ARIC Cohort Research Articles

Abstract 14594: Association Between Life's Simple 7 and Cardiovascular Disease in Cancer Patients Compared to Noncancer Controls in the Aric Cohort

Introduction: Cancer survivors have greater cardiovascular disease (CVD) risk through unclear mechanisms. Little is known about whether Life’s Simple 7 (LS7) metrics differ between persons with and without cancer and if the link between LS7 and CVD is similar in cancer survivors compared to persons without prior cancer. Hypothesis: Persons who develop cancer have poorer LS7 metrics compared to noncancer controls, and an ideal LS7 score is less protective against CVD events in persons with versus those without prior cancer. Methods: A total of 2950 ARIC participants who developed cancer were matched at the time of cancer diagnosis (incidence density sampling) on age, sex, race, and study center, to 5900 noncancer controls. We compared LS7 metrics in individuals who developed cancer (assessed prior to cancer diagnosis) and in matched controls. We used Cox regression to evaluate the prospective association between LS7 score and CVD events (coronary heart disease, heart failure or stroke) stratified by cancer status, with test for interaction between LS7 and cancer. Results: Compared to matched noncancer controls, those who developed cancer were less likely to have an ideal smoking history, body mass index, glucose control, physical activity levels, and diet (defined by LS7 metrics; Table ). Overall those with cancer were less likely to have an ideal LS7 score than noncancer controls (18 vs 23% p<0.0001). Compared to inadequate, an ideal LS7 score was similarly associated with lower CVD risk in persons with and without cancer (HRs 0.37 [95% CI: 0.26-0.52] and 0.40 [95% CI: 0.32-0.50], respectively), with no interaction between LS7 score and cancer status (p = 0.59). Conclusions: Individuals who develop cancer have poorer overall cardiovascular health as reflected by the LS7 score, but an ideal LS7 score is associated with similar cardio-protection in those with and without cancer. Cancer survivors may benefit from interventions targeting cardiovascular health metrics.

Human Brain Atlases in Stroke Management

Stroke is a leading cause of death and a major cause of permanent disability. Its management is demanding because of variety of protocols, imaging modalities, pulse sequences, hemodynamic maps, criteria for treatment, and time constraints to promptly evaluate and treat. To cope with some of these issues, we propose novel, patented solutions in stroke management by employing multiple brain atlases for diagnosis, treatment, and prediction. Numerous and diverse CT and MRI scans are used: ARIC cohort, ischemic and hemorrhagic stroke CT cases, MRI cases with multiple pulse sequences, and 128 stroke CT patients, each with 170 variables and one year follow-up. The method employs brain atlases of anatomy, blood supply territories, and probabilistic stroke atlas. It rapidly maps an atlas to scan and provides atlas-assisted scan processing. Atlas-to-scan mapping is application-dependent and handles three types of regions of interest (ROIs): atlas-defined ROIs, atlas-quantified ROIs, and ROIs creating an atlas. An ROI is defined by atlas-guided anatomy or scan-derived pathology. The atlas defines ROI or quantifies it. A brain atlas potential has been illustrated in four atlas-assisted applications for stroke occurrence prediction and screening, rapid and automatic stroke diagnosis in emergency room, quantitative decision support in thrombolysis in ischemic stroke, and stroke outcome prediction and treatment assessment. The use of brain atlases in stroke has many potential advantages, including rapid processing, automated and robust handling, wide range of applications, and quantitative assessment. Further work is needed to enhance the developed prototypes, clinically validate proposed solutions, and introduce them to clinical practice.

THE RELATIONSHIP OF APOE ε4 TO THE RELATIVE TIMES AND HAZARDS OF DEMENTIA

Although APOE ε4 is an established risk factor for dementia, it is unclear whether it is associated with elevated risk or earlier symptom onset. Longitudinal study of 10,400 white-race individuals in the ARIC cohort followed from age 60 to incident dementia diagnosis, death, or censoring. All-cause dementia was defined using standardized algorithms incorporating longitudinal cognitive change, proxy report, and hospital or death certificate dementia codes. Death was ascertained via the National Death Index and death certificates. We used a parametric mixture of generalized gamma distributions to simultaneously estimate the distribution of event times and the proportion of individuals who experience each outcome (i.e., dementia and its competing risk, dementia-free death) by APOE ε4 status (≥ 1 allele vs. no alleles). Age-adjustment was through use of age as the time scale. APOE ε4 carrier status was associated with a doubling of the overall frequency of dementia incidence to 25% compared to 13% (p < 0.001) in non- ε4 carriers. The distributions of time to dementia was modified by APOE ε4 status (p=0.007): median time to dementia onset among APOE ε4 carriers was 81.9 years compared to 83.3 years in non-APOE ε4 carriers (p = 0.005). No differences in results were found by sex. APOE ε4 carrier status is associated with both elevated risk and earlier time to dementia onset. These findings clarify the causal role of APOE in dementia etiology, could help better identify at-risk subgroups, and may help facilitate better research recruitment.

4302Machine-learning integration of complex echocardiographic patterns and clinical parameters from cohorts and trials

Abstract Introduction Contemporary machine learning (ML) allows comparing individuals based on a wide range of heterogenous data. We aimed to use similarity-based unsupervised ML to integrate clinical variables and complex imaging patterns from a population-based cohort (Atherosclerosis Risk in Communities study - ARIC) with a HFPEF (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist - TOPCAT) as well as a HFREF (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy - MADIT-CRT) clinical trial and to predict the outcome of the patients based on their location in the derived ML universe, rather than on their original cohort. Methods An unsupervised ML for dimensionality reduction algorithm (multiple kernel learning) was trained using 2123 subjects enrolled in ARIC. The algorithm positioned them based on similarities in longitudinal strain patterns of 12 LV regions and an LV volume curve, together with 17 clinical parameters (age, sex, myocardial infarct, QRS width, prior HF, LVEDVi, LAVi, race, heart rate, SBP, BP meds, diabetes, smoking status, BMI, GLS, LVMi, LVEF). Using the same descriptors, 105 untreated TOPCAT and 429 untreated MADIT-CRT patients were projected onto the learned space (upper-left figure). A k-means algorithm was subsequently used to partition the resulting space into 3 clusters (broadly speaking, the number of expected clinical categories: controls (ARIC), HFPEFs (TOPCAT) and HFREFs (MADIT-CRT) (upper-right figure). Finally, cluster-wise event rates (composite of death or HF hospitalization) were computed for the combination of the two trials (bottom-left figure) and only considering subjects from ARIC (bottom-right figure). Results The visualisation of the low-dimensional space (upper-left figure) showed a clear aggregation of individuals according to the study, highlighting their different clinical and deformation properties. The individuals located around the MADIT-CRT patients (predominantly in cluster 3) showed the highest event rate (26.6%, similar to the MADIT-CRT event rate 25.4%) while those around the majority of the ARIC cohort showed the lowest rates (5.3%, similar to the ARIC event rate 5.7%). The MADIT-CRT-like ARIC individuals showed a much higher event-rate compared to the one expected from the cohort (21.1% vs 5.7%). Figure 1 Conclusion Our results serve as a proof-of-concept that unsupervised ML based analysis of complex clinical and imaging data can be used to integrate patient-based data, including complex echocardiographic data, to project individuals onto a multi-dimensional space with event rates that track with multidimensional location. Acknowledgement/Funding ARIC and TOPCAT were funded by the National Heart, Lung and Blood Institute, MADIT-CRT by Boston Scientific

Abstract MP03: Aortic Stiffening and Intracranial Atherosclerosis: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS)

Introduction: Stiffening of the aorta is associated with increased pulse pressure and transmission of pulsatile energy into the cerebral circulation. An association between increased aortic stiffening with intracranial atherosclerotic disease (ICAD) has not been widely studied. We tested the hypothesis that loss of aortic elasticity (i.e. higher aortic stiffness) is associated with a higher presence of ICAD. Methods: ARIC-NCS participants (n=1412; mean age: 76 years; 42% male; 30% Black) with measures of aortic stiffness and vascular brain magnetic resonance imaging (MRI) at the visit 5 (2011-2013) examination were included. Aortic stiffness was measured by carotid-femoral pulse wave velocity (cfPWV) using the VP-1000 Plus device (Omron Co., Japan). cfPWV was discretized into high vs. low aortic stiffness based on the upper 25 th percentile, 13.4 m/s. Brain MRI was performed on 3.0 Tesla scanners using a standardized protocol that included an MR angiography (MRA) and high isotropic resolution vessel MRI. Presence of ICAD was defined as eccentric wall thickening with or without luminal stenosis on MRA. We first examined the functional form relationship between continuous measures of cfPWV and ICAD. Comparing those with high vs. low aortic stiffening, we estimated the prevalence odds of ICAD using logistic regression. Models were adjusted for age, sex, race-center, education, smoking, heart rate, blood-pressure lowering medication, diabetes, LDL-cholesterol, and minutes/week of physical activity. Sampling weights were used for generalizability to the full ARIC cohort at visit 5. We tested for effect modification by race, sex, diabetes, central systolic blood pressure, and use of blood pressure-lowering medication. Results: The mean cfPWV was higher among participants with ICAD (12.6 ± 3.2 m/s) compared to those without ICAD (11.2 ± 2.9 m/s). cfPWV was associated with ICAD in a monotonic, linear fashion (p&lt;0.05). The presence of ICAD was 50.6% among participants with high aortic stiffness (cfPWV above the upper 25th percentile; n=354) compared to 30.2% among participants with low aortic stiffness (n=1058). Compared to participants with low aortic stiffness, those with high aortic stiffness had two-fold higher odds of ICAD (odds ratio (OR): 1.97, 95% confidence interval (CI): 1.68, 2.33). No statistically significant modification of this association was observed. Results were robust to exclusions for prevalent stroke (n=43) and prevalent cardiovascular disease (n=153). Conclusions: Aortic stiffness, a highly prevalent trait among older men and women, is associated with ICAD presence quantified by magnetic resonance angiography. Aortic stiffness, its risk factors and the factors associated with the preservation of aortic elasticity, may play a role in modifying the risk of intracranial atherosclerosis.

P2546High birth weight and cardiovascular outcomes in the ARIC cohort study

P2546High birth weight and cardiovascular outcomes in the ARIC cohort study

Abstract P190: Triggering of Coronary Heart Disease by Infection Type: The Atherosclerosis Risk in Communities Study

Introduction: Acute infections are known triggers of coronary heart disease (CHD). It is unclear how the strength of the association varies by infection type. Hypothesis: We hypothesized that all acute infections increase CHD risk but the level of increased risk varies by infection type. Methods: Incident CHD (myocardial infarction and fatal CHD) cases were identified and adjudicated in the ARIC cohort. ARIC participants were linked to Medicare claims data. We used ICD-9 codes to identify 4 infection types based on infection frequency: cellulitis, pneumonia, urinary tract infections (UTI), and bloodstream infections. We used a case-crossover design and conditional logistic regression to compare infections among CHD cases 90 days before the event with two corresponding control periods 1 year and 2 years prior. The Wald test was used to assess differences between infection types. Results: A total of 1,312 CHD cases were identified. Among cases, 43 had cellulitis, 102 had pneumonia, 116 had a UTI, and 28 had a bloodstream infection within 90 days of the CHD event. All infection types were associated with higher CHD risk within 90 days of the infection; (odds ratios and 95% Cis) (cellulitis = 1.41 (0.93, 2.15), pneumonia = 5.60 (3.72, 8.43), UTI = 2.62 (1.92, 3.57), bloodstream infections = 4.77 (2.34, 9.71)) although cellulitis was not statistically significant (Figure). The association between infection and CHD was significantly stronger for pneumonia, UTI, and bloodstream infections compared to cellulitis (p&lt;0.05). Pneumonia and bloodstream infections were stronger CHD triggers compared to UTI but only pneumonia reached statistical significance (p&lt;0.05). Conclusions: Patients with pneumonia or bloodstream infections may be at particularly elevated CHD risk. Clinical trials of CHD preventive therapies during and immediately following infection to reduce the otherwise elevated CHD risk are needed. Healthcare providers should consider CHD risk during and immediately after infection and optimize preventive therapies.

Abstract P156: Comorbidity Profile Preceding Dementia Diagnosis: Findings From the Atherosclerosis Risk in Communities (ARIC) Study Cohort

Background: Most patients receive a diagnosis of dementia late in the course of the disease. In an effort to learn more about the potential for earlier detection, we examined comorbidity burden preceding a diagnosis of dementia in a cohort of older adults. Methods: Cognitive status of ARIC Study cohort participants (n=6,538) was adjudicated at Visit 5 (2011-2013) by a classification committee of physicians and neuropsychologists using a battery of neurocognitive tests, functional assessments, and neurologic exam. Additionally, cognitive status of participants who did not attend the Visit 5 examination, but were alive at the time of the visit (n= 2,289) was ascertained through a Telephone Interview for Cognitive Status-Modified (TICS) or Clinical Dementia Rating (CDR) informant interview. We examined the presence of dementia diagnostic codes in claims for inpatient and outpatient services occurring during the years 1991-2013 and preceding dementia diagnoses among all ARIC cohort participants with a dementia classification. In a sample of study participants who were enrolled in continuous fee-for-service (FFS) Medicare for at least 5 years prior to dementia ascertainment, we examined the comorbidity profile preceding the date of dementia ascertainment using ICD9 diagnostic codes obtained from inpatient records and claims for outpatient office visits. Results: Of the 7,283 ARIC participants enrolled in FFS Medicare at the time of ARIC dementia ascertainment (39.6% men, 26.4% black, mean age 76.7 years (SD 5.4)), 901 (12.4%) were classified as having dementia. Only 41.3% of those classified with dementia and 2.6% of those classified as cognitively intact had dementia diagnostic codes in any position in claims for inpatient or outpatient care preceding the ascertainment of cognitive status. In analyses limited to participants with 5 years of continuous FFS Medicare enrollment prior to the cognitive status ascertainment, we observed a consistently greater frequency of hospitalizations among study participants with a subsequent dementia classification, as compared to those with no cognitive impairment (1.62 (SD 0.08) vs. 1.10 (SD 0.05) hospitalizations per participant in the year preceding dementia diagnosis, respectively). No difference in the frequency of outpatient visits was observed. In addition to a greater frequency of diagnostic codes for cerebrovascular disease and cerebral degeneration, those with a positive dementia classification had a greater prior frequency of ICD9 codes for depression, heart failure, acute renal failure, and fluid and electrolyte disorders, as compared to those with no cognitive impairment. Conclusion: Dementia patients may have distinct comorbidity profiles in the years preceding a diagnosis. A greater understanding of these profiles is important for characterizing patient factors that may enable early detection and management.

Abstract P009: Association of MRI Signs With Development of Mild Cognitive Impairment and Dementia: The Atherosclerosis Risk in Communities (ARIC) Study

Background: Brain infarcts, white matter hyperintensities (WMH), and brain atrophy appear to contribute to the development of mild cognitive impairment (MCI) and dementia in selected populations, but few prospective studies are available in general populations. Methods: The study included 732 black and white participants, sampled from the original ARIC cohort, who had 3T brain Magnetic Resonance Imaging (MRI) scans, were free of MCI and dementia during 2011-13 (Visit 5), and were evaluated for cognitive impairment during 2016-17 (Visit 6, about 90% complete). We assessed the associations of brain infarcts, WMH, and brain volumes measured on MRI from 2011-2013 with incident MCI and dementia (combined), diagnosed using a computer algorithm based on specified criteria and comprehensive assessment at Visit 6. We used logistic regression, incorporating sampling weights, to evaluate the risk for incident MCI/dementia with adjustment for demographic covariates, major dementia risk factors, and history of cardiovascular diseases. Results: Participants had a median age of 75 (IQR: 71, 79) at Visit 5 (baseline); 62% (453) were female and 33% (242) were African American. There were 156 newly identified cases of MCI or dementia during a median follow-up time of 4.9 (IQR: 3.4, 5.2) years. The presence of any brain infarct was associated with a nonsignificantly higher risk of MCI/dementia (OR: 1.50; 95%CI: 0.87 to 2.58), but the only significant individual association was with cortical infarcts (OR: 1.99; 95%CI: 1.03 to 3.85). WMH volume above the median value was nonsignificantly associated with conversion to MCI/dementia. Smaller Alzheimer’s disease (AD) signature region was an independent predictor for greater risk of MCI/dementia (OR: 1.49; 95%CI: 1.00 to 2.22). A similar but nonsignificant association was observed for total brain volume. Conclusions: Brain infarcts (cortical infarcts) and lower brain volume (AD signature region), measured in community-based older residents, are risk factors for MCI and dementia incidence.

Admixture Mapping of Subclinical Atherosclerosis and Subsequent Clinical Events Among African Americans in 2 Large Cohort Studies.

Local ancestry may contribute to the disproportionate burden of subclinical and clinical cardiovascular disease among admixed African Americans compared with other populations, suggesting a rationale for admixture mapping. We estimated local European ancestry (LEA) using Local Ancestry inference in adMixed Populations using Linkage Disequilibrium method (LAMP-LD) and evaluated the association with common carotid artery intima-media thickness (cCIMT) using multivariable linear regression analysis among 1554 African Americans from MESA (Multi-Ethnic Study of Atherosclerosis). We conducted secondary analysis to examine the significant cCIMT-LEA associations with clinical cardiovascular disease events. We observed genome-wide significance in relation to cCIMT association with the SERGEF gene (secretion-regulating guanine nucleotide exchange factor; β=0.0137; P=2.98×10-4), also associated with higher odds of stroke (odds ratio=1.71; P=0.02). Several regions, in particular CADPS gene (Ca2+-dependent secretion activator 1) region identified in MESA, were also replicated in the ARIC cohort (Atherosclerosis Risk in Communities). We observed other cCIMT-LEA regions associated with other clinical events, most notably the regions harboring CKMT2 gene (creatine kinase, mitochondrial 2) and RASGRF2 gene (Ras protein-specific guanine nucleotide-releasing factor 2) with all clinical events except stroke, the LRRC3B gene (leucine-rich repeat containing 3B) with myocardial infarction, the PRMT3 gene (protein arginine methyltransferase 3) with stroke, and the LHFPL2 gene (lipoma high mobility group protein I-C fusion partner-like 2) with hard and all coronary heart disease. We identified several novel LEA regions, in addition to previously identified genetic variations, associated with cCIMT and cardiovascular disease events among African Americans.

Abstract P271: Association Between Nitric Oxide Synthase Gene Polymorphism ( Glu298Asp ) and Blood Pressure in Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Endothelial NO synthase ( eNOS ) gene polymorphism at position 894 (G&gt;T, Glu298Asp ) resulting in a T allele is related to higher blood pressure (BP) levels, but the association of Glu298Asp and temporal increase in BP in adulthood has not been studied, nor is it known whether the association between Glu298Asp and BP is modified by habitual intake of fruits and vegetables, an abundant source of nitrate for conversion to NO. Hypothesis: We hypothesized that homozygous (TT) or heterozygous genotype (GT) status of Glu298Asp is associated with BP increase over a course of 9 years among black and white adults, compared to normal genotype (GG). Further, the association is amplified by higher habitual intake of fruits and vegetables. Methods: Among 9488 white (mean age: 54.3 years, 47.0% men) and 2861 black members of the ARIC cohort (mean age: 53.4 years, 37.2% men) at baseline (1987-1989), genotyping of the NOS3 Glu298Asp polymorphism (rs1799983) was conducted using the TaqMan assay (Applied Biosystems, Foster City, CA, USA). The rs1799983 levels 1.5-2, 0.5-1.49, &lt;0.5 were categorized as TT, GT, GG, respectively. We used the average of repeated sitting blood pressure at 4 cohort examinations through 1996-1998. Average intake of vegetables and fruit was calculated from food frequency questionnaires at exams 1 and 3, and analyzed as quartiles. A diet score without fruit and vegetables intake was created using principal component analysis. Mixed models were used to estimate the association between NOS3 G894T (TT or GT vs. GG) with level and change of SBP and DBP, adjusting for age, sex, genotypes, BMI, smoking status, diabetes, and physical activity. The analysis was also conducted within each quartile of vegetables and fruit intake, with further adjustment for the diet score without fruit and vegetables intake. Results: The genotypes of TT, GT and GG of Glu298Asp were present in 800 (8.4%), 4057 (42.8%), 4631 (48.8%) white participants, and 26 (0.9%), 510 (17.8%), 2335 (81.3%) black participants. Among whites with the genotype GT/TT, DBP increased 2.46 mmHg (95% CI: 0.02, 4.90) over 9 years compared to GG participants. The interaction between Glu298Asp and intake of fruit and vegetables was not statistically significant. There was no statistically significant association between GT/TT and SBP, nor with 9-year change of SBP or DBP among black participants. Conclusion: Carrier status of the GT/TT genotypes of Glu298Asp is associated with higher level of DBP among white adults, but not with SBP over a course of 9 years compared to the GG genotype of Glu298Asp . There is no interaction found between Glu298Asp and intake of fruit and vegetables in association with SBP or DBP.

Best anthropometric discriminators of incident type 2 diabetes among white and black adults: A longitudinal ARIC study.

ObjectiveTo determine which anthropometric measures are the strongest discriminators of incident type 2 diabetes (T2DM) among White and Black males and females in a large U.S. cohort.MethodsWe used Atherosclerosis Risk in Communities study data from 12,121 participants aged 45–64 years without diabetes at baseline who were followed for over 11 years. Anthropometric measures included a body shape index (ABSI), body adiposity index (BAI), body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR), waist to height ratio (WHtR), and waist to hip to height ratio (WHHR). All anthropometric measures were repeated at each visit and converted to Z-scores. Hazard ratios and 95% confidence intervals adjusted for age were calculated using repeated measures Cox proportional hazard regression analysis. Akaike Information Criteria was used to select best-fit models. The magnitude of the hazard ratio effect sizes and the Harrell’s C-indexes were used to rank the highest associations and discriminators, respectively.ResultsThere were 1,359 incident diabetes cases. Higher values of all anthropometric measures increased the risk for development of T2DM (p < 0.0001) except ABSI, which was not significant in White and Black males. Statistically significant hazard ratios ranged from 1.26–1.63 for males and 1.15–1.88 for females. In general, the largest hazard ratios were those that corresponded to the highest Harrell’s C-Index and lowest Akaike Information Criteria values. Among White and Black males and females, BMI, WC, WHR, and WHtR were comparable in discriminating cases from non-cases of T2DM. ABSI, BAI, and WHHR were inferior discriminators of incident T2DM across all race-gender groups.ConclusionsBMI, the most commonly used anthropometric measure, and three anthropometric measures that included waist circumference (i.e., WC, WHR, WHtR) were the best anthropometric discriminators of incident T2DM across all race-gender groups in the ARIC cohort.

Factors Related to Differences in Retention among African American and White Participants in the Atherosclerosis Risk in Communities Study (ARIC) Prospective Cohort: 1987-2013.

Few studies have addressed retention of minorities, particularly African Americans, in longitudinal research. Our aim was to determine whether there was differential retention between African Americans and Whites in the ARIC cohort and identify cardiovascular disease (CVD) risk factors and indicators of socioeconomic status (SES) associated with these retention differences. 15,688 participants, 27% African American and 73% White, were included from baseline, 1987-1989, and classified as having died, lost or withdrew from study contact, or remained active in study calls through 2013. Life tables were created illustrating retention patterns stratified by race, from baseline through visit 5, 2011-2013. Prevalence tables stratified by race, participation status, and center were created to examine CVD risk factors and SES at baseline and visit 5. 54% of African Americans compared with 62% of Whites were still in follow-up by 2013. This difference was due to an 8% higher cumulative incidence of death among African Americans. Those who remained in follow-up had the lowest baseline CVD risk factors and better SES, followed by those who were lost/withdrew, then those who died. Whites had lower levels of most CVD risk factors and higher SES than African Americans overall at baseline and visit 5; though, the magnitude of visit 5 differences was less. In the ARIC cohort, retention differed among African Americans and Whites, but related more to mortality differences than dropping-out. Additional research is needed to better characterize the factors contributing to minority participants' recruitment and retention in longitudinal research.

Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease.

Genome-wide association studies (GWAS) of chronic periodontitis (CP) defined by clinical criteria alone have had modest success to-date. Here, we refine the CP phenotype by supplementing clinical data with biological intermediates of microbial burden (levels of eight periodontal pathogens) and local inflammatory response (gingival crevicular fluid IL-1β) and derive periodontal complex traits (PCTs) via principal component analysis. PCTs were carried forward to GWAS (∼2.5 million markers) to identify PCT-associated loci among 975 European American adult participants of the Dental ARIC study. We sought to validate these findings for CP in the larger ARIC cohort (n = 821 participants with severe CP, 2031—moderate CP, 1914—healthy/mild disease) and an independent German sample including 717 aggressive periodontitis cases and 4210 controls. We identified six PCTs with distinct microbial community/IL-1β structures, although with overlapping clinical presentations. PCT1 was characterized by a uniformly high pathogen load, whereas PCT3 and PCT5 were dominated by Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, respectively. We detected genome-wide significant signals for PCT1 (CLEC19A, TRA, GGTA2P, TM9SF2, IFI16, RBMS3), PCT4 (HPVC1) and PCT5 (SLC15A4, PKP2, SNRPN). Overall, the highlighted loci included genes associated with immune response and epithelial barrier function. With the exception of associations of BEGAIN with severe and UBE3D with moderate CP, no other loci were associated with CP in ARIC or aggressive periodontitis in the German sample. Although not associated with current clinically determined periodontal disease taxonomies, upon replication and mechanistic validation these candidate loci may highlight dysbiotic microbial community structures and altered inflammatory/immune responses underlying biological sub-types of CP.

Abstract P241: Correlates of Abdominal Aortic Diameters Among Persons without Abdominal Aortic Aneurysms: The Atherosclerosis Risk in Communities (ARIC) Study

Background: Evidence from cohort studies has demonstrated that advanced age, male gender, white race, greater height, smoking, hypertension and dyslipidemias for abdominal aortic aneurysm (AAA). However, the associations of these risk factors with increased abdominal aortic diameters among persons without AAA have not been extensively examined in prospective studies; such evidence may help further with AAA prevention strategies. Methods: We included participants of the ARIC cohort who underwent abdominal ultrasound in 2011-2013. We excluded participants with prior clinical AAAs identified from hospital discharge codes, death codes, Medicare outpatient claims, or an infrarenal abdominal aortic maximum diameter ≥ 3 cm in the ultrasound exam. Risk factors, when available, across five visits during 1987-2013 were analyzed as the weighted average, weighting by the number of years exposed, in logistic regression models to examine the relationships with risk of being in the highest quartile of infrarenal abdominal aortic maximum diameter (≥2.2 cm). The models were adjusted for attrition by using inverse probability weighting. Results: Of 5,671 participants included in the analysis, 40.4% were men and 22.1% were blacks. After adjustment for age, sex, race, and ARIC field center, greater smoking pack years and height were associated with great abdominal aortic diameter (odds ratio Highest Quintile vs. Lowest Quintile: 1.66 [95% CI: 1.41, 1.96; P for linear trend: 0.027] for smoking pack years, and 2.61 [95% CI: 1.99, 3.43; P for linear trend: &lt;0.001] for height), and high-density lipoprotein cholesterol was negatively associated with great abdominal aortic diameter (odds ratio Highest Quintile vs. Lowest Quintile: 0.69 [95% CI: 0.55, 0.87; P for linear trend: 0.007]). Men were more likely (odds ratio: 4.15 [95% CI: 3.67, 4.69]; P &lt;0.001) to be in the highest quartile of abdominal aortic diameters than women; and the association persisted after further adjusting for height and smoking pack years (odds ratio: 2.34 [95% CI: 1.94, 2.84]; P &lt;0.001). Other established AAA risk factors were not associated with abdominal aortic diameter. Conclusions: Among well-established AAA risk factors, male gender, cigarette smoking and greater height were positively associated while high-density lipoprotein cholesterol was inversely associated with greater abdominal aortic diameters among persons without AAA in this large population-based cohort.

Identifying a Deletion Affecting Total Lung Capacity Among Subjects in the COPDGene Study Cohort.

Chronic obstructive pulmonary disease (COPD) is a progressive disease with both environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified multiple genomic regions influencing risk of COPD. To thoroughly investigate the genetic etiology of COPD, however, it is also important to explore the role of copy number variants (CNVs) because the presence of structural variants can alter gene expression and can be causal for some diseases. Here, we investigated effects of polymorphic CNVs on quantitative measures of pulmonary function and chest computed tomography (CT) phenotypes among subjects enrolled in COPDGene, a multisite study. COPDGene subjects consist of roughly one-third African American (AA) and two-thirds non-Hispanic white adult smokers (with or without COPD). We estimated CNVs using PennCNV on 9,076 COPDGene subjects using Illumina's Omni-Express genome-wide marker array. We tested for association between polymorphic CNV components (defined as disjoint intervals of copy number regions) for several quantitative phenotypes associated with COPD within each racial group. Among the AAs, we identified a polymorphic CNV on chromosome 5q35.2 located between two genes (FAM153B and SIMK1, but also harboring several pseudo-genes) giving genome-wide significance in tests of association with total lung capacity (TLCCT ) as measured by chest CT scans. This is the first study of genome-wide association tests of polymorphic CNVs and TLCCT . Although the ARIC cohort did not have the phenotype of TLCCT , we found similar counts of CNV deletions and amplifications among AA and European subjects in this second cohort.

Positive association of tomato consumption with serum urate: support for tomato consumption as an anecdotal trigger of gout flares.

BackgroundGout is a consequence of an innate immune reaction to monosodium urate crystals deposited in joints. Acute gout attacks can be triggered by dietary factors that are themselves associated with serum urate levels. Tomato consumption is an anecdotal trigger of gout flares. This study aimed to measure the frequency of tomato consumption as a self-reported trigger of gout attacks in a large New Zealand sample set, and to test the hypothesis that tomato consumption is associated with serum urate levels.MethodsTwo thousand fifty one New Zealanders (of Māori, Pacific Island, European or other ancestry) with clinically-ascertained gout were asked about gout trigger foods. European individuals from the Atherosclerosis Risk In Communities (ARIC; n = 7517) Study, Cardiovascular Health Study (CHS; n = 2151) and Framingham Heart Study (FHS; n = 3052) were used to test, in multivariate-adjusted analyses, for association between serum urate and tomato intake.ResultsSeventy one percent of people with gout reported having ≥1 gout trigger food. Of these 20 % specifically mentioned tomatoes, the 4th most commonly reported trigger food. There was association between tomato intake and serum urate levels in the ARIC, CHS and FHS combined cohort (β = 0.66 μmolL−1 increase in serum urate per additional serve per week; P = 0.006) - evident in both sexes (men: β = 0.84 μmolL−1, P = 0.035; women: β = 0.59 μmolL −1, P = 0.041).ConclusionsWhile our descriptive and observational data are unable to support the claim that tomato consumption is a trigger of gout attacks, the positive association between tomato consumption and serum urate levels suggests that the self-reporting of tomatoes as a dietary trigger by people with gout has a biological basis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12891-015-0661-8) contains supplementary material, which is available to authorized users.

Periodontitis and retinal microcirculation in the Atherosclerosis Risk in Communities study.

The aim of this cross-sectional study is to explore if periodontitis is associated with alterations of the retinal microcirculation, a predictive marker of cardiovascular events. Of 457 subjects aged 52years and more from the ARIC cohort were included. Retinal vascular diameters were measured and summarized as central retinal arteriolar/venular equivalents (CRAE/CRVE). Periodontitis was determined by using the CDC/AAP definition. Multivariable linear regression models were used to estimate the relationships between CRAE, CRVE and periodontitis. No association was found between CRAE and periodontal status. However, CRVE and severe periodontitis were positively and significantly associated. Mean CRVE (±SD) was 187.0±17.2μm in the health-gingivitis group, and, respectively, 188.5±16.3μm (p=0.39) and 191.6±16.8μm (p=0.04) in moderate and severe periodontitis groups, after adjustment for a propensity score based on confounders. Results were consistent when analyses were restricted to participants with diabetes mellitus (n=66), but not diabetes-free subjects. Severe periodontitis is associated with larger retinal venular diameter in patients with type 2 diabetes. Further studies are needed to explore the impact of diabetes mellitus on the association between periodontitis and retinal microcirculation.

X-inactivation informs variance-based testing for X-linked association of a quantitative trait.

BackgroundThe X chromosome plays an important role in human diseases and traits. However, few X-linked associations have been reported in genome-wide association studies, partly due to analytical complications and low statistical power.ResultsIn this study, we propose tests of X-linked association that capitalize on variance heterogeneity caused by various factors, predominantly the process of X-inactivation. In the presence of X-inactivation, the expression of one copy of the chromosome is randomly silenced. Due to the consequent elevated randomness of expressed variants, females that are heterozygotes for a quantitative trait locus might exhibit higher phenotypic variance for that trait. We propose three tests that build on this phenomenon: 1) A test for inflated variance in heterozygous females; 2) A weighted association test; and 3) A combined test. Test 1 captures the novel signal proposed herein by directly testing for higher phenotypic variance of heterozygous than homozygous females. As a test of variance it is generally less powerful than standard tests of association that consider means, which is supported by extensive simulations. Test 2 is similar to a standard association test in considering the phenotypic mean, but differs by accounting for (rather than testing) the variance heterogeneity. As expected in light of X-inactivation, this test is slightly more powerful than a standard association test. Finally, test 3 further improves power by combining the results of the first two tests. We applied the these tests to the ARIC cohort data and identified a novel X-linked association near gene AFF2 with blood pressure, which was not significant based on standard association testing of mean blood pressure.ConclusionsVariance-based tests examine overdispersion, thereby providing a complementary type of signal to a standard association test. Our results point to the potential to improve power of detecting X-linked associations in the presence of variance heterogeneity.

Association of hospitalization with long-term cognitive and brain MRI changes in the ARIC cohort.

To determine whether hospitalization is associated with subsequent cognitive decline or changes on brain MRI in a community-based cohort. Baseline and follow-up cognitive testing (n = 2,386) and MRI scans with standardized assessments (n = 885) were available from a subset of white and black participants in the Atherosclerosis Risk in Communities study. Cognitive tests included the Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test (WFT). Hospitalization characteristics were determined using ICD-9 codes. Regression models adjusted for demographics, education, comorbidities, and APOE ε4 were used to estimate the independent association of hospitalization with changes in cognition or neuroimaging. Over a mean 14.1 years between visits, 1,266 participants (53.1%) were hospitalized. Hospitalization compared with no hospitalization was associated with greater decline in DSST scores (1.25 points greater decline, p < 0.001) but no difference in DWRT or WFT score change. Each additional hospitalization, as well as a critical illness vs noncritical illness hospitalization, was associated with greater decline in DSST scores. A subset of participants (n = 885) underwent MRI scans separated by 10.5 years. Hospitalization (n = 392) compared with no hospitalization was associated with a 57% higher odds of increasing ventricular size at follow-up. Each additional hospitalization, as well as having a critical illness vs noncritical illness hospitalization, and having a hospitalization with major surgery vs no surgery was associated with greater odds of increased ventricular size. Cognitive decline and neuroimaging changes may occur after hospitalization, independent of baseline demographics and comorbidities.