ABC | Volume 114, Nº4, April 2020

Original Article Albuquerque et al. Ser49Gly Polymorphism in heart failure Arq Bras Cardiol. 2020; 114(4):613-615 Gene and haplotype frequencies were tested for the Hardy-Weinberg equilibrium, 20 using the software ARLEQUIN version 2000. The project was approved by the Research Ethics Committee of Hospital Universitário Pedro Ernesto on 12/16/2009. An Informed Consent Form (ICF) was signed by all patients. This study was partially funded by FAPERJ (Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro). Results Characteristics of the sample population and GP-Rβ1 Table 1 shows the general characteristics of the study population. Mean age of 64.4 ± 12.8 years (variation: 24–93 years), a higher prevalence of males, white skin color and ischemic etiology were observed. The mean follow-up time at the HF clinic was 6.7 ± 4.4 years. As for the genetic profile, the Ser allele occurred 295 times (82.8%) whereas the Gly allele occurred 61 times (17.2%). In relation to the genotypes, 122 (68.5%) were classified as Ser-Ser, 51 (28.7%) as Ser-Gly and only 5 (2.8%) as Gly-Gly. A significant difference (p = 0.003) was found between GP-R β 1 and skin color: there was a higher prevalence of whites among those with Ser-Ser genotype and virtually an equilibrium between Ser-Gly individuals with white skin and others, as shown in Table 1. The population was in genetic equilibrium, according to the Hardy-Weinberg theorem. 20 There were no significant differences between the genotypes regarding clinical characteristics, baseline NYHA functional class, electrocardiographic, echocardiographic and laboratory characteristics or medical treatment, as shown in Table 1. Clinical outcome Clinical outcome data are shown in Table 2. The R β 1 genotype showed a significant association with the final NYHA functional class (p = 0.014), with Ser-Ser being associated with the most advanced functional class. Of the eighteen NYHA IV patients, Ser-Ser was found in 88.9% of the cases. The Ser-Gly GP was responsible for the other two cases. All five patients with Gly-Gly genotype progressed with NYHA I or II at the end of the follow-up. Mean NYHA functional class was lower than baseline (2.15 ± 0.9 → 2.02 ± 1.0). As for outcomes, 24.9% showed improved functional class, 38.4% remained stable and 36.7% showed NYHA worsening. There was no significant difference between GP-R β 1 and NYHA mean values or change in functional class during clinical follow-up. Outcomes: Deaths and hospital admissions due to HF The clinical outcomes of hospital admission due to HF and death were investigated both separately and in association. Combined outcome of admission due to HF+Death occurred in 100 patients (56.2%). It was more frequent in the Ser-Ser group (60.7%) with no significant difference when comparing Ser-Gly (47.1%) with Gly-Gly (40.0%) cases. In relation to the number of hospitalizations alone, 182 events were observed in 74 patients, with no significant difference between GP-R β 1 types. Finally, deaths only were analyzed: 67 events – an overall mortality rate of 37.6%. The Ser-Ser genotype accounted for 80.5% of these deaths and only 1.5% of patients who died had the Gly-Gly genotype. In the comparative analysis of the distribution of deaths by GP, there was a significant difference (p = 0.026) between the genotypes Ser-Ser, Ser-Gly and Gly-Gly, with mortality rates of 44.3%, 23.5% and 20.0%, respectively. Table 2 and Figure 1 depict these findings. The impact of GP-R β 1 on the mortality of these patients was shown through multivariate analysis: the Gly allele had a protective effect independent of other factors after adjustment for final NYHA, final LVEF, creatinine, low adherence and final heart rate. The presence of each copy of the Gly allele was associated with risk of death reduced by 63% (p = 0.03; Odds Ratio 0.37 – CI 0.15–0.91). These data are shown in Table 3. The cause of death was determined in 56% (34) of the cases: 61.8% were related to HF worsening, 29.4% of sudden deaths and 8.8% due to other causes. There was no difference between the genotypes regarding the cause of death. Discussion This study describes the association between the Beta‑1 Genetic Polymorphism Ser49Gly genotypes and clinical outcome in 178 patients with HF, with mean follow-up of 6.7 years. Of all the studies published on Ser49Gly genotyping in the context of HF, this one has the longest follow-up time. Its main finding was the association of Gly‑Gly GP-R β 1 with a protective effect for clinical outcomes, with better clinical outcome evaluated by NYHA functional class and lower risk of death. Whenwe comparedwithother Brazilianpopulations,we found a relatively similar allelic distribution: the Gly allele was present in 13 to 17% of the HF cases. 10,16 In relation to the genotypes, it was largely similar to a study including 201 patients from the state of Rio Grande do Sul 10 but different from the cohort of 146 patients from the municipality of Niterói, in the state of Rio de Janeiro. 16 Due to the intense miscegenation of the Brazilian population, skin color is probably not a good determinant of the genetic profile, as despite the similarity in the percentage of whites between this study and that of Pereira et al., 16 there is a difference in their genetic profile. Thus, ethnicity assessed by skin color alone could not explain the high percentage of the Gly-Gly genotype found by Pereira et al. 16 Stressing this point, international studies have shown a strong similarity with this cohort, as to the genotypic distribution of GP-R β 1: 7,9,17 63 to 73% of Ser-Ser, 27 to 35% of Ser-Gly and 0 to 3% of Gly-Gly individuals, although the studies included other ethnicities. It may be worth conducting other national studies in order to evaluate the genotypic distribution of this genetic polymorphism in our population. 618