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ABO Blood Group and Risk of Coronary Heart Disease in Two Prospective Cohort
Meian He, Brian Wolpin, Kathy Rexrode, JoAnn E. Manson, Eric Rimm, Frank B. Hu and Lu Arterioscler Thromb Vasc Biol. 2012;32:2314-2320; originally published online August 14, Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright 2012 American Heart Association, Inc. All rights reserved.
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Two Prospective Cohort Studies
Meian He, Brian Wolpin, Kathy Rexrode, JoAnn E. Manson, Eric Rimm, Frank B. Hu, Lu Qi Objective—Epidemiological data regarding the association between ABO blood groups and risk of coronary heart disease
(CHD) have been inconsistent. We sought to investigate the associations between ABO blood group and CHD risk in prospective cohort studies.
Methods and Results—Two large, prospective cohort studies (the Nurses' Health Study [NHS] including 62 073 women
and the Health Professionals Follow-up Study [HPFS] including 27 428 men) were conducted with more than 20 years of follow-up (26 years in NHS and 24 years in HPFS). A meta-analysis was performed to summarize the associations from the present study and previous studies. In NHS, during 1 567 144 person-years of follow-up, 2055 participants developed CHD; in HPFS, 2015 participants developed CHD during 517 312 person-years of follow-up. ABO blood group was significantly associated with the risk of developing CHD in both women and men (log-rank test; P=0.0048 and 0.0002, respectively). In the combined analysis adjusted for cardiovascular risk factors, compared with participants with blood group O, those with blood groups A, B, or AB were more likely to develop CHD (adjusted hazard ratios [95% CI] for incident CHD were 1.06 [0.99–1.15], 1.15 [1.04–1.26], and 1.23 [1.11–1.36], respectively). Overall, 6.27% of the CHD cases were attributable to inheriting a non-O blood group. Meta-analysis indicated that non-O blood group had higher risk of CHD (relative risk =1.11; 95% CI, 1.05–1.18; P=0.001) compared with O blood group.
Conclusion—These data suggest that ABO blood group is significantly associated with CHD risk. Compared with other
blood groups, those with the blood type O have moderately lower risk of developing CHD. (Arterioscler Thromb Vasc
Biol
. 2012;32:2314-2320.)
Key Words: ABO ◼ coronary heart disease ◼ cohort study ◼ meta-analysis
Human blood group antigens are glycoproteins and gly- A number of epidemiological studies have examined the colipids expressed on the surface of red blood cells relation between ABO blood type and risk of cardiovascular and a variety of human tissues, including epithelium, sen- diseases. In 2008, a meta-analysis investigated the associa- sory neurons, platelets, and vascular endothelium.1 It has tions between several types of vascular disease and ABO blood long been acknowledged that human ABO blood type groups.14 A consistent relation between non-O blood group might affect the risk factors of cardiovascular disease. and an increased CHD risk was observed in cross- sectional In non-O individuals, plasma levels of factor VIII–von case–control studies15–17; however, data from prospective Willebrand factor (vWF) complex are ≈25% higher than cohort studies were inconsistent,18–22 probably because of the group O individuals.2 Accumulating evidence indicates small sample size of these cohort studies.
that elevated factor VIII–vWF levels are a risk factor for In this study, we conducted prospective analyses on human coronary heart disease (CHD).3,4 Other studies also indi- blood groups and CHD risk in 2 large cohorts: the Nurses' cate that ABO blood group might influence plasma lipid Health Study (NHS) and the Health Professionals Follow-up levels.5,6 Recently, several genome-wide association stud- Study (HPFS). In addition, we also combined our data with ies found that variants at ABO locus were associated with previously published prospective studies in a meta-analysis.
plasma lipid levels7,8 and inflammatory markers, including soluble intercellular adhesion molecule 1,9,10 plasma solu- Patients and Methods
ble E-selectin levels11,12 and P-selectin levels,10 and tumor necrosis factor-α,13 which were markers of inflammation The NHS cohort began in 1976 when 121 700 female nurses aged associated with the CHD risk.
30 to 55 years living in 11 U.S. states responded to a questionnaire Received on: February 27, 2012; final version accepted on: June 25, 2012.
From the Department of Nutrition, Harvard School of Public Health, Boston, MA (M.H., E.R., F.B.H., L.Q.); Institute of Occupational Medicine and Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (M.H.); Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (B.W.); Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (K.R., J.E.M.); and Channing Laboratory, Harvard Medical School, Boston, MA, (E.R., F.B.H., L.Q.).
The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/doi:10.1161/ATVBAHA.112.248757/-/DC1.
Correspondence to Lu Qi, MD, PhD, Department of Nutrition, Harvard School of Public Health, Boston, MA 02115. E-mail nhlqi@channing.harvard.
2012 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org
He et al ABO and Coronary Heart Disease Risk 2315
regarding medical, lifestyle, and other health-related information. Questionnaires have been sent biennially to update this information. We used Cox proportional hazards models to assess the association Diet intakes were assessed by food frequency questionnaire in 1980, between the ABO blood group and risk of CHD. For multivariate 1984, 1986, 1990, 1994, 1998, and 2002. At baseline, we excluded analysis, we adjusted for the following potential confounders, which those with a history of CHD, cancer, stroke, coronary artery bypass were updated at each 2-year cycle: age (continuous), smoking (never, graft, or angina. After these exclusions, 62 073 women reporting their past, or current with cigarette use of 1–14 per day, 15–24 per day, 25+ ABO blood group had follow-up from 1980 through 2006 and were per day, missing), BMI (<22.0, 22.0–22.9, 23.0–24.9, 25.0–28.9, and included in the analyses.
≥29.0 kg/m2), alcohol intake (0 g/day, up to 5 g/day, 5–15 g/day, or The HPFS enrolled 51 529 men aged 40 to 75 years at baseline >15 g/day), parental history of CHD before age 60 (yes/no), physi- in 1986. The cohort participants are sent a biennial questionnaire cal activity (metabolic equivalents h/wk in quintiles), aspirin use (<1 regarding medical conditions and lifestyle characteristics, such as per week, 1–2 per week, 3–6 per week, 7–14 per week, and 15+ per smoking status, medication use, and physical activity. Every 4 years, week), menopausal status and postmenopausal hormone use (pre- the participants are sent a food frequency questionnaire to assess their menopausal, never, past, or current hormone use) in women, history diet intakes. We excluded those who reported a history of myocardial of hypertension (yes or no), history of high blood cholesterol (yes or infarction (MI), angina, coronary artery bypass graft, stroke, or can- no), and history of diabetes mellitus (yes or no). We also adjusted for cer in the baseline questionnaire, resulting in a baseline population race/ethnicity (white or nonwhite) and dietary factors, which were of 27 428 with ABO blood group data for the current analysis. This updated at 4-year cycle: multiple vitamin or vitamin E supplement study was approved by the Harvard Institutional Review Board, and (yes or no), total energy intake, polyunsaturated, saturated, and trans- all participants provided written informed consent.
fats; long-chain omega-3 fatty acids, dietary fiber, and folate intake (all in quintiles). In secondary analyses, we conducted stratified anal- Assessment of ABO Blood Group
yses by age (<65 and ≥65 years), BMI (<25 and ≥25 kg/m2), smok- ing (never or past and current smoking), alcohol intake (drinking and The assessment of ABO blood group has been described in detail nondrinking), physical activity (median as cut point), and diabetes elsewhere.23 Briefly, in both the NHS and HPFS, participants were mellitus history (yes or no). Tests of interaction between ABO blood asked to report their blood type (A, B, AB, O, or unknown) and their group and potential effect modifiers were assessed by entering the Rh factor (positive, negative, or unknown) in the 1996 question- cross product of ABO blood group and the dichotomized covariate naire. We conducted a validation study by performing serologic test- into the Cox proportional hazard model. We used the log-rank test to ing in a subsample of 98 subjects. The consistency of self-reported compare the CHD-free survival among ABO blood group and cumu- and serologically confirmed ABO blood type was 93% for NHS and lative pure incidence curves with plot 1–Kaplan-Meier survival rate.27 90% for HPFS, and the consistency of self-reported and serologically confirmed Rh type was 100% for NHS and 96% for HPFS. We also validated the self-report ABO blood type using germline genetic data in 187 participants from NHS and HPFS and found 92% concor- The MEDLINE and EMBASE database was searched up to May 2010 dance.24 Of the participants in the NHS and HPFS who returned the for published articles on cohort studies that examined ABO blood 1996 questionnaire, 75% reported ABO blood group; of these, 92.3% group in relation to risk of CHD. Keywords used to identify relevant also reported Rh factor type. The characteristics of those participants articles were as follows: cardiovascular disease (as standardized med- who provided blood type and those who did not were similar (data ical subject heading [MeSH] term) and (ABO blood group system). Together with the current study, a total of 7 studies were included in our meta-analysis. Data extraction was independently performed by Assessment of Covariates
2 of the authors (M.A.H. and L.Q.) and there were no differences in the extracted information. We used the STATA version 9.2 statistical Body mass index (BMI) was calculated as weight in kilograms program (STATA, College Station, TX) to conduct the meta-analysis. divided by the square of height in meters (kg/m2). Physical activity Summary measures were calculated from the logarithm of the rela- was expressed as metabolic equivalents per hour, which were calcu- tive risks and corresponding standard errors of the individual studies lated with data from a self-report questionnaire that focused on the using random effects models that incorporate both a within-study and types and durations of activities over the previous year. Participants an additive between-studies component of variance.28 The heteroge- were also asked about recent smoking status (current, past, or never), neity of study results was calculated using the Cochran Q test29 and alcohol intake, and aspirin use; history of hypertension, high blood the I2 statistic.29 Visual inspection of the funnel plot, Begg, and Egger cholesterol, and diabetes mellitus; and parental history of CHD tests were used to evaluate possible publication bias.30,31 before age 60. To represent the long-term intake of dietary factors and to reduce measurement error, we conducted analyses using updated dietary data by taking the average of all available dietary Ascertainment of CHD End Point
In both NHS and HPFS, the baseline characteristics of the participants were similar across the four ABO blood groups We identified incident cases of CHD (nonfatal MI or fatal CHD) that occurred after the return of the 1980 questionnaire but before June (Table 1). The distributions of the ABO blood groups were 1, 2006, in women (NHS) and occurred between the return of the comparable between NHS and HPFS cohorts. The frequency 1986 questionnaire and June 1, 2006, in men (HPFS). We requested for blood type O, A, B, and AB was 42.9%, 36.0%, 13.3%, permission to review medical records of the participants who reported and 7.8% in women and 43.0%, 37.2%, 12.3%, and 7.5% having an MI on each biennial questionnaire. A physician unaware of the self-reported risk factor status verified the report of MI through review of medical/hospital records by using the World Health Organization criteria of symptoms and either typical ECG changes ABO Blood Group and CHD Risk
or elevated cardiac enzymes.26 Fatal CHD was confirmed by medical During up to 26 years of follow-up of 62 073 women records or autopsy reports or by CHD listed as the cause of death on (1 567 143 person-years) in the NHS, we confirmed 2055 the death certificate, and there was evidence of previous CHD in the records. Deaths were ascertained from state vital statistics records CHD cases (including 1666 nonfatal MI and 389 fatal CHD); and the National Death Index or reported by the family members and w-up was 20 years and 2015 CHD the postal system.
cases (including 1420 nonfatal MI and 595 fatal CHD) were 2316 Arterioscler Thromb Vasc Biol September 2012
Table 1. Baseline Characteristics of Study Subjects According to ABO Blood Type in NHS (1980) and HPFS (1986)
Percentage of subjects, % Physical activity, METs* Current smoking, % Alcohol intake, g/d Postmenopausal, % Current PMH users, % Total energy intake, kcal/d History of hypertension, % History of high cholesterol, % History of diabetes mellitus, % Family history of CHD, % NHS indicates Nurses' Health Study; HPFS, Health Professionals Follow-up Study; BMI, body mass index; METs, metabolic equivalents; PMH, postmenopausal hormones; CHD, coronary heart disease. The continuous variables are presented as mean (SD) and the categories variables presented as percentage.
*In NHS, the physical activity data in 1986 was used.
documented in 27 428 subjects (517 313 person-years). The and CHD risk in either cohort or in the combined analyses; incident rates of CHD per 100 000 person-years were 125, compared with participants who were Rh-positive, those who 128, 142, and 161 for those with blood type O, A, B, and AB were Rh-negative experienced a multivariate-adjusted hazard in women and 373, 382, 387, and 524 for those with blood ratio of 0.98 (95% CI, 0.90–1.06; P=0.58) in the combined type O, A, B, and AB in men. The cumulative incidence of samples (Table 3).
CHD was statistically significantly different among the 4 In the stratified analyses, the association between ABO ABO blood groups in both cohorts (log-rank test; P=0.0048 in blood group and risk of CHD was not modified by age, physi- NHS and 0.0002 in HPFS, respectively; Figure 1). In the com- cal activity, alcohol consumption, smoking status, or diabetes bined analysis, compared with participants with blood group mellitus history in men or women. In women, menopausal sta- O, those with blood groups A, B, or AB were more likely to tus did not modify the association between ABO blood group develop CHD (age–adjusted hazard ratios [95% CI] for CHD, and CHD risk. We found a significant interaction between the 1.05 [0.98–1.13], 1.11 [1.01–1.23], and 1.23 [1.10–1.37], BMI and ABO blood type in relation to CHD risk in women respectively) (Table 2). The associations were not substan- (P for interaction=0.026). Compared with the O blood group, tially altered by multivariate adjustment for other potential the non-O blood type (A, B, and AB) had a stronger relation- risk factors and dietary factors (multivariate–adjusted hazard ship with CHD risk in overweight and obese women than ratios [95% CI] for CHD, 1.08 [1.00–1.16], 1.11 [1.00–1.24], those with BMI <25 kg/m2. However, this interaction was not and 1.20 [1.07–1.36], respectively) (Table 2). The associations confirmed in men (P for interaction =0.75; data not shown).
of the risks of CHD with ABO blood groups were not sub-stantially altered by excluding patients with diabetes mellitus diagnosed at baseline. In addition, restriction of the analysis to whites only (97.1% in NHS and 95.7% in HPFS) did not Characteristics of the 7 prospective cohort studies included alter these associations; compared with the O blood group, in the meta-analysis are shown in Table I in the online-only the A, B, and AB groups had increasing risk of CHD (com- Data Supplement. The study populations included both men bined hazard ratios [95% CI] for CHD, 1.08 [1.00–1.16], 1.10 and women, predominantly white populations. Based on [1.00–1.21], and 1.20 [1.07–1.35]).
data from all prospective studies combined, which included We also examined the risk of CHD by comparing the non-O 114 648 participants and 5741 cases of CHD, the pooled rela- blood type (A, B and AB) with the O blood type. Compared tive risk was 1.06 (95% CI, 0.96–1.17; P=0.266) for non-O with participants reporting blood group O, those with non-O blood group compared with O blood group. There was sig- blood type had an age–adjusted hazard ratio of 1.09 (95% CI, nificant heterogeneity among the studies (I2, 58%; 95% CI, 1.03–1.17). Adjustment for other potential risk factors for 4%–82%; P value for homogeneity test=0.026). In the meta- CHD did not materially alter the associations (hazard ratio, regression analysis, the mean age, sex, publication year, 1.10; 95% CI, 1.03–1.18). The population attributable risk of follow-up period, and sample size did not modify the asso- the non-O blood group (A, B, and AB) for CHD was 6.27%. ve meta-analysis indicated that In contrast, we did not find an association between Rh type only the study by Suadicani et al21 was significantly inversely He et al ABO and Coronary Heart Disease Risk 2317
Figure 1. Cumulative inci-
dence curves for coronary heart disease by ABO blood group in Nurses' Health Study (NHS) and Health Profession- als Follow-up Study (HPFS). Number of participants at risk is shown for selected times.
associated with CHD risk. After excluding this study, the het- Supplement) and the Begg (P=0.71) and Egger (P=0.74) tests erogeneity test was not significant (I2, 0%; 95% CI, 0%–75%; did not suggest a publication bias.
P value for homogeneity test =0.68) and the pooled relative risk was 1.11 (95% CI, 1.05–1.18; P=0.001; Figure 2). We then conducted a sensitivity analysis by omitting 1 study at In the 2 large, prospective cohorts of the NHS and HPFS, a time and calculating the pooled estimate for the remaining we observed a significantly elevated risk of incident CHD studies. The pooled relative risks did not change, ranging from for participants with blood group A or B or AB, compared 1.09 (95% CI, 1.03–1.17) to 1.12 (95% CI, 1.03–1.21), indi- with those with blood group O. The highest risk was observed cating that the overall results were not excessively influenced for blood group AB, followed by blood groups B and A. The by any 1 study of the remaining 6 cohorts. Visual inspection of the funnel plot (Figures I and II in the online-only Data significantly modified by other known risk factors for CHD, 2318 Arterioscler Thromb Vasc Biol September 2012
Table 2. Age-Adjusted and Multivariable-Adjusted Hazard Ratios and 95% CIs for Coronary Heart Disease by ABO Blood Type
NHS No. of cases/No. of person-years Age-adjusted HR (95% CI) 1.04 (0.94–1.15) 1.14 (1.00–1.30) 1.20 (1.02–1.40) Multivariate model 1 HR (95% CI)* 1.06 (0.96–1.17) 1.15 (1.00–1.31) 1.20 (1.03–1.41) Multivariate model 2 HR (95% CI)† 1.08 (0.97–1.21) 1.15 (0.99–1.33) 1.24 (1.05–1.48) HPFS No. of cases/No. of person-years Age-adjusted HR (95% CI) 1.07 (0.96–1.18) 1.10 (0.95–1.27) 1.26 (1.07–1.48) Multivariate model 1 HR (95% CI)* 1.08 (0.97–1.19) 1.08 (0.93–1.25) 1.18 (1.00–1.39) Multivariate model 2 HR (95% CI)† 1.08 (0.97–1.19) 1.08 (0.93–1.25) 1.17 (1.00–1.38) Combined Age-adjusted HR (95% CI) 1.05 (0.98–1.13) 1.11 (1.01–1.23) 1.23 (1.10–1.37) Multivariate model 1 HR (95% CI) 1.07 (0.99–1.15) 1.11 (1.01–1.23) 1.19 (1.06–1.33) Multivariate model 2 HR (95% CI) 1.08 (1.00–1.16) 1.11 (1.00–1.24) 1.20 (1.07–1.36) NHS indicates Nurses' Health Study; HR, hazard ratios; HPFS, Health Professionals Follow-up Study; HR, hazard ratios; BMI, body mass index; MET, metabolic equivalent.
*Adjusted for age (continuous), smoking (never, past, or current with cigarette use of 1–14 per day, 15–24 per day, 25+ per day, missing), BMI (<23.0, 23.0–25.0, 25.0–29.0, and ≥29.0), alcohol intake (0 g per day, up to 5 g per day, 5–15 g per day, and >15 g per day), parental history of myocardial infarction before age 60 (yes/no), physical activity (MET h/wk in quintiles), aspirin use (<1 per week, 1–2 per week, 3–6 per week, 7–14 per week, and 15+ per week), history of hypertension and high blood cholesterol and type 2 diabetes mellitus (yes or no), race/ethnicity (white or nonwhite), and menopausal status and postmenopausal hormone use (premenopausal, never, past, or current hormone use) in women.
†Adjusted for covariates in model 1 plus dietary factors including multiple vitamin or vitamin E supplement (yes or no), total energy intake, polyunsaturated, saturated, and transfats; long-chain omega-3 fatty acids, dietary fiber, and folate intake (all in quintiles).
including age, sex, alcohol consumption, smoking, physical blood types). A meta-analysis of 6 prospective studies indi- activity, or diabetes mellitus history. In total, 6.27% of CHD cated that non-O blood group was associated with an 11% cases were attributable to a non-O blood group (A, B, or AB increased risk of CHD compared with O blood group.
Table 3. Age-Adjusted and Multivariable-Adjusted Hazard Ratios and 95% CIs for Coronary Heart Disease by ABO Blood Type and
Rh Factor Type
NHS No. of cases/No. of person-years Age-adjusted HR (95% CI) 1.05 (0.94–1.16) 1.08 (0.99–1.18) Multivariate model 1 HR (95% CI)* 1.03 (0.93–1.14) 1.10 (1.01–1.20) Multivariate model 2 HR (95% CI)† 1.05 (0.93–1.18) 1.12 (1.02–1.24) HPFS No. of cases/No. of person-years Age-adjusted HR (95% CI) 0.88 (0.78–1.00) 1.10 (1.01–1.21) Multivariate model 1 HR (95% CI)* 0.91 (0.80–1.03) 1.09 (1.00–1.20) Multivariate model 2 HR (95% CI)† 0.90 (0.79–1.02) 1.09 (0.99–1.20) Combined Age-adjusted HR (95% CI) 0.97 (0.90–1.06) 1.09 (1.03–1.17) Multivariate model 1 HR (95% CI) 0.98 (0.90–1.06) 1.10 (1.03–1.17) Multivariate model 2 HR (95% CI) 0.98 (0.90–1.06) 1.10 (1.03–1.18) NHS indicates Nurses' Health Study; HR, hazard ratios; HPFS, Health Professionals Follow-up Study; BMI, body mass index; MET, metabolic equivalent.
*Adjusted for age (continuous), smoking (never, past, or current with cigarette use of 1–14 per day, 15–24 per day, 25+ per day, missing), BMI (<23.0, 23.0–25.0, 25.0–29.0, and ≥29.0), alcohol intake (0 g per day, up to 5 g per day, 5–15 g per day, and >15 g per day), parental history of myocardial infarction before age 60 (yes/no), physical activity (MET h/wk in quintiles), aspirin use (<1 per week, 1–2 per week, 3–6 per week, 7–14 per week, and 15+ per week), history of hypertension and high blood cholesterol and type 2 diabetes mellitus (yes or no), race/ethnicity (white or nonwhite), and menopausal status and postmenopausal hormone use (premenopausal, never, past, or current hormone use) in women.
†energy intake, polyunsaturated, saturated, and transfats; long-chain omega-3 fatty acids, dietary fiber, and folate intake (all in quintiles).
He et al ABO and Coronary Heart Disease Risk 2319
Figure 2. Forest plot showing the relative
risk (RR) of coronary heart disease for non-O blood group for individual cohort studies and all studies combined. Bars and the diamond indicate 95% confi- dence intervals. The size of the squares corresponds to the weight of the study in the meta-analysis.
Associations between ABO blood groups and CHD have prospective analyses minimized selection bias. Nevertheless, been investigated for several decades. However, the results there are several potential limitations that need to be have been conflicting, especially for the prospective cohort considered. First, participants included in this study are of studies. Recently a meta-analysis reported that individuals different ethnicities. It is known that the prevalence of blood with non-O blood group had a statistically significantly higher types varies across different ethnic groups. However, 97.1% risk of MI than those with O blood group; however, restricting participants in NHS and 95.7% in HPFS were white. When the analysis to the prospective cohorts did not find significant we restricted the analysis to whites, the associations were not associations.14 This might be because of the small sample size appreciably altered. However, it still remains to be determined of these studies.
whether our findings apply to other ethnicities. Also, population The mechanisms underlying the associations between ABO stratification might be a potential confounding in our analysis. blood group and CHD risk remain unclear. However, several However, population stratification has negligible influence on lines of evidence support its potential cardiovascular effects. genetic analysis in our study samples, including analysis on Several studies have reported that plasma levels of factor ABO blood type.11 In addition, the cryptic relatedness might VIII–vWf complex in non-O individuals were ≈25% higher bias the associations. Nevertheless, our previous genome- than in group O individuals.2 The vWf has an important role wide analyses have indicated that cryptic relatedness was in hemostasis and thrombosis by mediating platelet adhesion very rare in our study samples and less likely affected our to the vascular wall, especially under high shear stress condi- current analysis.11 Second, although genetic studies have tions. Along with fibrinogen, vWF also participates in platelet found associations between the ABO locus and risk factors aggregation32,33 and plays a role in the development of athero- of CHD, it is possible that the ABO locus might be only a sclerosis. ABO blood group has been associated with plasma marker for other genes because of linkage disequilibrium and lipid levels; in particular, the A blood group has been noted to might not be directly involved in regulating these risk factors have higher levels of serum total cholesterol5,6 and low-density and associated with CHD risk. Also, lack of information about genotypic variation at the ABO gene locus in the whole study Recent genetic studies lend further support to the relation samples limited us to distinguish the exact genotype of ABO between ABO blood type and cardiovascular risk. The ABO blood group. Third, because the blood group in our study was gene is located on chromosome 9q34 with 3 variant alleles self-reported, measurement errors are inevitable. However, (A, B, and O), which encodes glycosyltransferases with dif- because our participants are healthcare professionals, they ferent substrate specificities and determines blood type.34 tend to report their blood type more accurately than the We recently found that the ABO locus was associated with general population. Our validation study indicated that more the plasma soluble E-selectin levels in the NHS,11 consistent than 90% of the participants reported their blood group with findings from another genome-wide association study.12 correctly. In addition, in prospective studies, nondifferential ABO locus was also associated with plasma soluble intercel- measurement errors are likely to attenuate the associations lular adhesion molecule 19,10 and soluble P-selectin concentra- toward null. Finally, although we adjusted for the lifestyle tions.10 In addition, ABO locus was related to tumor necrosis and dietary factors in our analyses, residual confounding factor-α,13 which can mediate endothelial cell activation by because of unmeasured factors might still remain. However, increasing the expression of adhesion molecules including the consistency of findings in NHS and HPFS and the relative intercellular adhesion molecule 1, vascular adhesion molecule homogeneity of the 2 cohorts with similar educational level 1, and E-selectin.35,36 All of these inflammatory markers have and socioeconomic status reduces the likelihood that residual been associated with increased CHD risk.37–39 confounding can fully explain the findings in the present study.
Our findings are less likely to be false positive because of In summary, our results from the 2 large, prospective consistent replications in 2 independent cohorts and because of prospective studies suggest that the meta-analysis confirmed these associations. Also, the ABO blood group is associated with CHD risk independent of 2320 Arterioscler Thromb Vasc Biol September 2012
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Código orgánico tributario.doc

Código Orgánico Tributario LA ASAMBLEA NACIONAL DE LA REPÚBLICA BOLIVARIANA DE VENEZUELA CÓDIGO ORGÁNICO TRIBUTARIO DISPOSICIONES PRELIMINARES Artículo 1: Las disposiciones de este Código Orgánico son aplicables a los tributos nacionales y a las relaciones jurídicas derivadas de ellos. Para los tributos aduaneros se aplicará en lo atinente a los medios de extinción de las obligaciones, para los recursos administrativos y judiciales, la determinación de intereses y lo referente a las normas para la administración de tales tributos que se indican en este Código; para los demás efectos se aplicará con carácter supletorio.