Association of Blood Group A with Coronary Artery Disease in Young Adults in Taiwan

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1 ORIGINAL ARTICLE Association of Blood Grou A with Coronary Artery Disease in Young Adults in Taiwan Hsin-Fu Lee, Yen-Chen Lin, Chia-Pin Lin, Chun-Li Wang, Chi-Jen Chang and Lung-An Hsu Abstract Objective We aimed to investigate the association between the ABO blood grous and the risk of coronary artery disease (CAD) and myocardial infartion (MI) in a young Taiwanese oulation. Methods We retrosectively recruited 277 consecutive subjects (men younger than 45 years and women younger than 55 years) who underwent coronary angiograhy (136 with documented CAD and 129 without CAD) at our center, between 2005 and Their ABO blood grous were determined using standard agglutination techniques. Results Patients with CAD showed a significantly different blood grou distribution (O, 30.1%; A, 39.7%; B, 26.5%; AB, 3.7%) than that shown by the controls (O, 42.6%; A, 24.0%; B, 27.1%; AB, 6.2%; =0.032). Patients with blood grou A had a greater risk of CAD and MI than those with non-a blood grous (OR= 2.08, 95% CI= ; OR=2.21, 95% CI= , resectively). After adjustment for common cardiovascular risk factors such as age, gender, hyertension, cigarette smoking, diabetes mellitus, body mass index, family history of CAD, and liid rofiles; blood grou A remained significantly associated with an increased risk of CAD and MI (OR=2.61, 95% CI , =0.028; OR=3.53, 95% CI= , = 0.021, resectively). Conclusion Our findings suggest that blood grou A is an indeendent risk factor for CAD and MI in young eole in Taiwan. Key words: ABO blood grou, coronary artery disease, risk factor (Intern Med 51: , 2012) () Introduction Coronary artery disease (CAD) is a comlex disease with multile risk factors such as sex, age, obesity, cigarette smoking, diabetes mellitus, hyertension, dysliidemia, and family history (1). In the last few decades, several reorts have shown that the ABO blood grous, articularly the non-o blood grous, are associated with a risk of ischemic heart disease (2-10). Results from the Framingham study and other studies have indicated that the incidence of ischemic heart disease may be higher in atients with blood grou A than in those with the other blood grous (2-5, 7, 8). However, studies erformed in Finnish and Iranian oulations did not show any significant difference in the distributions of the ABO blood grous between atients undergoing coronary artery byass graft surgery comared to the general oulation (11, 12). Furthermore, the findings ertaining to the association between the ABO blood grous and cardiovascular mortality rate have been inconsistent (3, 10, 13). Although one study has shown the association of blood grou A with an increased risk of CAD in women younger than 50 years (14), no study has focused on the relationshi between the ABO blood grous and angiograhically verified CAD in young subjects (men younger than 45 years, and women younger than 55 years). The ABO blood grous are genetically transmitted. In most cases, remature CAD may be linked to inheritable risk factors, and the inheritance of the ABO grous could lay an imortant role in the develoment of remature CAD. We The First Cardiovascular Division, Deartment of Internal Medicine, Chang Gung Memorial Hosital, Chang Gung University College of Medicine, Taiwan Received for ublication December 23, 2011; Acceted for ublication Aril 15, 2012 Corresondence to Dr. Lung-An Hsu, hsula@adm.cgmh.org.tw 1815

2 conducted a retrosective case-control study to evaluate the effect of the ABO blood grous on the risk of CAD, in a young cohort with angiograhically verified CAD. Materials and Methods This study included 277 consecutive atients (men younger than 45 years and women younger than 55 years), who underwent coronary angiograhy at the First Cardiovascular Division, Chang Gung Memorial Hosital, Linkou, Taiwan, between 2005 and The age criteria for enrollment were based on the National Cholesterol Educational Program Adult Treatment Panel III (NCEP-ATPIII) guidelines. These guidelines defined age (men 45 years; women 55 years) as one of the major risk factors for CAD (15), and younger atients were considered to have early-onset or remature CAD in the GENECARD (Genetics of Early Onset Cardiovascular Disease) (16) and AD- VANCE (Atherosclerotic Disease, Vascular Function, and Genetic Eidemiology) (17) studies. Presence of CAD was defined as >50% stenosis in at least 1 major coronary branch, on coronary angiograhy. Acute myocardial infarction (AMI) was diagnosed as er the universal definition ublished in 2007 (18). Subjects without angiograhically demonstrable lesions served as controls (n=138). The controls consisted of subjects with cardiac syndrome X (n=52, 38%), valvular disease (n=39, 28%), heart failure (n=17, 12%), congenital heart disease (n=13, 9%), arrhythmias (n= 9, 7%), and other conditions when knowledge of coronary artery involvement or the resence of CAD necessarily (n=8, 6%). ABO blood grous were determined using standard agglutination techniques. All atients gave written informed consent to the coronary angiograhy study. The ethics committee at Chang Gung Memorial Hosital aroved this study. Conventional CAD risk factors, such as cigarette smoking, diabetes mellitus, hyertension, dysliidemia, obesity, and family history of CAD, were recorded for all the study articiants. Cigarette smoking was defined as smoking of at least 1 cigarette er day at the time of survey; diabetes mellitus was defined as a fasting lasma glucose 126 mg/ dl, glycohemoglobin value 6.5%, or the use of hyoglycemic agents; hyertension was defined as systolic blood ressure (BP) >140 mmhg and/or diastolic BP >90 mmhg or use of antihyertensive drugs. Family history of CAD was self-reorted by the atients and was defined as MI or known CAD in a arent or sibling before the age of 65 years. Liid rofile included total cholesterol (TC), lowdensity liorotein cholesterol (LDL-C), high-density liorotein cholesterol (HDL-C), and triglyceride (TG). Blood samles for liid rofile were drawn after a 12-hour fast. Obesity was defined as a body mass index (BMI) 27 kg/ m 2, as er the definition rovided by the Deartment of Health, Taiwan. Statistical analysis The Chi-square test (along with Fisher exact test, if necessary) was used to comare categorical variables. The twosamle t test or a one-way ANOVA was used to test the continuous variables, and the results were exressed as mean ± SD. Multivariate logistic regression analysis was used to evaluate the indeendent effect of the investigated variables on the risk of remature CAD and MI. TG values were normalized by logarithmic transformation rior to the statistical analyses. A value <0.05 (using a two-sided test) was considered statistically significant. General characteristics Results Twelve atients were excluded from this analysis because of the lack of information about the ABO blood grous. Of the 265 study atients, 136 (51%) were diagnosed with CAD and 129 (49%) served as controls, on the basis of the coronary angiograhy results. Among the CAD atients, 73 exerienced an MI, which was clinically verified by electrocardiograhy (ECG), and develoed regional wall motion abnormalities that were detected on left ventriculograhy or echocardiograhy. Table 1 lists the characteristics of the CAD atients and the control subjects. The frequencies of classical CAD risk factors, such as male gender, hyertension, diabetes mellitus, obesity, smoking, and family history of CAD were significantly higher in the CAD atients than in the control subjects. The CAD grou also had significantly higher values of BMI, TC, TG, TC/HDL-C, and LDL-C/HDL-C; and a significantly lower value of HDL-C. The overall distribution of the ABO grous was also significantly different between the CAD atients and controls (= 0.032; Table 1). Although our controls were from a hositalized oulation, the distribution of the ABO grous in the controls was similar to that reorted in a large 2010 survey conducted in 1,849,242 volunteer blood donors from among the general Taiwanese oulation (O, 43.57%; A, 26.65%; B, 23.72%; AB, 6.06%) (19). The distribution of sex, hyertension, diabetes, obesity, smoking, and family history of CAD and the mean values of age, BMI, HDL-C, TG, TC/ HDL-C, and LDL-C/HDL-C did not differ significantly among the ABO blood grous (Table 2). However, subjects with blood grou A had significantly higher TC and LDL-C levels than those with blood grou O (199±46 mg/dl vs. 179±36 mg/dl, =0.029 and 124±42 mg/dl vs. 104±29 mg/ dl, =0.010, resectively; Table 2). CAD and ABO grous As shown in Table 3, the frequency of blood grou A in subjects in the CAD and MI grous was significantly higher than that in the control subjects (39.7% vs. 24%, =0.006 and 41.1% vs. 24%, =0.011, resectively). The frequency of blood grou O in the CAD atients was significantly 1816

3 Table 1. Baseline Characteristics of the Study Poulation Controls Young atients with CAD n Men, n (%) 52 (40.3) 86 (60.2) < Age (years) 43 ± 7 43 ± Hyertension, n (%) 35 (27.1) 71 (52.2) < Diabetes mellitus, n (%) 9 (7.0) 42 (30.9) < Smoking, n (%) 49 (38.0) 76 (55.9) Obesity, n (%) 38 (31.1) 59 (49.2) Family history of CAD, n (%) 19 (14.7) 34 (25.0) TC, mg/dl (n) 175 ± 38 (104) 197 ± 52 (133) < LDL cholesterol, mg/dl (n) 103 ± 30 (94) 119 ± 46 (128) HDL cholesterol, mg/dl (n) 45 ± 14 (98) 39 ± 10 (130) TG, mg/dl (n) 136 ± 88 (103) 196 ± 145 (133) < TC/HDL-C ratio, (n) 4.31 ± 1.68 (96) 5.31 ± 1.89 (130) < LDL-C/HDL-C ratio, (n) 2.60 ± 1.33 (94) 3.21 ± 1.51 (128) BMI, kg/m 2 (n) 25.5 ± 5.2 (128) 27.0 ± 4.2 (132) Blood grou, n (%) O A B AB 55 (42.6) 31 (24.0) 35 (27.1) 8 (6.2) 41 (30.1) 54 (39.7) 36 (26.5) 5 (3.7) CAD: coronary artery disease, TC: total cholesterol, LDL-C: low-density liorotein cholesterol, HDL-C: high-density liorotein cholesterol, TG: triglycerides, BMI: body mass index Obesity, BMI 27 kg/m 2 TG values were normalized by logarithmic transformation rior to statistical analysis; however, untransformed data is resented throughout. Table 2. Baseline Characteristics according to Blood Grou A B AB O n Men, n (%) 49 (57.6) 37 (52.1) 6 (46.2) 46 (47.9) Age (years) 43 ± 7 43 ± 7 42 ± 7 43 ± Hyertension, 33 (38.8) 31 (43.7) 4 (30.8) 38 (39.6) n (%) Diabetes 13 (15.3) 16 (22.5) 2 (15.4) 20 (20.8) mellitus, n (%) Smoking, n 40 (47.1) 40 (56.3) 6 (46.2) 39 (40.2) (%) Obesity, n (%) 33 (41.8) 26 (41.3) 5 (45.5) 33 (37.1) Family history 25 (29.4) 11 (15.5) 2 (15.4) 15 (15.6) of CAD, n (%) TC, mg/dl (n) 199 ± 46 (77) 187 ± 59 (67) 168 ± 41 (10) 179 ± 36 (83) LDL cholesterol, mg/dl (n) HDL cholesterol, mg/dl (n) 124 ± 42 (72) 113 ± 49 (62) 94 ± 37 (10) 104 ± 29 (78) ± 12 (75) 41 ± 10 (63) 43 ± 15 (10) 43 ± 15 (80) TG, mg/dl (n) 179 ± ± ± ± (77) (66) (10) (83) TC/HDL-C 5.30 ± ± ± ± ratio, (n) (74) (63) (10) (79) LDL-C/HDL ± ± ± ± C ratio, (n) (72) (62) (10) (78) BMI, kg/m 2 (n) 27.0 ± 4.8 (84) 26.1 ± 4.4 (68) 26.6 ± 4.6 (13) 25.6 ± 5.0 (95) CAD: coronary artery disease, TC: total cholesterol, LDL-C: low-density liorotein cholesterol, HDL-C: high-density liorotein cholesterol, TG: triglycerides, BMI: body mass index Obesity, BMI 27 kg/m 2 TG values were normalized by logarithmic transformation rior to statistical analysis; however, untransformed data is resented throughout. 1817

4 Table 3. Distribution of ABO Blood Grous in Cases and Controls Controls (n = 129) Young atients with CAD (n = 136) OR (95% CI) Young atients with MI (n = 73) OR (95% CI) Young atients without MI (n = 63) OR (95% CI) ABO grou O, n (%) 55 (42.6) 41 (30.1) 0.58 ( ) (34.2) 0.70 ( ) (25.4) 0.70 ( ) A, n (%) 31 (24.0) 54 (39.7) (41.1) (38.1) 1.95 ( ) ( ) ( ) B, n (%) 35 (27.1) 36 (26.5) (20.5) (33.3) 1.34 ( ) ( ) ( ) AB, n (%) 8 (6.2) 5 (3.7) (4.1) (3.2) 0.50 ( ) ( ) ( ) CAD: coronary artery disease, MI: myocardial infarction, OR: odds ratio, CI: confidence interval Table 4. Multile Logistic Regression Analysis for the Association between ABO Blood Grous and Risk for CAD OR (95% CI) Model 1 Sex (male/female) 5.50 ( ) Age 1.08 ( ) Diabetes (Y/N) 6.52 ( ) <0.001 Hyertension (Y/N) 2.03 ( ) Blood grou A (Y/N) 2.19 ( ) Blood grou O (Y/N) 0.86 ( ) Model 2 Sex (male/female) 6.09 ( ) Age each increment 1.10 ( ) Diabetes (Y/N) 5.08 ( ) HDL-C each increment 0.87 ( ) Blood grou A (Y/N) 2.61 ( ) Blood grou O (Y/N) 1.07 ( ) HDL-C: high-density liorotein cholesterol Variables included in model 1 are age, sex, hyertension, smoking, diabetes mellitus, BMI, family history of CAD, and blood grous O and A. Variables included in model 2 are age, sex, hyertension, smoking, diabetes mellitus, BMI, family history of CAD, blood grous O and A, and liid rofile arameter values (TC, LDL-C, HDL-C, TG, TC/HDL-C, and LDL-C/HDL-C). OR: odds ratio, CI: confidence interval lower than that in the control subjects (30.1% vs. 42.6%, = 0.035). The frequencies of blood grous B and AB were not significantly different between the CAD/MI and control grous. Similar results were obtained when we comared the CAD atients without MI history (n=63) to the control grou (Table 3). Subjects with blood grou A had a greater risk of CAD and MI than did the non-a blood grous (OR= 2.08, 95% CI, ; and OR=2.21, 95% CI, , resectively). Subjects with blood grou O were significantly associated with a decreased risk of CAD, not MI (OR=0.58, 95% CI, ). After adjustment for common cardiovascular risk factors such as age, gender, hyertension, smoking, diabetes, BMI, and family history of CAD; blood grou A remained significantly associated with the increased risk of CAD and MI (OR=2.19, 95% CI, , =0.033 and OR=2.90, 95% CI, , =0.024, resectively; Table 4, 5). Although the liid rofile for the study oulation was incomlete, the association between Table 5. Multile Logistic Regression Analysis for the Association between ABO Blood Grous and Risk for MI OR (95% CI) Model 1 Sex (male/female) 8.66 ( ) Diabetes (Y/N) 5.87 ( ) < Blood grou A (Y/N) 2.90 ( ) Blood grou O (Y/N) 1.48 ( ) Model 2 Sex (male/female) 6.40 ( ) Diabetes (Y/N) 4.17 ( ) Blood grou A (Y/N) 3.53 ( ) Blood grou O (Y/N) 1.92 ( ) Variables included in model 1 are age, sex, hyertension, smoking, diabetes mellitus, BMI, family history of CAD, and blood grous O and A. Variables included in model 2 are age, sex, hyertension, smoking, diabetes mellitus, BMI, family history of CAD, blood grous O and A, and liid rofile arameter values (TC, LDL-C, HDL-C, TG, TC/HDL-C, and LDL-C/HDL-C). OR: odds ratio, CI: confidence interval the ABO blood grous and CAD was analyzed after adjusting for TC, LDL-C, HDL-C, TG, TC/HDL-C, and LDL-C/ HDL-C levels. Notably, adding liid rofile arameters to the model did not change the outcome (OR=2.61, 95% CI, , =0.028 for CAD and OR=3.53, 95% CI, , =0.021 for MI; Table 4, 5). These results indicated that influence of blood grou A on the suscetibility to CAD/MI is robably indeendent of these variables. However, because of the small samle size, the association between the ABO blood grous and isolated CAD without MI was insignificant after adjusting for common cardiovascular risk factors and liid rofile (data not shown). Lastly, there was no consistent relationshi between the ABO blood grous and the number of significantly diseased vessels (=0.849, Table 6). Discussion In this study, we analyzed the association between the ABO blood grous and angiograhically determined CAD in a young Taiwanese oulation. A significant association was observed between blood grou A and an increased risk of 1818

5 Table 6. Relationshi between ABO Blood Grous and the Severity of CAD, Graded by the Number of Significantly Stenosed Vessels ABO blood grou Number of significantly (>50%) stenosed vessels O, n (%) 19 (27.5) 7 (24.1) 10 (26.3) A, n (%) 29 (42.0) 12 (41.4) 13 (34.2) B, n (%) 18 (26.1) 10 (34.5) 13 (34.2) AB, n (%) 3 (4.4) 0 (0) 2 (5.3) 2 = 2.670, = CAD, in both univariate and multivariate analyses. Our results suggest that blood grou A is an indeendent risk factor for CAD/MI in Taiwanese men younger than 45 years and women younger than 55 years. Consistent with revious reorts in several oulations, including American (2), Norwegian (3), German (4), British (5), Pakistani (6), Hungarian (7), and Italian (10) oulations, this study showed an association between blood grou A and CAD in a samle of young Taiwanese. The findings of our study are in accordance with those of 2 revious studies that showed that the age of CAD detection and the age of first MI occurrence were lower in atients with blood grou A than in those with non-a blood grous (20, 21). The finding of elevated serum TC in subjects having blood grou A was also in agreement with the findings of revious reorts (22-26). Unlike the control subjects in our study, the control subjects recruited in most of the reviously reorted studies were not angiograhically examined. To the best of our knowledge, this is the first study to focus on a urely young adult oulation including men and women. The athogenic mechanism underlying the association between the ABO blood grous and CAD remains unclear. Interestingly, the ATP-binding cassette 2 (ABCA2) gene, which lays a role in cholesterol homeostasis, and the ABO gene, are both located on chromosome 9q34 (27). Although subjects with blood grou A had significantly higher TC and LDL-C levels than subjects with blood grou O, the association of blood grou A and CAD/MI was indeendent of atherogenic liid rofiles. Blood tye antigens A and B are exressed not only on the red blood cells but also on other cells such as latelets and vascular endothelial cells (28). The increased risk of thrombosis in non-o blood grous has been attributed to high lasma levels of the von Willebrand factor (29-32). Additionally, genome-wide association studies (GWAS) have identified the ABO gene as a locus for LDL-C metabolism (33); tye 2 diabetes (34); and the inflammatory biomarkers soluble E-selectin, P-selectin, and ICAM-1 (34-37). Recently, another GWAS also showed that an ABO genetic variant linked to blood grou O lowers the risk of MI in atients with angiograhically verified CAD (38). Therefore, blood tye antigens may modulate the risk of CAD/MI by influencing the levels of hemostasis and inflammatory roteins in circulation. However, we did not find a significant association between the ABO grou and the severity of CAD, which was graded on the basis of the number of significantly diseased vessels. The association between the ABO blood grous and isolated CAD without MI was also insignificant after adjusting for common cardiovascular risk factors and the liid rofile. This could be due to the small samle size and the resence of remature CAD cases, with half of the cases involving only single-vessel disease. Otherwise, the resent results imly that an increased risk of thrombosis is more lausible than atheroma rogression in exlaining the observed association between the ABO blood grous and CAD. Aart from the intrinsic limitations associated with a retrosective study, the other limitations of the study were single-center design of the study, small samle size, incomlete liid rofile data, and lack of detailed genotye information of the ABO alleles. In addition, the resent results may reflect a selection bias, because comared to subjects without CAD who did not undergo coronary angiograhy, our controls who underwent coronary angiograhy for heart disease may have differed in factors such as ABO grou. The distribution of the ABO grous among our controls is consistent with the general findings among the ethnic Chinese living in South China and Taiwan (19, 39, 40). However, the association between ABO grous and CAD remained after controlling for a large number of CAD risk factors. Furthermore, there was no reduction in the odds ratio, suggesting that a residual confounding effect is unlikely. We also suggest that analyses with our hositalized controls might be more referable than community controls, because coronary angiograhy has a better accuracy in comaring CAD characteristics between cases and controls. Finally, we did not routinely use the intravascular ultrasound and rovocation test to detect early atherosclerosis and determine the resence of coronary artery sasm in our study oulation. Therefore, a larger, rosective, longitudinal study in which atients are stratified according to the ABO blood grou genotyes, lasma levels of liids, inflammatory markers, hemostasis markers, would be necessary to elucidate the underlying mechanisms by which the ABO grous influence the risk of CAD/MI in Taiwanese and other ethnic oulations. In conclusion, the resent findings suggest that blood grou A might be an indeendent risk factor for CAD and AMI in Taiwanese men younger than 45 years and women younger than 55 years. 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