ABC | Volume 110, Nº1, January 2018

Original Article Fischer et al Gene polymorphisms and coronary disease extension Arq Bras Cardiol. 2018; 110(1):16-23 Table 4 – Distribution of genetic score considering all polymorphisms of the PON-1, MTHFR, ENOS, ACE, AT1R), APOC3 and LPL genes Genetic score N 116 Mean 13.3 Median 13.5 Standard deviation 1.58 Minimum 10 Maximum 17 Asymmetry -0.263 Kurtosis -0.146 P25 12.0 P75 14.0 PON-1: paraoxonase-1; MTHFR: methylenotetrahydrofolate reductase; ENOS: endothelial nitric oxide synthase; ACE: angiotensin-converting enzyme; AT1R: angiotensin II type 1 receptor; APOC3: apolipoprotein C3; LPL: lipoprotein lipase. had no effect on clinical or laboratory variables (Supplementary Tables 9 and 10), (access the link: http://publicacoes.cardiol.br/ portal/2017/abc/english/v11001/pdf/i11001005_anexo.pdf) . For the APOC3 gene, FMD (%) was higher among S2S2 patients than in S1S1/S1S2 patients (14.7 ± 9.6 vs. 11.5 ± 5.2, p = 0.026) (Supplementary Tables 11 and 12), (access the link: http://publicacoes.cardiol.br/portal/2017/abc/english/v11001/ pdf/i11001005_anexo.pdf) , and for the LPL gene, diastolic arterial pressure (mmHg) was lower in the DD genotype as compared with DN/NN (79 ± 15 vs. 87 ± 16, p = 0.043). In addition, a more severe degree of coronary atherosclerosis, evaluated by the Gensini score > median (%) value was found in patients with DD genotype compared with DN/NN (77% vs. 46%, p = 0.039) (Supplementary Tables 13 and 14) (access the link: http://publicacoes.cardiol.br/portal/2017/abc/english/v11001/ pdf/i11001005_anexo.pdf) . Associations of genotypes with CAD extension and severity A dominant model was assumed, as well as the score from 1 to 3 for the isolated genotypes – 1 for absence of risk allele; 2 for the presence of one risk allele; and 3 for the presence of 2 risk alleles in the same gene. Then, score 1 was assigned to the genotypes QQ of PON-1 , CC of MTHFR , GG of ENOS , II of ACE , AA of AT1R , S2S2 of APOC3 and DD of LPL . The score 2 was assigned to the genotypes QR of PON-1 , CT of MTHFR , GT of ENOS , ID of ACE , AC of AT1R , S1S2 of APOC3 and DN of LPL . The score 3 was assigned to the genotypes RR of PON-1 , TT of MTHFR , TT of ENOS , DD of ACE , CC of AT1R , S1S1 of APOC3 and NN of LPL . The sum of the values assigned to each gene (7-21) yielded a genetic score, which was evaluated in absolute values and also in relation with the median (above or below) value. Correlations between genetic and Gensini scores were performed in absolute values and in relation to the median. Results are described in Table 4 and Supplementary Table 15 (access the link: http://publicacoes.cardiol.br/portal/2017/abc/ english/v11001/pdf/i11001005_anexo.pdf) . Both genetic and Gensini scores had a normal distribution. Genetic score tended to be higher in patients with a Gensini score < 50 th percentile (13.7 ± 1.5 vs. 13.0 ± 1.6; p = 0.066, Student’s t test for independent samples). Gensini score was not different between genetic scores above and below the median (p50) [26 (0.00-44.00) vs. 18 (0.25-33.70), P=0.329]. In this population of patients with recent ACS and MS, a weak, inverse correlation was observed between the genetic and the Gensini scores (R = –0.194, p = 0.078, Pearson correlation coefficient). Discussion The present study demonstrated that the genetic polymorphisms analyzed in patients with MS and recent ACS had a modest association with the severity of obstructive coronary disease. Only theDD genotype of D9Npolymorphism of LPL was associated with higher prevalence of more severe coronary lesions. Analysis of the genetic score revealed that the combinations of the studied polymorphisms showed a trend of negative correlation with the anatomical extension of the coronary disease. This finding suggests that in these MS patients, coronary disease may be primarily associated with other mechanisms, with a strong environmental influence. Many of the studied polymorphisms were associated with clinical and laboratory variables, such as heart frequency, diastolic arterial pressure, CRP, HbA1c and adiponectin. A study involving six polymorphisms of LPL, including the D9N, showed that the severity of obstructive lesions, analyzed by the Gensini score, was associated with LPL haplotypes. 32 Corsetti et al. 33 showed an interaction of D9N polymorphism with Taq1B of CETP, which was a predictor of cardiovascular disease risk in women. In addition, LPL polymorphisms have been associated with increased concentrations of triglycerides; 34 in our study, a trend towards higher values was found for the DD genotype as compared with the DN/NN genotype (p = 0.07), possibly due to the high prevalence of overweight/obesity and changes in glucose metabolism in these MS patients. APOC3 polymorphism has an important role in the metabolism of triglyceride-rich lipoproteins and an influence on the development of CAD, particularly in MS and diabetes, with an association of haplotypes in the AI-C3-AIV gene cluster with coronary disease. 35 Renin-angiotensin system genetic polymorphisms (I/D of ACE and AT1R ) were not associated with CAD severity in our study. However, the ACE gene was previously associated with higher ACE levels in D/D patients with CAD, 36 which was not confirmed in a larger sample. In our study, the 192R allele of PON-1 was associated with higher CRP levels, which is a biomarker of cardiovascular outcomes. In a large, three-year follow-up study (n = 3668), arylesterase activity, but not paraoxonase levels or PON-1 polymorphism, was associated with cardiovascular outcomes. 37 For the MTHFR C677T polymorphism, a meta-analysis (n = 6912) demonstrated its association with early CAD, 38 with higher homocysteine levels in the presence of T allele. 39 In our study, CT/TT individuals had higher HbA1c and adiponectin levels as compared with CC individuals. ENOS polymorphisms are involved in endothelial dysfunction. The T allele of the G894T polymorphism 20