNA methylation loci associated with insulin resistance, but data in African Americans are lacking. Using DNA methylation profiles of blood samples obtained from the Illumina Infinium® HumanMethylation450 BeadChip, we performed an epigenome-wide association study to identify DNA methylation loci associated with insulin resistance among 136 non-diabetic, unrelated African American men (mean age 41.6 years) from the Howard University Family Study.ResultsWe identified three differentially methylated positions (DMPs) for homeostatic model assessment of insulin resistance (HOMA-IR) at 5% FDR. One DMP (cg14013695, HOXA5) is a known locus among Mexican Americans, while the other two DMPs are novel-cg00456326 (OSR1; beta = 0.027) and cg20259981 (ST18; beta = 0.010). Although the cg00456326 DMP is novel, the OSR1 gene has previously been found associated with both insulin resistance and T2D in Europeans. The genes HOXA5 and ST18 have been implicated in biological processes relevant to insulin resistance. Differential methylation at the significant HOXA5 and OSR1 DMPs is associated with differences in gene expression in the iMETHYL database. Analysis of differentially methylated regions (DMRs) did not identify any epigenome-wide DMRs for HOMA-IR. We tested transferability of HOMA-IR associated DMPs from five previous EWAS in Mexican Americans, Indian Asians, Europeans, and European ancestry Americans. Out of the 730 previously reported HOMA-IR DMPs, 47 (6.4%) were associated with HOMA-IR in this cohort of African Americans.ConclusionsThe findings from our study suggest substantial differences in DNA methylation patterns associated with insulin resistance across populations. Two of the DMPs we identified in African Americans have not been reported in other populations, and we found low transferability of HOMA-IR DMPs reported in other populations in African Americans. More work in African-ancestry populations is needed to confirm our findings as well as functional analyses to understand how such DNA methylation alterations contribute to T2D pathology.

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Synergistic role of inflammation and insulin resistance as coronary artery disease risk factors in African Americans and Caucasians.

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Synergistic role of inflammation and insulin resistance as coronary artery disease risk factors in African Americans and Caucasians.

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