James S. Pankow

Type 2 diabetes, glucose homeostasis and incident atrial fibrillation: the Atherosclerosis Risk in Communities study

Background Type 2 diabetes has been inconsistently associated with the risk of atrial fibrillation (AF) in previous studies that have frequently been beset by methodological challenges. Design Prospective cohort study. Setting The Atherosclerosis Risk in Communities (ARIC) study. Participants Detailed medical histories were obtained from 13 025 participants. Individuals were categorised as having no diabetes, pre-diabetes or diabetes based on the 2010 American Diabetes Association criteria at study baseline (1990–2). Main outcome measures Diagnoses of incident AF were obtained to the end of 2007. Associations between type 2 diabetes and markers of glucose homeostasis and the incidence of AF were estimated using Cox proportional hazards models after adjusting for possible confounders. Results Type 2 diabetes was associated with a significant increase in the risk of AF (HR 1.35, 95% CI 1.14 to 1.60) after adjustment for confounders. There was no indication that individuals with pre-diabetes or those with undiagnosed diabetes were at increased risk of AF compared with those without diabetes. A positive linear association was observed between HbA1c and the risk of AF in those with and without diabetes (HR 1.13, 95% CI 1.07 to 1.20) and HR 1.05, 95% CI 0.96 to 1.15 per 1% point increase, respectively). There was no association between fasting glucose or insulin in those without diabetes, but a significant association with fasting glucose was found in those with the condition. The results were similar in white subjects and African-Americans. Conclusions Diabetes, HbA1c level and poor glycaemic control are independently associated with an increased risk of AF, but the underlying mechanisms governing the relationship are unknown and warrant further investigation.

Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Nondiabetic Adults

BACKGROUND Fasting glucose is the standard measure used to diagnose diabetes in the United States. Recently, glycated hemoglobin was also recommended for this purpose. METHODS We compared the prognostic value of glycated hemoglobin and fasting glucose for identifying adults at risk for diabetes or cardiovascular disease. We measured glycated hemoglobin in whole-blood samples from 11,092 black or white adults who did not have a history of diabetes or cardiovascular disease and who attended the second visit (occurring in the 1990-1992 period) of the Atherosclerosis Risk in Communities (ARIC) study. RESULTS The glycated hemoglobin value at baseline was associated with newly diagnosed diabetes and cardiovascular outcomes. For glycated hemoglobin values of less than 5.0%, 5.0 to less than 5.5%, 5.5 to less than 6.0%, 6.0 to less than 6.5%, and 6.5% or greater, the multivariable-adjusted hazard ratios (with 95% confidence intervals) for diagnosed diabetes were 0.52 (0.40 to 0.69), 1.00 (reference), 1.86 (1.67 to 2.08), 4.48 (3.92 to 5.13), and 16.47 (14.22 to 19.08), respectively. For coronary heart disease, the hazard ratios were 0.96 (0.74 to 1.24), 1.00 (reference), 1.23 (1.07 to 1.41), 1.78 (1.48 to 2.15), and 1.95 (1.53 to 2.48), respectively. The hazard ratios for stroke were similar. In contrast, glycated hemoglobin and death from any cause were found to have a J-shaped association curve. All these associations remained significant after adjustment for the baseline fasting glucose level. The association between the fasting glucose levels and the risk of cardiovascular disease or death from any cause was not significant in models with adjustment for all covariates as well as glycated hemoglobin. For coronary heart disease, measures of risk discrimination showed significant improvement when glycated hemoglobin was added to models including fasting glucose. CONCLUSIONS In this community-based population of nondiabetic adults, glycated hemoglobin was similarly associated with a risk of diabetes and more strongly associated with risks of cardiovascular disease and death from any cause as compared with fasting glucose. These data add to the evidence supporting the use of glycated hemoglobin as a diagnostic test for diabetes.

Recent trends in acute coronary heart disease : Mortality, morbidity, medical care, and risk factors

BACKGROUND Mortality from coronary heart disease (CHD) has declined in the United States since the late 1960s. To understand the reasons for the decline during the period form 1985 to 1990, we examined trends in mortality and morbidity due to CHD, medical care, and risk factors for CHD in a large metropolitan population. METHODS We identified all deaths from CHD in residents of the Minneapolis-St. Paul, Minnesota, metropolitan area who were 30 to 74 years old and classified the deaths according to whether they occurred in or out of the hospital. For 1985 and 1990, we obtained lists of patients in this age range who were discharged with a diagnosis of acute CHD from all area hospitals, and we selected the medical records of 50 percent of these patients for abstraction. Definite myocardial infarctions were identified with standardized diagnostic algorithm. The 1985 and 1990 cohorts of patients hospitalized for myocardial infarction were followed for at least three years to identify those who died from any cause. Trends in risk factors for CHD were investigated through surveys of 25-to-74-year-olds that were conducted in 1985 through 1987 and 1990 through 1992. RESULTS Between 1985 and 1990, mortality from CHD fell by 25 percent for both men and women, and the decline in in-hospital mortality (41 percent) exceeded the decline in out-of-hospital mortality (17 percent) among men. The rates of hospitalization for acute myocardial infarction declined slightly, by 5 to 10 percent, between 1985 and 1990. Survival among patients hospitalized for acute myocardial infarction increased substantially during that period. After adjustment for age and previous myocardial infarction, the relative risk of dying within three years of hospitalization for a myocardial infarction (for the 1990 cohort as compared with the 1985 cohort) was 0.76 for men (95 percent confidence interval, 0.65 to 0.89) and 0.84 for women (95 percent confidence interval, 0.71 to 1.00). Substantial increases in the use of thrombolytic therapy, heparin, aspirin, and coronary angioplasty paralleled the survival trends. In general, the risk-factor profile of the area population with respect to CHD also improved considerably during that time. CONCLUSIONS The recent decline in mortality due to CHD in the Minneapolis-St. Paul metropolitan area can be explained by both the declining incidence of myocardial infarction in the population and the improved survival of patients with myocardial infarction.

Genetic Structure, Self-Identified Race/Ethnicity, and Confounding in Case-Control Association Studies

We have analyzed genetic data for 326 microsatellite markers that were typed uniformly in a large multiethnic population-based sample of individuals as part of a study of the genetics of hypertension (Family Blood Pressure Program). Subjects identified themselves as belonging to one of four major racial/ethnic groups (white, African American, East Asian, and Hispanic) and were recruited from 15 different geographic locales within the United States and Taiwan. Genetic cluster analysis of the microsatellite markers produced four major clusters, which showed near-perfect correspondence with the four self-reported race/ethnicity categories. Of 3,636 subjects of varying race/ethnicity, only 5 (0.14%) showed genetic cluster membership different from their self-identified race/ethnicity. On the other hand, we detected only modest genetic differentiation between different current geographic locales within each race/ethnicity group. Thus, ancient geographic ancestry, which is highly correlated with self-identified race/ethnicity--as opposed to current residence--is the major determinant of genetic structure in the U.S. population. Implications of this genetic structure for case-control association studies are discussed.

Acute-phase Inflammatory Response to Periodontal Disease in the US Population

Moderate elevation of serum C-reactive protein (CRP) is a risk factor for cardiovascular disease among apparently healthy individuals, although factors that create this inflammatory response in the absence of systemic illness have not been clarified. This study aimed to: (1) evaluate associations among periodontal disease, established risk factors for elevated CRP, and CRP levels within the US population; and (2) determine whether total tooth loss is associated with reduced CRP. Data were obtained from the third National Health and Nutrition Examination Survey. A random sample of the US population was interviewed in their homes and examined at mobile examination centers. CRP was quantified from peripheral blood samples and analyzed as a continuous variable and as the prevalence of elevated CRP (≥ 10 mg/L). Some 12,949 people aged 18+ years who had periodontal examinations and an additional 1817 edentulous people aged 18+ years were included in the analysis. Dentate people with extensive periodontal disease (> 10% of sites with periodontal pockets 4+ mm) had an increase of approximately one-third in mean CRP and a doubling in prevalence of elevated CRP compared with periodontally healthy people. Raised CRP levels among people with extensive periodontal disease persisted in multivariate analyses (P < 0.01), with established risk factors for elevated CRP (diabetes, arthritis, emphysema, smoking, and anti-inflammatory medications) and sociodemographic factors controlled for. However, CRP levels were similarly raised in edentulous people. Furthermore, the established risk factors for elevated CRP modified relationships between oral status and CRP levels. Periodontal disease and edentulism were associated with systemic inflammatory response in the US population, most notably among people who had no established risk factors for elevated CRP.

Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study.

Inflammation is thought to play a central role in the etiology and outcome of atherosclerosis. Animal studies as well as in vitro and in vivo human studies suggest that host factors modulate the magnitude and extent of inflammatory responses. We investigated familial aggregation of three systemic markers of inflammation (C-reactive protein (CRP), white blood cell count (WBC), and albumin) in a large, cross-sectional study conducted in four US communities. We found evidence of substantial heritability (35-40%) for CRP levels as well as for WBC and albumin levels. Negligible spouse correlations suggested little influence of shared household environment on these traits. The combination of sociodemographic factors (age, center, education), behavioral and lifestyle factors (cigarette smoking, alcohol intake, hormone replacement therapy), obesity and fat patterning, and prevalent diabetes explained 13-30% the interindividual variability of these traits. There was no evidence that these inflammation phenotypes were linked to a microsatellite marker in the interleukin-1 gene cluster on chromosome 2q, a region that includes several candidate genes for chronic inflammatory diseases. Our findings suggest that CRP levels, albumin levels, and WBC are determined at least partially by genetic factors. Further efforts to identify gene loci affecting these traits are warranted.

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

NRXN3 Is a Novel Locus for Waist Circumference: A Genome-Wide Association Study from the CHARGE Consortium

Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4×10−7)]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3×10−8 for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4×10−6, 0.024 z-score units (0.10 kg/m2) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07–1.19; p = 3.2×10−5 per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

Association of C-reactive protein with markers of prevalent atherosclerotic disease

Recent prospective studies have demonstrated that elevated C-reactive protein (CRP) is a marker of increased risk of atherothrombotic clinical events. We examined in a large, cross-sectional family-based study (n = 875 men, 948 women) whether serum CRP was associated with prevalent coronary heart disease (CHD), the ankle/brachial blood pressure index, or carotid intima-media thickness, an indicator of subclinical atherosclerosis as assessed by B-mode ultrasound. CRP was associated with many other cardiovascular risk factors, particularly markers of obesity and insulin resistance, markers of inflammation and acute phase reaction, and hormone replacement therapy. Adjusted for age and family type, there was a weak positive association of CRP with carotid intima-media thickness in both genders and with prevalent CHD in women. However, adjustment for other risk factors completely eliminated the associations. For example, among women, the risk factor-adjusted mean values of intima-media thickness across quartiles of CRP were 0.76, 0.74, 0.75, and 0.76 mm (p >0.5). In men there was a weak inverse association between CRP and ankle/brachial blood pressure index, independent of other risk factors, but no such association in women. Our findings indicate that CRP is not strongly and independently associated with prevalent atherosclerosis. Because CRP has been associated with clinical events, it could be that elevated CRP may be a stronger marker of thrombotic risk than of the degree of atherosclerosis.

Cardiovascular Events in Diabetic and Nondiabetic Adults With or Without History of Myocardial Infarction

Background—Whether diabetic patients without a history of myocardial infarction (MI) have the same risk of coronary heart disease (CHD) events as nondiabetic patients with a history of MI remains controversial. We compared risks of CHD and stroke events and mortality from cardiovascular disease (CVD) in diabetic and nondiabetic men and women with and without a history of MI. Methods and Results—We followed a total of 13 790 African American and white men and women ages 45 to 64 years who participated in the Atherosclerosis Risk in Communities study, beginning in 1987 to 1989. There were 634 fatal CHD or nonfatal MI events, 312 fatal or nonfatal strokes, and 358 deaths from CVD during an average of 9 years of follow-up (125 998 person-years). After adjustment for age, sex, race, Atherosclerosis Risk in Communities field center, and multiple baseline risk factors, patients who had a history of MI without diabetes at baseline had 1.9 times the risk of fatal CHD or nonfatal MI (95% CI, 1.35 to 2.56; P <0.001) compared with diabetic patients without a prior history of MI. The nondiabetic patients with MI also had 1.8 times the risk of CVD mortality compared with diabetic patients without MI (95% CI, 1.22 to 2.72; P =0.003). However, stroke risk was similar between diabetic patients without MI and nondiabetic patients with MI (RR, 1.05; 95% CI, 0.61 to 1.79; P =0.87). We also observed that nondiabetic patients with MI had a carotid artery wall thickness similar to diabetic patients without MI (P =0.77). Conclusions—Diabetic patients without MI had lower risk of CHD events and mortality from CVD compared with nondiabetic patients with MI, but stroke risk was similar between these 2 groups.