Effects of Age and Sex on Systemic Inflammation and Cardiometabolic Function in Individuals with Type 2 Diabetes.

Objective: Systemic inflammation, aging, and type 2 diabetes (T2DM) all contribute to the development of cardiovascular dysfunction and impaired aerobic exercise capacity but their interplay remains unclear. This study evaluates the impact of age, sex, and inflammation on coronary and peripheral vascular function and exercise capacity in elderly individuals with and without type 2 diabetes (T2DM). Research Design and Methods: Elderly individuals (age ≥65 years) underwent biochemical and tissue inflammatory phenotyping, cardiopulmonary exercise testing (CPET), cardiovascular magnetic resonance (CMR) imaging, and vascular reactivity testing. Correlation and regression analyses determined the effects of systemic inflammation, older age, and sex on cardiovascular health, stratified by T2DM status. Results: For the 133 recruited individuals (44% female; median age 71, IQR=7 years, 41% with T2DM) the presence of T2DM did not have an effect on most blood serum inflammatory markers and skin biopsies. Hyperemic myocardial blood flow (hMBF), flow-mediated, and flow-independent nitroglycerin induced brachial artery dilation were significantly impaired in males, but not females with T2DM. Peak VO2 was lower with T2DM (p=0.022), mostly because of the effect of T2DM in females. Females showed more adverse myocardial remodeling assessed by extracellular volume (p=0.008), independent of T2DM status. Conclusions: Our findings suggest that the pathophysiological manifestations of T2DM on vascular function and aerobic exercise capacity are distinct in elderly males and females and this may reflect underlying differences in vascular and myocardial aging in the presence of T2DM.

T-wave heterogeneity in standard resting 12-lead ECGs is associated with 90-day cardiac mortality in women following emergency department admission: A nested case-control study.

BACKGROUND: We investigated whether T-wave heterogeneity (TWH) can identify patients who are at risk for near-term cardiac mortality. METHODS: A nested case-control analysis was performed in the 888 patients admitted to the Emergency Department (ED) of our medical center in July through September 2018 who had ≥2 serial troponin measurement tests within 6 hr for acute coronary syndrome evaluation to rule-in or rule-out the presence of acute myocardial infarction. Patients who died from cardiac causes during 90 days after ED admission were considered cases (n = 20; 10 women) and were matched 1:4 on sex and age with patients who survived during this period (n = 80, 40 women). TWH, that is, interlead splay of T waves, was automatically assessed from precordial leads by second central moment analysis. RESULTS: TWHV4-6 was significantly elevated at ED admission in 12-lead resting ECGs of female patients who died of cardiac causes during the following 90 days compared to female survivors (100 ± 14.9 vs. 40 ± 3.6 µV, p < .0001). TWHV4-6 generated areas under the receiver-operating characteristic (ROC) curve (AUC) of 0.933 in women (p < .0001) and 0.573 in men (p = .4). In women, the ROC-guided 48-µV TWHV4-6 cut point for near-term cardiac mortality produced an adjusted odds ratio of 121.37 (95% CI: 2.89-6,699.84; p = .02) with 100% sensitivity and 82.5% specificity. In Kaplan-Meier survival analysis, TWHV4-6  ≥ 48 µV predicted cardiac mortality in women during 90-day follow-up with a hazard ratio of 27.84 (95% CI: 7.29-106.36, p < .0001). CONCLUSION: Elevated TWHV4-6 is associated with near-term cardiac mortality among women evaluated for acute coronary syndrome.

Regadenoson-induced T-wave heterogeneity complements coronary stenosis detection by myocardial perfusion imaging in men and women.

AIMS: We analysed whether incorporating electrocardiographic interlead T-wave heterogeneity (TWH) with myocardial perfusion imaging (MPI) during pharmacologic stress improves detection of flow-limiting lesions (FLL). METHODS AND RESULTS: Medical records of all 103 patients at our institution who underwent stress testing with regadenoson (0.4 mg IV bolus) within 3 months of coronary angiography from September 2017 to March 2019 were studied. Cases (N = 59) had angiographically significant FLL (≥50% of left main or ≥70% of other epicardial coronary arteries ≥2 mm in diameter); controls (N = 44) were normal or had non-FLL. TWH, i.e., interlead splay of T waves, was assessed from precordial leads V4-6 by second central moment analysis. Maximum TWHV4-6 levels during regadenoson stress were 68% higher in cases than in controls (P < 0.0001). TWHV4-6 generated areas under the receiver-operating characteristic (ROC) curve of 0.79 in men (P < 0.0001) and 0.71 in women (P = 0.007). In men, the ROC-guided 54-µV TWHV4-6 cut-point for FLL produced adjusted odds of 7.3 [95% confidence interval (CI): 1.3-41.5, P = 0.03], 79% sensitivity, and 78% specificity. In women, the ROC-guided 35-µV TWHV4-6 cut-point produced adjusted odds of 4.5 (95% CI: 1.1-18.9, P = 0.04), 84% sensitivity, and 52% specificity. Adding TWHV4-6 to MPI determinations reduced false-positive results by 70%, more than doubled true-negative results, and improved adjusted odds ratio to 6.8 (95% CI: 2.2-21.4, P = 0.001) with specificity of 78% in men and 86% in women. CONCLUSION: This observational study is the first to demonstrate the benefit of combining TWHV4-6 with MPI to enhance FLL detection during MPI with regadenoson in both men and women.

The Role of Disease Conviction: Exploring Its Effects on Chest Pain and Anxiety-Related Models of Non-cardiac Chest Pain.

The aim of this study was to investigate the role of disease conviction in the chest pain and life interference of patients with non-cardiac chest pain (NCCP), after controlling for anxiety sensitivity and body vigilance. While all three psychological constructs are theoretically implicated and empirically associated with the experience of NCCP, no research has examined the influence of disease conviction in the context of other relevant constructs. The sample included 229 participants with NCCP who were recruited after a medical evaluation failed to elicit an organic explanation for their chest pain. Hierarchical regression analyses revealed that while anxiety sensitivity significantly predicted chest pain severity and interference, only body vigilance contributed significant additional variance to chest pain severity, and only disease conviction contributed significant additional variance to chest pain interference. While anxiety sensitivity, body vigilance, and disease conviction all appear to affect those with NCCP, it seems that their impact is manifest in different domains (i.e., pain perception vs. psychosocial impairment).

Heart-Focused Anxiety in Patients With Noncardiac Chest Pain: Structure and Validity.

Heart-focused anxiety (HFA) is a fear of cardiac sensations driven by worries of physical health catastrophe. HFA is impairing and distressing and has been shown to disproportionately affect individuals with noncardiac chest pain (NCCP), chest pain that persists in the absence of an identifiable source. The Cardiac Anxiety Questionnaire (CAQ) is a measure designed to assess HFA. The aim of this study was to evaluate the psychometric properties and factor structure of the CAQ in a sample of 229 adults diagnosed with NCCP. Results demonstrated that the CAQ is a useful measure of HFA in patients with NCCP and that a four-factor model including fear of cardiac sensations, avoidance of activities that elicit cardiac sensations, heart-focused attention, and reassurance seeking was the best fit for the data. Additionally, associations between CAQ subscales and two measures of health-related behaviors-pain-related interference and health care utilization-provided evidence of concurrent validity. Treatment implications are also discussed.

Painful left bundle branch block syndrome: Clinical and electrocardiographic features and further directions for evaluation and treatment.

BACKGROUND: Painful left bundle branch block (LBBB) is a rarely diagnosed chest pain syndrome caused by intermittent LBBB in the absence of myocardial ischemia. Its prevalence, mechanism, detailed electrocardiographic (ECG) features, and effective treatments are not well described. OBJECTIVES: The purpose of this study was to characterize clinical and ECG features of patients with painful LBBB syndrome with respect to the LBBB ECG morphology (in particular QRS axis and the precordial S/T wave ratio), clarify diagnostic criteria and possible mechanisms, and provide directions for further evaluation and treatment. METHODS: We analyzed clinical (n = 50) and ECG (n = 15) features of patients with painful LBBB syndrome (4 patients in our practice and 46 cases identified in the literature). RESULTS: All 15 ECGs of patients with painful LBBB syndrome had an inferior QRS axis and a very low (<1.8) precordial S/T wave ratio, which was consistent with the "new LBBB" pattern. We report a case of painful LBBB syndrome coexisting with coronary artery disease. Right ventricular apical pacing resolved intractable chest pain in 1 case of painful LBBB. CONCLUSION: Painful LBBB ECG morphology within seconds/minutes of its onset is consistent with the new LBBB pattern with a very low (<1.8) precordial S/T wave ratio and inferior QRS axis. Painful LBBB syndrome can coexist with coronary artery disease, complicating the assessment of chest pain in the setting of LBBB. An electrophysiology study might be considered to investigate whether changing ventricular activation pattern by pacing provides consistent pain control and to select the most effective pacing configuration.

Illness perceptions, negative emotions, and pain in patients with noncardiac chest pain.

Illness-specific cognitions are associated with outcomes in numerous health conditions, however, little is known about their role in noncardiac chest pain (NCCP). NCCP is prevalent, impairing, and associated with elevated health care utilization. Our objective was to investigate the relations between illness perceptions, emotion, and pain in a sample of 196 adult patients diagnosed with NCCP. We found that negative illness perceptions were associated with greater anxiety, depression, chest pain, and pain-related life interference while controlling for the effects of demographic and pain-related variables. These results expand current NCCP theory and may inform future treatment development.

Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes.

IMPORTANCE: Diabetes is associated with an elevated risk of coronary heart disease (CHD). Previous studies have suggested that the genetic factors predisposing to excess cardiovascular risk may be different in diabetic and nondiabetic individuals. OBJECTIVE: To identify genetic determinants of CHD that are specific to patients with diabetes. DESIGN, SETTING, AND PARTICIPANTS: We studied 5 independent sets of CHD cases and CHD-negative controls from the Nurses' Health Study (enrolled in 1976 and followed up through 2008), Health Professionals Follow-up Study (enrolled in 1986 and followed up through 2008), Joslin Heart Study (enrolled in 2001-2008), Gargano Heart Study (enrolled in 2001-2008), and Catanzaro Study (enrolled in 2004-2010). Included were a total of 1517 CHD cases and 2671 CHD-negative controls, all with type 2 diabetes. Results in diabetic patients were compared with those in 737 nondiabetic CHD cases and 1637 nondiabetic CHD-negative controls from the Nurses' Health Study and Health Professionals Follow-up Study cohorts. Exposures included 2,543,016 common genetic variants occurring throughout the genome. MAIN OUTCOMES AND MEASURES: Coronary heart disease--defined as fatal or nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or angiographic evidence of significant stenosis of the coronary arteries. RESULTS: A variant on chromosome 1q25 (rs10911021) was consistently associated with CHD risk among diabetic participants, with risk allele frequencies of 0.733 in cases vs 0.679 in controls (odds ratio, 1.36 [95% CI, 1.22-1.51]; P = 2 × 10(-8)). No association between this variant and CHD was detected among nondiabetic participants, with risk allele frequencies of 0.697 in cases vs 0.696 in controls (odds ratio, 0.99 [95% CI, 0.87-1.13]; P = .89), consistent with a significant gene × diabetes interaction on CHD risk (P = 2 × 10(-4)). Compared with protective allele homozygotes, rs10911021 risk allele homozygotes were characterized by a 32% decrease in the expression of the neighboring glutamate-ammonia ligase (GLUL) gene in human endothelial cells (P = .0048). A decreased ratio between plasma levels of γ-glutamyl cycle intermediates pyroglutamic and glutamic acid was also shown in risk allele homozygotes (P = .029). CONCLUSION AND RELEVANCE: A single-nucleotide polymorphism (rs10911021) was identified that was significantly associated with CHD among persons with diabetes but not in those without diabetes and was functionally related to glutamic acid metabolism, suggesting a mechanistic link.

Health care utilisation in patients with non-cardiac chest pain: a longitudinal analysis of chest pain, anxiety and interoceptive fear.

Chest pain can be a frightening experience that leads many to seek medical evaluation. The symptom results in costly health care utilisation. Over half of patients referred for cardiac evaluations of chest pain do not obtain definitive medical explanations for their symptoms; these cases are described as non-cardiac chest pain (NCCP). Some patients with NCCP are not reassured after being informed their chest pain is non-cardiac in origin and seek repeated medical evaluation. Co-morbid anxiety and mood disorders often coexist with NCCP and are associated with health care utilisation. The current study examined chest pain, general anxiety, interoceptive fear and health care utilisation in a sample of 196 chest pain patients near the time of cardiac evaluation (Time 1), and 70 of these patients one year later (Time 2). Results indicate that anxiety and interoceptive fear were significantly associated with health care utilisation at Time 1, and only interoceptive fear (at Time 1) predicted health care utilisation at Time 2. This study develops research in this area by examining the relation of anxiety and health care utilisation longitudinally in patients with NCCP.

The 9p21 coronary artery disease locus and kidney dysfunction in patients with Type 2 diabetes mellitus.

BACKGROUND: We investigated whether the coronary artery disease (CAD) locus on chromosome 9p21 (as represented by single nucleotide polymorphism rs2383206) is associated with low estimated glomerular filtration rate (eGFR) or increased urinary albumin excretion in patients with Type 2 diabetes mellitus (T2DM). METHODS: Four samples, including a total of 3167 patients, were studied. The presence of low eGFR (<60 mL/min/1.73m(2)) was estimated from serum creatinine by means of the Modification of Diet in Renal Disease Study equation. Increased urinary albumin excretion was defined as an albumin-creatinine ratio (ACR) ≥2.5 mg/mmol in men and ≥3.5 mg/mmol in women. RESULTS: No association was found between rs2383206 and low eGFR or increased ACR in each sample as well as in a pooled analysis (overall odds ratio = 1.07, 95% confidence interval 0.94-1.22, P = 0.31 and overall odds ratio = 1.00, 95% confidence interval 0.90-1.12, P = 0.95, respectively). No interaction was observed between rs2383206 and poor glycemic control [HbA1c was above the median in the pooled sample (7.7%) in modulating eGFR or ACR (P for interaction = 0.42 and 0.90, respectively)]. CONCLUSION: Variability at the 9p21 CAD locus is unlikely to play a role in modulating susceptibility to kidney dysfunction in patients with T2DM.

The impact of perceived stress and perceived control on anxiety and mood disorders in noncardiac chest pain.

Chest pain without detectable heart disease, noncardiac chest pain (NCCP), is linked with anxiety and depression. Theory posits stress and perceived control may relate to NCCP. We hypothesized stress would have direct and mediated effects via perceived control on anxiety and mood disorders in NCCP. Patients (N = 113) completed questionnaires and a structured diagnostic interview. Stress and perceived control were associated with anxiety and mood disorder severity. Perceived control fully mediated the relation between stress and mood disorder severity but not anxiety disorder severity. Results are partially supportive of anxiety-based theories of NCCP.

Genetic susceptibility to coronary heart disease in type 2 diabetes: 3 independent studies.

OBJECTIVES: The aim of this study was to evaluate whether coronary heart disease (CHD)-susceptibility loci identified by genome-wide association studies of the general population also contribute to CHD in type 2 diabetes. BACKGROUND: No study has examined the effects of these genetic variants on CHD in diabetic patients. METHODS: We genotyped 15 genetic markers of 12 loci in 3 studies of diabetic patients: the prospective Nurses' Health Study (309 CHD cases, and 544 control subjects) and Health Professional Follow-up Study (345 CHD cases, and 451 control subjects) and the cross-sectional Joslin Heart Study (422 CHD cases, and 435 control subjects). RESULTS: Five single-nucleotide polymorphisms, rs4977574 (CDKN2A/2B), rs12526453 (PHACTR1), rs646776 (CELSR2-PSRC1-SORT1), rs2259816 (HNF1A), and rs11206510 (PCSK9) showed directionally consistent associations with CHD in the 3 studies, with combined odds ratios (ORs) ranging from 1.17 to 1.25 (p = 0.03 to 0.0002). None of the other single-nucleotide polymorphisms reached significance in individual or combined analyses. A genetic risk score (GRS) was created by combining the risk alleles of the 5 significantly associated loci. The OR of CHD/GRS unit was 1.19 (95% confidence interval: 1.13 to 1.26; p < 0.0001). Individuals with GRS ≥8 (19% of diabetic subjects) had almost a 2-fold increase in CHD risk (OR: 1.94, 95% confidence interval: 1.60 to 2.35) as compared with individuals with GRS ≤5 (30% of diabetic subjects). Prediction of CHD was significantly improved (p < 0.001) when the GRS was added to a model including clinical predictors in the combined samples. CONCLUSIONS: Our results illustrate the consistency and differences in the determinants of genetic susceptibility to CHD in diabetic patients and the general populations.

The SH2B1 obesity locus is associated with myocardial infarction in diabetic patients and with NO synthase activity in endothelial cells.

OBJECTIVE: Obesity and cardiovascular disease recognize a common metabolic soil and may therefore share part of their genetic background. Genome-wide association studies have identified variability at the SH2B1 locus as a predictor of obesity. We investigated whether SNP rs4788102, which captures the entire SH2B1 variability, is associated with coronary artery disease (CAD) and/or myocardial infarction (MI) in patients with type 2 diabetes mellitus (T2DM). DESIGN AND SETTING: SNP rs4788102 was typed in 2015 White subjects with T2DM from three CAD case-control studies [n=740 from the Gargano Hearth Study (GHS, Italy); n=818 from the Joslin Hearth Study (JHS, Boston); n=457 from the University of Catanzaro (CZ, Italy)]. RESULTS: SNP rs4788102 (G/A) was not associated with CAD (overall allelic OR=1.06, 95% CI=0.93-1.21; p=0.37). On the contrary, it was associated with MI in GHS (1.42, 1.12-1.81; p=0.004) and in the three samples analyzed together (1.21, 1.04-1.41; p=0.016). Insulin stimulated nitric oxide synthase (NOS) activity in human vein endothelial cells from G/G (n=4, p=0.03) but not the G/A (n=5, p=0.83) genotype. Of the SNPs in perfect LD with rs4788102, one (rs7498665) affects amino acid polarity (Ala484Thr) and falls into a highly conserved protein segment of SH2B1 containing a class II SH3 domain binding site. CONCLUSIONS: Variability at the SH2B1 obesity locus is associated with MI in diabetic patients and with reduced insulin-stimulated NOS activity in human endothelial cells. Further studies are needed to replicate this association and dissect the biology underlying this finding.

Alexithymia and anxiety sensitivity in patients with non-cardiac chest pain.

The aim of this study was to examine independent and combined influences of alexithymia and anxiety sensitivity on chest pain and life interference in patients with non-cardiac chest pain (NCCP). Theories of NCCP posit a central role for emotion in the experience of chest pain, however, studies have not examined how alexithymia characterized by a difficulty identifying or verbalizing emotions, may influence this relationship. This study examined 231 patients (56% females, M age=50 years) with chest pain seeking cardiac evaluation, who showed no abnormalities during exercise tolerance testing. Forty percent (40%) scored at or above the moderate range of alexithymia. Whereas health care utilization was associated with elevated alexithymia among men, health care utilization was associated with elevated anxiety sensitivity among women. Hierarchical regression analyses revealed that alexithymia and anxiety sensitivity were both uniquely and independently associated with pain severity and life interference due to pain. Alexithymia-pain links were stronger for men compared to women. Secondary analyses conducted with a subsample suggest that alexithymia may be increasingly stable over time (i.e., 18-month follow-up). Findings are largely congruent with theoretical models of NCCP showing that personality and emotional factors are important in this medically unexplained syndrome.

The type 2 diabetes and insulin-resistance locus near IRS1 is a determinant of HDL cholesterol and triglycerides levels among diabetic subjects.

OBJECTIVE: SNP rs2943641 near the insulin receptor substrate 1 (IRS1) gene has been found to be associated with type 2 diabetes (T2D) and insulin-resistance in genome-wide association studies. We investigated whether this SNP is associated with cardiovascular risk factors and coronary artery disease (CAD) among diabetic individuals. METHODS: SNP rs2943641 was typed in 2133 White T2D subjects and tested for association with BMI, serum HDL cholesterol and triglycerides, hypertension history, and CAD risk. RESULTS: HDL cholesterol decreased by 1mg/dl (p = 0.004) and serum triglycerides increased by 6 mg/dl (p = 0.016) for each copy of the insulin-resistance allele. Despite these effects, no association was found with increased CAD risk (OR = 1.00, 95% CI 0.88-1.13). CONCLUSIONS: The insulin-resistance and T2D locus near the IRS1 gene is a determinant of lower HDL cholesterol among T2D subjects. However, this effect is small and does not translate into a detectable increase in CAD risk in this population.

The ENPP1 Q121 variant predicts major cardiovascular events in high-risk individuals: evidence for interaction with obesity in diabetic patients.

OBJECTIVE: Insulin resistance (IR) and cardiovascular disease may share a common genetic background. We investigated the role of IR-associated ENPP1 K121Q polymorphism (rs1044498) on cardiovascular disease in high-risk individuals. RESEARCH DESIGN AND METHODS: A prospective study (average follow-up, 37 months) was conducted for major cardiovascular events (myocardial infarction [MI], stroke, cardiovascular death) from the Gargano Heart Study (GHS; n = 330 with type 2 diabetes and coronary artery disease), the Tor Vergata Atherosclerosis Study (TVAS; n = 141 who had MI), and the Cardiovascular Risk Extended Evaluation in Dialysis (CREED) database (n = 266 with end-stage renal disease). Age at MI was investigated in cross-sectional studies of 339 type 2 diabetic patients (n = 169 from Italy, n = 170 from the U.S.). RESULTS: Incidence of cardiovascular events per 100 person--years was 4.2 in GHS, 10.8 in TVAS, and 11.7 in CREED. Hazard ratios (HRs) for KQ+QQ versus individuals carrying the K121/K121 genotype (KK) individuals were 1.47 (95% CI 0.80-2.70) in GHS, 2.31 (95% CI 1.22-4.34) in TVAS, and 1.36 (95% CI 0.88-2.10) in CREED, and 1.56 (95% CI 1.15-2.12) in the three cohorts combined. In the 395 diabetic patients, the Q121 variant predicted cardiovascular events among obese but not among nonobese individuals (HR 5.94 vs. 0.62, P = 0.003 for interaction). A similar synergism was observed in cross-sectional studies, with age at MI being 3 years younger in Q121 carriers than in KK homozygotes among obese but not among nonobese patients (P = 0.035 for interaction). CONCLUSIONS: The ENPP1 K121Q polymorphism is an independent predictor of major cardiovascular events in high-risk individuals. In type 2 diabetes, this effect is exacerbated by obesity. Future larger studies are needed to confirm our finding.

Anxiety and hypervigilance to cardiopulmonary sensations in non-cardiac chest pain patients with and without psychiatric disorders.

We investigated body vigilance, cardiac anxiety, and the mediating role of interoceptive fear on pain in patients with non-cardiac chest pain (NCCP; a syndrome of chest pain in the absence of identifiable organic etiology). Patients were more attentive to cardiac-congruent sensations than cardiac-incongruent sensations (e.g., gastrointestinal, cognitive dyscontrol; p's < .001). Patients with a DSM-IV Axis I anxiety or mood disorder were more body vigilant compared to patients who did not have a disorder (p's < .05). Patients with anxiety disorders were particularly vigilant to and fearful of cardiac sensations relative to patients without anxiety disorders. Latent variable path models examined the extent that interoceptive fear mediated the association between body vigilance and cardiac anxiety on chest pain. Within each model, diagnostic status, body vigilance, and cardiac anxiety were exogenous and predicted interoceptive fear that in turn predicted pain. Separate models examined body vigilance and cardiac anxiety, and both models fit the data well. Findings showed partial mediation for the body vigilance factor, and full mediation for the cardiac anxiety factor. Interoceptive fear played a mediating role in both models. The syndrome of NCCP may persist partly due to conscious hypervigilance to and fear of cardiac-congruent body sensations, particularly among anxious patients.

Interaction between poor glycemic control and 9p21 locus on risk of coronary artery disease in type 2 diabetes.

CONTEXT: A common allele on chromosome 9p21 has been repeatedly associated with increased risk of coronary artery disease (CAD) in the general population. However, the magnitude of this effect in the population with diabetes has not been well characterized. OBJECTIVE: To examine the association of the 9p21 variant with CAD in individuals with type 2 diabetes and evaluate its interaction with poor glycemic control. DESIGN, SETTING, AND PARTICIPANTS: (1) Case-control study of 734 type 2 diabetes patients (322 with angiographically diagnosed CAD and 412 with no evidence of CAD) who were recruited between 2001 and 2006 at the Joslin Clinic, Beth Israel Deaconess Medical Center; and (2) independent cohort study of 475 type 2 diabetes patients from the Joslin Clinic whose survival status was monitored from their recruitment between 1993 and 1996 until December 31, 2004. Participants for both studies were genotyped for a representative single-nucleotide polymorphism at 9p21 (rs2383206) and characterized for their long-term glycemic control by averaging multiple hemoglobin A(1c) (HbA(1c)) measurements taken in the years before study entry. MAIN OUTCOME MEASURES: For the case-control study, association between single-nucleotide polymorphism rs2383206 and CAD defined as angiographically documented stenosis greater than 50% in a major coronary artery or a main branch thereof was assessed and for the cohort study, cumulative 10-year mortality was documented. RESULTS: Individuals who were homozygous for the risk allele were significantly more frequent among case than control participants (42.3% vs 28.9P = .0002). This association was unaffected by adjustment for cardiovascular risk factors, but the effect of the risk genotype was significantly magnified (adjusted P for interaction = .048) in the presence of poor glycemic control (worst tertile of the distribution of HbA(1c) at examination). Relative to the CAD risk for patients with neither a 9p21 risk allele nor poor glycemic control, the CAD odds for participants having 2 risk alleles but not poor glycemic control were increased 2-fold (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.17-3.41), whereas the odds for study participants with the same genotype and with poor glycemic control were increased 4-fold (OR, 4.27; 95% CI, 2.26-8.01). The interaction was stronger (adjusted P = .005) when a measure of long-term glycemic control (7-year average rather than most recent HbA(1c)) was used with ORs of 7.83 (95% CI, 3.49-17.6) for participants having 2 risk alleles and a history of poor glycemia and 1.54 (95% CI, 0.72-3.30) for participants with the same genotype but without this exposure. A similar interaction between 9p21 variant and poor glycemic control was observed with respect to cumulative 10-year mortality in the cohort study (43.6% in patients with 2 risk alleles and poor glycemic control, 23.1% in individuals with only the 2 risk alleles, 30.0% in individuals with only poor glycemic control, and 31.6% in individuals with neither factor, P for interaction, = .036). CONCLUSION: In this study population, the CAD risk associated with the 9p21 variant was increased in the presence of poor glycemic control in type 2 diabetes.

Tag polymorphisms at the A20 (TNFAIP3) locus are associated with lower gene expression and increased risk of coronary artery disease in type 2 diabetes.

A20 or tumor necrosis factor (TNF)-induced protein 3 (TNFAIP3) is a negative regulator of nuclear factor-kappaB (NF-kappaB). We have investigated whether polymorphisms in this gene are associated with increased atherosclerosis in diabetic patients. Five tag single nucleotide polymorphisms (SNPs) were typed in 479 type 2 diabetic patients from Boston, including 239 coronary artery disease (CAD)-positive case subjects and 240 CAD-negative control subjects. Two tag SNPs (rs5029930 and rs610604) were independently associated with CAD; adjusted odds ratios (ORs) for minor allele carriers were 2.3 (95% CI 1.4-3.8, P = 0.001) and 2.0 (1.3-2.9, P = 0.0008), respectively. The association with rs610604 was dependent on glycemic control, with ORs of 3.9 among subjects with A1C < or =7.0% and 1.2 for those with A1C >7.0% (P for interaction = 0.015). A similar interaction pattern was found among 231 CAD-positive and 332 CAD-negative type 2 diabetic patients from Italy (OR 2.2, P = 0.05 vs. OR 0.9, P = 0.63 in the low vs. high A1C strata, P for interaction = 0.05). Quantitative RT-PCR in blood mononuclear cells from 83 nondiabetic subjects showed that rs610604 and rs5029930 minor allele homozygotes have 30-45% lower levels of A20 mRNA than major allele homozygotes, and heterozygotes have intermediate levels (P = 0.04 and 0.028, respectively). These findings point to variability in the A20/TNFAIP3 gene as a modulator of CAD risk in type 2 diabetes. This effect is mediated by allelic differences in A20 expression.

Genetic variability at the leptin receptor (LEPR) locus is a determinant of plasma fibrinogen and C-reactive protein levels.

OBJECTIVE: Cellular and animal studies suggest that leptin has proinflammatory and prothrombotic effects that could link increased adipose mass directly to atherogenesis. To investigate this hypothesis, we examined the effect of genetic variability at the leptin receptor (LEPR) locus on the plasma levels of fibrinogen and CRP--two markers of inflammation and susceptibility to atherosclerosis. METHODS AND RESULTS: Linkage disequilibrium analysis of 71 single-nucleotide polymorphisms (SNPs) spanning the LEPR locus revealed four haplotype blocks that could be tagged by 11 SNPs. In 630 healthy Caucasian individuals, variability in block #4 was significantly associated with plasma fibrinogen (p=0.005), accounting for 3% of its variance (r2=0.030). The same block was also associated with CRP levels (p=0.049, r2=0.022). The effect was strongest for two of the SNPs in this block. At rs3790432, fibrinogen was 10% higher in minor allele homozygotes than in major allele homozygotes and intermediate in heterozygotes (p=0.015). At rs1805096, it was 5% higher (p=0.007) and CRP 32% higher (p=0.011) in major allele homozygotes than in minor allele carriers. This pattern of association was also evident in the haplotype analysis. CONCLUSIONS: Association of leptin receptor variability with inflammatory traits supports the hypothesis that leptin may play a role in atherogenesis.