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Hypothesis: We hypothesized that outpatient management of patients at risk for a HF hospitalization is associated with lower mortality following an incident HF hospitalization. Methods: Patterns of outpatient visits prior to incident HF hospitalization were assessed among CMS Medicare beneficiaries with continuous fee-for-service eligibility residing during 2003-2006 in four geographic areas of CVD surveillance conducted by the ARIC Study. Incident HF hospitalization was defined as hospitalization with ICD9 code 428.x with no HF hospitalizations in preceding 2 years. Outpatient visits to primary care physicians, general internists, or cardiologists were identified from Carrier files. A comorbidity score was calculated from ICD9 codes at the time of incident HF hospitalization. Cox proportional hazard models adjusted for age, comorbidity score, gender, and race were used to estimate mortality. Results: Mean age among beneficiaries with observed incident HF hospitalization (n=2006; 90.4% white, 45.1% male) was 79.8 years (SD 7.4). Mean comorbidity score was 3.6 (SD 1.9). Mean number of outpatient physician visits occurring in two years preceding the incident HF hospitalization, was 9.6 (SD 9.0); 19.6% beneficiaries had no observed prior outpatient physician visits. Risk of death within one year of incident HF hospitalization was greater among those with no preceding outpatient physician visits as compared to those with at least one physician visit (adjusted HR=1.81 (95% CI 1.50, 2.18); Figure). Adjustment for the presence of an outpatient visit within 2 weeks following the HF hospitalization attenuated the risk of death (HR=1.56 (1.29, 1.89)). Conclusion: Lack of outpatient care in two years prior to a HF-related hospitalization is associated with increased mortality within one year following hospitalization. Further inquiry is warranted to assess whether the association reflects diversity in causes/manifestations of HF, ambulatory care received in ED settings, or benefits associated with outpatient care.

BACKGROUND: Where a person lives is not usually thought of as an independent predictor of his or her health, although physical and social features of places of residence may affect health and health-related behavior. METHODS: Using data from the Atherosclerosis Risk in Communities Study, we examined the relation between characteristics of neighborhoods and the incidence of coronary heart disease. Participants were 45 to 64 years of age at base line and were sampled from four study sites in the United States: Forsyth County, North Carolina; Jackson, Mississippi; the northwestern suburbs of Minneapolis; and Washington County, Maryland. As proxies for neighborhoods, we used block groups containing an average of 1000 people, as defined by the U.S. Census. We constructed a summary score for the socioeconomic environment of each neighborhood that included information about wealth and income, education, and occupation. RESULTS: During a median of 9.1 years of follow-up, 615 coronary events occurred in 13,009 participants. Residents of disadvantaged neighborhoods (those with lower summary scores) had a higher risk of disease than residents of advantaged neighborhoods, even after we controlled for personal income, education, and occupation. Hazard ratios for coronary events in the most disadvantaged group of neighborhoods as compared with the most advantaged group--adjusted for age, study site, and personal socioeconomic indicators--were 1.7 among whites (95 percent confidence interval, 1.3 to 2.3) and 1.4 among blacks (95 percent confidence interval, 0.9 to 2.0). Neighborhood and personal socioeconomic indicators contributed independently to the risk of disease. Hazard ratios for coronary heart disease among low-income persons living in the most disadvantaged neighborhoods, as compared with high-income persons in the most advantaged neighborhoods were 3.1 among whites (95 percent confidence interval, 2.1 to 4.8) and 2.5 among blacks (95 percent confidence interval, 1.4 to 4.5). These associations remained unchanged after adjustment for established risk factors for coronary heart disease. CONCLUSIONS: Even after controlling for personal income, education, and occupation, we found that living in a disadvantaged neighborhood is associated with an increased incidence of coronary heart disease.

Few studies have evaluated between-country differences in medical care and survival after acute myocardial infarction, and none have compared the US with countries from Eastern Europe. Comparable data from the US (Atherosclerosis Risk in Communities Study [US-ARIC]) and Poland (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease project [Pol-MONICA]) were developed. From 1987 through 1993, a total of 3,694 patients were hospitalized with acute myocardial infarction events in the 2 Pol-MONICA communities and 4,801 in the 4 US-ARIC communities. Patients in the US-ARIC were 1.7 times more likely to be treated in a coronary care unit and received cardiac procedures, calcium channel blockers, and thrombolytic agents significantly more often than patients in the Pol-MONICA. The use of antiplatelet agents, nitrates, angiotensin-converting enzyme inhibitors, and β blockade agents was similar in both countries. Case fatality (28-day) rates after hospitalized acute myocardial infarction were nearly identical (men, 7% in Pol-MONICA vs 6% in US-ARIC; women, 9% in Pol-MONICA vs 8% in US-ARIC). However, when fatal coronary heart disease events not associated with a hospitalized myocardial infarction were included, the US-ARIC rates were less than half than those seen in Pol-MONICA. Substantial differences in treatment of hospitalized acute myocardial infarction between countries did not translate into a survival advantage for patients reaching clinical attention. Differences in case severity, arising from the high out-of-hospital coronary death rate in Poland may play an important role in this finding.

Background The clinical view of case fatality (CF) from acute myocardial infarction (AMI) in those reaching the hospital alive is different from the population view. Registration of both hospitalized AMI cases and out-of-hospital coronary heart disease (CHD) deaths in the WHO MONICA Project allows both views to be reconciled. The WHO MONICA Project provides the largest data set worldwide to explore the relationship between CHD CF and age, sex, coronary event rate, and first versus recurrent event. Methods and Results All 79 669 events of definite AMI or possible coronary death, occurring from 1985 to 90 among 5 725 762 people, 35 to 64 years of age, in 29 MONICA populations are the basis for CF calculations. Age-adjusted CF (percentage of CHD events that were fatal) was calculated across populations, stratified for different time periods, and related to age, sex, and CHD event rate. Median 28-day population CF was 49% (range, 35% to 60%) in men and 51% (range, 34% to 70%) in women and was particularly higher in women than men in populations in which CHD event rates were low. Median 28-day CF for hospitalized events was much lower: in men 22% (range, 15% to 36%) and in women 27% (range, 19% to 46%). Among hospitalized events CF was twice as high for recurrent as for first events. Conclusions Overall 28-day CF is halved for hospitalized events compared with all events and again nearly halved for hospitalized 24-hour survivors. Because approximately two thirds of 28-day CHD deaths in men and women occurred before reaching the hospital, opportunities for reducing CF through improved care in the acute event are limited. Major emphasis should be on primary and secondary prevention.

The International Study of Asthma and Allergies in Childhood (ISAAC) was founded to maximize the value of epidemiological research into asthma and allergic disease by establishing a standardized methodology and facilitating international collaboration and comparison of data. The ISAAC design comprises three phases: Phase I uses validated core questionnaires designed to assess the prevalence and severity of asthma and allergic disease in defined populations; Phase II will investigate possible aetiological factors suggested by findings of Phase I and apply lung, blood and skin tests; Phase III will be a repetition of Phase I after 5 years to assess time trends in the prevalence and severity of wheezing, rhinitis and eczema in each ISAAC centre. In 1991 a survey on wheezing and allergic rhinitis in 2050 12–15 year old adolescents in Bochum showed a positive correlation between the prevalence of wheezing as well as allergic rhinitis and indicators of traffic density, controlling for putative confounders such as age, sex, passive smoking, active smoking, etc. In 1994–1995 an ISAAC Phase I survey conducted on adolescents in Munster, applying methodology similar to that in Bochum, found positive associations between surrogate measures of traffic density and 12 months prevalence of wheezing and lifetime prevalence of allergic rhinitis of a magnitude very close to that found in Bochum. The results from the two German cities provide support to the hypothesis that exposure to automobile emissions is related to wheezing and allergic rhinitis in children.

We evaluated whether carotid intima-media thickness (CIMT) and the presence or absence of plaque improved coronary heart disease (CHD) risk prediction when added to traditional risk factors (TRF).Traditional CHD risk prediction schemes need further improvement as the majority of the CHD events occur in the "low" and "intermediate" risk groups. On an ultrasound scan, CIMT and presence of plaque are associated with CHD, and therefore could potentially help improve CHD risk prediction.Risk prediction models (overall, and in men and women) considered included TRF only, TRF plus CIMT, TRF plus plaque, and TRF plus CIMT plus plaque. Model predictivity was determined by calculating the area under the receiver-operating characteristic curve (AUC) adjusted for optimism. Cox proportional hazards models were used to estimate 10-year CHD risk for each model, and the number of subjects reclassified was determined. Observed events were compared with expected events, and the net reclassification index was calculated.Of 13,145 eligible subjects (5,682 men, 7,463 women), approximately 23% were reclassified by adding CIMT plus plaque information. Overall, the CIMT plus TRF plus plaque model provided the most improvement in AUC, which increased from 0.742 (TRF only) to 0.755 (95% confidence interval for the difference in adjusted AUC: 0.008 to 0.017) in the overall sample. Similarly, the CIMT plus TRF plus plaque model had the best net reclassification index of 9.9% in the overall population. Sex-specific analyses are presented in the manuscript.Adding plaque and CIMT to TRF improves CHD risk prediction in the ARIC (Atherosclerosis Risk In Communities) study.

The purpose of this study is to describe the proportion of "JUPITER-eligible" (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) individuals and clinical outcomes of individuals based on high-sensitivity C-reactive protein (hs-CRP) and low-density lipoprotein cholesterol (LDL-C) strata in the ARIC (Atherosclerosis Risk in Communities) study.Questions remain after the JUPITER study, including whether the observed cardiovascular disease (CVD) event rates would persist with time and how these event rates would compare with other populations (lower hs-CRP and/or higher LDL-C levels).After stratification into 4 groups based on LDL-C and hs-CRP levels, with cutoffs at 130 mg/dl and 2.0 mg/l, respectively, incident CVD events were examined (mean follow-up, 6.9 years) and compared.Of 8,907 age-eligible participants, 18.2% (n = 1,621) were JUPITER-eligible (hs-CRPor = 2.0 mg/l, LDL-C130 mg/dl) and had an absolute CVD risk of approximately 10.9% over a mean follow-up of 6.9 years (1.57% per year). If JUPITER hazard ratios were applied to this group, the number needed to treat to prevent 1 CVD event would be estimated at 38 over 5 years and 26 over 6.9 years.ARIC participants with elevated hs-CRP and low LDL-C had a CVD event rate of 1.57% per year over 6.9 years, similar to the CVD event rate noted in the JUPITER study placebo group (1.36% per year over 1.9 years). The association of hs-CRPor = 2.0 mg/l with increased CVD risk and mortality regardless of LDL-C provides us a simple method of using age and hs-CRP level for identifying higher risk individuals. (Atherosclerosis Risk in Communities study; NCT00005131).

Background— A single-nucleotide polymorphism on chromosome 9p21, rs10757274 (9p21 allele), has been shown to predict coronary heart disease (CHD) in whites. We evaluated whether adding the 9p21 allele to traditional risk factors (RFs) improved CHD risk prediction in whites from the Atherosclerosis Risk in Communities study and whether changes in risk prediction would modify lipid therapy recommendations. Methods and Results— Whites (n=9998) in the Atherosclerosis Risk in Communities study for whom the 9p21 genotype and traditional RF information was available were included. Using Cox proportional hazards models, the Atherosclerosis Risk in Communities Cardiovascular Risk Score, which is based on traditional RFs, was determined. A total of 1349 individuals (13.5%) developed incident CHD events during a period of 14.6 years. Adding the 9p21 allele to traditional RFs was associated with a hazard ratio of incident CHD of 1.2 per allele ( P 5% to ≤10% 10-year CHD risk) and intermediate-high (>10% to ≤20% 10-year CHD risk) categories, with 12.1% and 12.6% reclassified, respectively. This may impact therapy because 90% of these reclassified individuals had low-density lipoprotein cholesterol >100 mg/dL. Conclusion— Adding the 9p21 allele to traditional RFs in whites in the Atherosclerosis Risk in Communities study modestly improved CHD risk prediction in the intermediate categories.

Background: Previous data are conflicting as to whether imbalance between hemostatic factors is associated with clinical strokes. We evaluated the association between hemostatic factor levels and subclinical lacunar infarcts in a nested sample from a subset of the Atherosclerosis Risk in Communities (ARIC) cohort. Methods: 196 cases without clinical strokes had lacunar infarcts by MRI, and 214 controls without radiographic infarcts were frequency-matched by age group and sex. Logistic regression models were fitted to assess the association between levels of hemostatic markers and case status. Results: In age-, race- and sex-adjusted models, von Willebrand factor (vWF) and D-dimer were positively associated with case status, with odds ratios for the highest vs. lowest tertile of 2.0 (95% CI 1.2–3.6) for vWF and 1.76 (95% CI 1.02–3.0) for D-dimer. Plasminogen had nonsignificant inverse associations with presence of silent lacunar infarcts. Conclusions: vWF and D-dimer were positively associated, and plasminogen was nonsignificantly inversely associated with subclinical radiographic infarct. Further studies on the role of these hemostatic factors in the development of silent lacunar infarcts may help elucidate the mechanisms behind this injury and may even point to potential targets for future intervention.

Aim: A single nucleotide polymorphism on chromosome 9p21, rs10757274 (9p21 allele), has been shown to be a predictor of coronary heart disease (CHD) in whites. We evaluated if the addition of the 9p21 allele to traditional risk factors (TRF) improved CHD risk prediction in the white population of the Atherosclerosis Risk in Communities (ARIC) study, and whether changes in risk prediction will modify lipid therapy recommendation. Methods: Whites (n=10,004) in the ARIC study for whom the 9p21 genotype and TRF (age, gender, systolic blood pressure, total cholesterol, smoking, diabetes, HDL-C, and anti-hypertensive medication use) information was available were included. Using Cox proportional hazards models, the ARIC Cardiovascular Risk Score (ACRS) which is based on TRF was determined. The impact of adding the 9p21 allele to TRF with respect to the area under the curve (AUC) of a receiver operating characteristic (ROC) curve and then risk strata reclassification was determined. Results: The addition of 9p21 allele to TRF was associated with a hazard ratio (HR) of 1.25 (p ) was observed in the intermediate (5–10% 10-year CHD risk) and intermediate-high (10 –20% 10-year CHD risk) categories with 19.3% and 16.9% reclassified, respectively, which would impact therapy, as approximately 90% of these individuals had LDL-C >100 mg/dL. Table: Reclassification in the different ACRS categories after the addition of the 9p21 allele to the traditional risk factors

Low risk for coronary heart disease (CHD) is defined by ATP III as a 10 year risk of th , 25 th to 75 th and >75 th percentile). The absolute event rates were then described in each group (table ). Over a mean follow up of 13.8 years, 1601 (12.2%) individuals had incident CHD events. Approximately 31% of these incident CHD events were in the 5–10% risk group which made up 28% of the study while only 16% of the incident CHD events occurred in the 0–5% risk group which made up 47% of the study population. The 5–10% group had event rates (13.7%) greater than the study average (12.2%), especially in those with thicker CIMT (>75 th percentile, event rate 17%), and greater event rates than those in the 0–5% risk group (4.1%) (table ). Given the notably higher observed CHD risk in the 5–10% group (especially in those with thicker CIMT) relative to the 0–5% group, the availability of safe, low cost lipid lowering medications and low risk tests such as ultrasound that may improve risk stratification, it may be time to evaluate the low risk group more carefully for cardiovascular preventive therapies. Table. Incident CHD in the various risk groups over a mean follow up of 13.8 years in the ARIC study

Although sex differences have been reported for associations between obesity and inflammation, the question of whether there is an effect modification by sex in the association between inflammation and type 2 diabetes has not been investigated in detail. Therefore, the aim of this study was to compare associations of markers of inflammation with type 2 diabetes risk between men and women.Following a case-cohort design, cases of incident type 2 diabetes were identified from 7,936 subjects aged 35-74 years at baseline who participated in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Research in the Region of Augsburg (KORA) studies conducted between 1984 and 2002. Concentrations of C-reactive protein (CRP) and interleukin (IL)-6 were measured in 527 cases of incident type 2 diabetes (305 men and 222 women) and 1,698 noncases (889 men and 809 women).After adjustment for age and survey and lifestyle factors including smoking, alcohol intake, and physical activity, elevated concentrations of CRP showed a considerably stronger association with risk of type 2 diabetes in women (hazard ratio comparing tertile extremes 7.60 [95% CI 4.43-13.04]) than in men (1.84 [1.27-2.67]). The P value for the sex interaction was0.001. Further adjustment for metabolic risk factors considerably attenuated these associations, and they became nonsignificant in men but remained significant in women. IL-6 was also more strongly associated with type 2 diabetes in women, but there was no significant sex interaction.Our data suggest that inflammatory processes may be of particular importance in the pathogenesis of type 2 diabetes in women.

Purpose We describe a method for testing and estimating a two-way additive interaction between two categorical variables, each of which has greater than or equal to two levels. Methods We test additive and multiplicative interactions in the same proportional hazards model and measure additivity by relative excess risk due to interaction (RERI), proportion of disease attributable to interaction (AP), and synergy index (S). A simulation study was used to compare the performance of these measures of additivity. Data from the Atherosclerosis Risk in Communities cohort study with a total of 15,792 subjects were used to exemplify the methods. Results The test and measures of departure from additivity depend neither on follow-up time nor on the covariates. The simulation study indicates that RERI is the best choice of measures of additivity using a proportional hazards model. The examples indicated that an interaction between two variables can be statistically significant on additive measure (RERI = 1.14, p = 0.04) but not on multiplicative measure (β3 = 0.59, p = 0.12) and that additive and multiplicative interactions can be in opposite directions (RERI = 0.08, β3 = –0.08). Conclusions The method has broader application for any regression models with a rate as the dependent variable. In the case that both additive and multiplicative interactions are statistically significant and in the opposite direction, the interpretation needs caution.

The authors aimed to investigate the relation between components of adult height (leg and trunk length) and atherosclerosis in middle age, using data from 12,254 participants (aged 44-65 years) in the Atherosclerosis Risk in Communities (ARIC) Study. Intimal-medial thickness (IMT) as measured by B-mode ultrasound was the outcome, and exposures were trunk and leg lengths as estimated (using sitting height and the difference between sitting and standing height) at the first study examination in 1987-1989. The mean IMT was 0.73 (standard deviation, 0.17) mm. Greater leg length was associated with lower IMT, with the largest difference being for Black men (a 0.045 (95% confidence interval: 0.023, 0.068)-mm lower IMT per 10-cm higher leg length). Greater trunk length was associated with higher IMT, with the largest difference being for White men (a 0.024 (95% confidence interval: 0.005, 0.044)-mm higher IMT per 10-cm higher trunk length). Although the effect sizes were small, leg length was inversely associated with atherosclerosis, consistent with the results of other studies with cardiovascular disease outcomes.

We investigated prospectively the association between serum levels of interleukin (IL)-18 and the risk of type 2 diabetes in a case-cohort study conducted in middle-aged men and women who represented 7,936 participants of the three MONItoring of trends and determinants in CArdiovascular disease (MONICA)/Cooperative Research in the Region of Augsburg (KORA) surveys. Levels of IL-18 were measured in stored samples of 527 case subjects with incident type 2 diabetes and 1,698 noncase subjects. Elevated levels of IL-18 were associated with a significantly increased risk of type 2 diabetes after adjustment for age, sex, survey, BMI, systolic blood pressure, ratio of total cholesterol to HDL cholesterol, physical activity, alcohol intake, smoking status, and parental history of diabetes. Hazard ratios and 95% confidence intervals comparing quartile extremes were 1.73 (1.25-2.40). Further adjustment for C-reactive protein and IL-6 had no impact on the observed associations. However, the risk of developing type 2 diabetes was highest among subjects with elevated levels of both IL-18 and CRP or IL-18 and IL-6, respectively. In conclusion, elevated levels of IL-18 are associated with a considerably increased risk of type 2 diabetes. This association is independent of a generalized proinflammatory state, but subjects with elevated levels of several inflammatory markers seem to be particularly prone to develop type 2 diabetes.

Due to the sparse data on the repeatability of short and ultra-short term heart rate variability (HRV) measures, we measured the repeatability of common HRV measures derived from 10-second, 2-minute, and 6-minute recordings in 63 healthy men and women, aged 45-64, in Chapel Hill, North Carolina. Three 10-second and 2 six-minute heart rate recordings were obtained during each of 2 visits, separated by 1 to 2 weeks. We partitioned the measurement error into components and computed intraclass correlation coefficients using nested, random effects models. Repeatability improved with the length of recording: intraclass correlation coefficients were greater than 0.7 for 6-minute measures and 2-minute time domain measures and greater than 0.5 for 2-minute frequency domain measures. Repeatability of measures from 10-second records was lower, but improved considerably when the mean from 2 or 3 records was used. Correlations between the same measures from different length recordings were quite high. Our findings support the use of records of at least 5 minutes in length in epidemiological studies, in accordance with previous guidelines. Researchers using 10-second records should consider taking the mean of several recordings, when possible, or using statistical methods to correct for measurement error.

This study compared rates of performance of cardiac procedures in relation to gender, race, and geographic location in patients hospitalized for myocardial infarction. The Atherosclerosis Risk in Communities (ARIC) study provides population data and standardized data collection methods. Hospital records of eligible people aged 35 to 74 years were abstracted in communities of 4 states in the United States: North Carolina, Mississippi, Maryland, and Minnesota. Between January 1987 and December 1991, 5,462 “definite” hospitalized patients with myocardial infarctions were identified. Women treated in nonteaching hospitals were less likely than men to have coronary angiography (odds ratio [OR] 0.7, 95% confidence interval [CI] 0.5 to 1.0), coronary artery bypass graft surgery (CABG) (OR 0.6, 95% CI 0.4 to 0.8), and thrombolytic therapy (OR 0.8, 95% CI 0.6 to 1.0), after controlling for age, race, severity of myocardial infarction, co-morbidity, and geographic area. Findings were similar in teaching hospitals. Blacks in the biracial communities were significantly less likely than whites to have coronary angiography, percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery, and thrombolytic therapy. After controlling for age, race, severity of myocardial infarction and co-morbidity, no consistent geographic differences were observed, except for Forsyth whites having the highest and Washington County the lowest odds for coronary angiography. Appropriate outcome measures would serve to evaluate the effect, if any, of the differences described on the ARIC population. This study compared rates of performance of cardiac procedures in relation to gender, race, and geographic location in patients hospitalized for myocardial infarction. Women were less likely than men to have coronary angiography, coronary bypass graft surgery, and thrombolytic therapy after controlling for age, race, disease severity, comorbidity, and geographic area.

The association of estrogen replacement therapy (ERT) with cognitive functioning was assessed in 6,110 women aged 48-67 years participating in the Atherosclerosis Risk in Communities (ARIC) study, a multicenter longitudinal investigation. ERT was evaluated in relation to results of three cognitive tests (the Delayed Word Recall (DWR) Test, the Digit Symbol Subtest of the Wechsler Adult intelligence Scale-Revised (DSS/WAIS-R), and the Word Fluency (WF) Test) using data from the first follow-up visit of the cohort (1990-1992). No consistent associations were seen between ERT and either the DWR test or the DSS/WAIS-R after adjusting for age, education, and additional covariates previously found to be associated with cognitive function scores. Among surgically menopausal women aged 48-57 years, adjusted mean WF scores were slightly greater in ERT current users (mean WF 35.9) than in never users (mean WF 33.5) (p < 0.02); and within current users, adjusted WF scores increased with duration of ERT use. However, the finding that ERT was associated with a slightly higher level of performance on only one of three measures offers little support for the hypothesis that ERT has a major protective effect on cognitive function in women less than 68 years of age. The generalizability of these findings to older women who are more likely to experience cognitive decline and who may be using ERT for longer periods of time is limited by the relatively young age of the cohort.

Abstract 4310 Background and Objectives: Von Willebrand factor (VWF) is an essential component of hemostasis. It is known that multimer size and the amount of circulating VWF impact its hemostatic function. Genetic factors play a major role in regulating VWF synthesis and clearance and are reported to contribute to 66% of the variation in plasma VWF antigen level. We have analyzed 78 SNPs distributed throughout the VWF gene and haplotypes constructed from those SNPs for an association with VWF antigen level in 7,856 subjects of European descent in the Atherosclerosis Risk in Communities cohort. Methods and Results: Blood was drawn after an 8 hour fasting period and VWF antigen level was determined by a commercial ELISA kit. All subjects underwent analysis for 78 SNPs available from Affymetrix 6.0 chip in the region encompassing the VWF gene. We used the fastPHASE 1.2 program to resolve haplotypes from the unphased SNP genotype data. Using Haploview we determined SNPs in strong linkage disequilibrium (LD), their co-segregation rates and underlying haplotypes. Linear models were used to evaluate the association of actual or log VWF antigen levels with each SNP and haplotypes derived from those SNPs. Eighteen (16 are intronic) of the 78 SNPs were found to significantly associate with levels of VWF antigen (Table 1). All are clustered in a 50 kb region of the VWF gene in spite of the fact that the 78 SNPs studied are distributed throughout the VWF gene without apparent clusters. All 78 SNPs are co-segregated in 9 LD haplotype blocks, but a majority of positive SNPs (88.9%) are located in Block 5 and 6, which significantly correlate with VWF antigen level. The O blood type contributes to ∼ 15% of variation in VWF antigen levels. The association for SNPs and Haplotypes grows stronger after ABO effects are removed. Among non-genomic factors, age and BMI are the most significant factors and contribute to 4.8% and 1.4% of variation in VWF antigen level. Conclusions: We have found a strongly positive association between VWF level and SNPs and haplotypes from a strikingly concentrated region of the VWF gene. This region encodes the D2, D' and D3 domains of VWF, including the propeptide and multimerization and Factor VIII binding sites. The physiological significance of these clustered SNPs on VWF synthesis or clearance remains to be further investigated. Our data suggest that this region plays an important role in regulating VWF antigen level and support the idea that combinations of SNPs in LD can provide additive affects. Disclosures: No relevant conflicts of interest to declare.

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