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GNB3 C825T Polymorphism and Myocardial Recovery in Peripartum Cardiomyopathy: Results of the Multicenter Investigations of Pregnancy-Associated Cardiomyopathy Study.

ABSTRACT: Black women are at greater risk for peripartum cardiomyopathy (PPCM). The guanine nucleotide-binding proteins ?-3 subunit (GNB3) has a polymorphism C825T. The GNB3 TT genotype more prevalent in blacks is associated with poorer outcomes. We evaluated GNB3 genotype and myocardial recovery in PPCM.A total of 97 women with PPCM were enrolled and genotyped for the GNB3 T/C polymorphism. Left ventricular ejection fraction (LVEF) was assessed by echocardiography at entry, 6 and 12 months postpartum. LVEF over time in subjects with the GNB3 TT genotype was compared with those with the C allele overall and in black and white subsets. The cohort was 30% black, age 30+6, LVEF 0.34+0.10 at entry 31+25 days postpartum. The % GNB3 genotype for TT/CT/CC=23/41/36 and differed markedly by race (blacks=52/38/10 versus whites=10/44/46, P<0.001). In subjects with the TT genotype, LVEF at entry was lower (TT=0.31+0.09; CT+CC=0.35+0.09, P=0.054) and this difference increased at 6 (TT=0.45+0.15; CT+CC=0.53+0.08, P=0.002) and 12 months (TT=0.45+0.15; CT+CC=0.56+0.07, P<0.001.). The difference in LVEF at 12 months by genotype was most pronounced in blacks (12 months LVEF for GNB3 TT=0.39+0.16; versus CT+CC=0.53+0.09, P=0.02) but evident in whites (TT=0.50++0.11; CT+CC=0.56+0.06, P=0.04).The GNB3 TT genotype was associated with lower LVEF at 6 and 12 months in women with PPCM, and this was particularly evident in blacks. Racial differences in the prevalence and impact of GNB3 TT may contribute to poorer outcomes in black women with PPCM.

SUBMITTER: Sheppard R

PROVIDER: S-EPMC4770544 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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GNB3 C825T Polymorphism and Myocardial Recovery in Peripartum Cardiomyopathy: Results of the Multicenter Investigations of Pregnancy-Associated Cardiomyopathy Study.

Sheppard Richard R Hsich Eileen E Damp Julie J Elkayam Uri U Kealey Angela A Ramani Gautam G Zucker Mark M Alexis Jeffrey D JD Horne Benjamin D BD Hanley-Yanez Karen K Pisarcik Jessica J Halder Indrani I Fett James D JD McNamara Dennis M DM

Circulation. Heart failure 20160301 3

<h4>Background</h4>Black women are at greater risk for peripartum cardiomyopathy (PPCM). The guanine nucleotide-binding proteins β-3 subunit (GNB3) has a polymorphism C825T. The GNB3 TT genotype more prevalent in blacks is associated with poorer outcomes. We evaluated GNB3 genotype and myocardial recovery in PPCM.<h4>Methods and results</h4>A total of 97 women with PPCM were enrolled and genotyped for the GNB3 T/C polymorphism. Left ventricular ejection fraction (LVEF) was assessed by echocardio ...[more]

PMID: 26915373

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Project description:BackgroundPeripartum cardiomyopathy (PPCM) remains a major cause of maternal morbidity and mortality.ObjectivesThis study sought to prospectively evaluate recovery of the left ventricular ejection fraction (LVEF) and clinical outcomes in the multicenter IPAC (Investigations of Pregnancy Associated Cardiomyopathy) study.MethodsWe enrolled and followed 100 women with PPCM through 1 year post-partum. The LVEF was assessed by echocardiography at baseline and at 2, 6, and 12 months post-partum. Survival free from major cardiovascular events (death, transplantation, or left ventricular [LV] assist device) was determined. Predictors of outcome, particularly race, parameters of LV dysfunction (LVEF), and remodeling (left ventricular end-diastolic diameter [LVEDD]) at presentation, were assessed by univariate and multivariate analyses.ResultsThe cohort was 30% black, 65% white, 5% other; the mean patient age was 30 ± 6 years; and 88% were receiving beta-blockers and 81% angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The LVEF at study entry was 0.35 ± 0.10, 0.51 ± 0.11 at 6 months, and 0.53 ± 0.10 at 12 months. By 1 year, 13% had experienced major events or had persistent severe cardiomyopathy with an LVEF <0.35, and 72% achieved an LVEF ≥0.50. An initial LVEF <0.30 (p = 0.001), an LVEDD ≥6.0 cm (p < 0.001), black race (p = 0.001), and presentation after 6 weeks post-partum (p = 0.02) were associated with a lower LVEF at 12 months. No subjects with both a baseline LVEF <0.30 and an LVEDD ≥6.0 cm recovered by 1 year post-partum, whereas 91% with both a baseline LVEF ≥0.30 and an LVEDD <6.0 cm recovered (p < 0.00001).ConclusionsIn a prospective cohort with PPCM, most women recovered; however, 13% had major events or persistent severe cardiomyopathy. Black women had more LV dysfunction at presentation and at 6 and 12 months post-partum. Severe LV dysfunction and greater remodeling at study entry were associated with less recovery. (Investigations of Pregnancy Associated Cardiomyopathy [IPAC]; NCT01085955).

Project description:The GNB3 C825T polymorphism is associated with increased G protein-mediated signal transduction, SDF-1?-mediated lymphocyte chemotaxis, accelerated HIV-1 progression, and altered responses to antiretroviral therapy among Caucasian subjects. The GNB3 825T allele is highly prevalent in African populations, and as such any impact on HIV-1 acquisition or progression rates could have a dramatic impact. This study examines the association of the 825T polymorphism with HIV-1 acquisition, disease progression and immune activation in two African cohorts. GNB3 825 genotyping was performed for enrolees in both a commercial sex worker cohort and a perinatal HIV transmission (PHT) cohort in Nairobi, Kenya. Ex vivo immune activation was quantified by flow cytometry, and plasma chemokine levels were assessed by cytokine bead array.GNB3 genotype was not associated with sexual or vertical HIV-1 acquisition within these cohorts. Within the Pumwani cohort, GNB3 genotype did not affect HIV-1 disease progression among seroconverters or among HIV-1-positive individuals after adjustment for baseline CD4 count. Maternal CD4 decline and viral load increase in the PHT cohort did not differ between genotypes. Multi-parametric flow cytometry assessment of T cell activation (CD69, HLA-DR, CD38) and Treg frequency (CD25(+)FOXP3(+)) found no differences between genotype groups. Plasma SDF-1?, MIP-1? and TRAIL levels quantified by cytokine bead array were also similar between groups.In contrast to previous reports, we were unable to provide evidence to suggest that the GNB3 C825T polymorphism affects HIV-1 acquisition or disease progression within African populations. Ex vivo immune activation and plasma chemokine levels were similarly unaffected by GNB3 genotype in both HIV-1-negative and HIV-1-positive individuals. The paucity of studies investigating the impact of GNB3 polymorphism among African populations and the lack of mechanistic studies make it difficult to assess the true biological significance of this polymorphism in HIV-1 infection.

Project description:BACKGROUND:The C825T polymorphism (rs5443) of the Guanine Nucleotide-Binding protein subunit ?3 (GNB3) gene has been associated with obesity, essential hypertension, atherosclerosis, coronary diseases, and cerebrovascular events, but with some sex-specific effects. Its association with inflammatory mediators such as cell adhesion molecules has not been studied, although they are heavily involved in cardiovascular diseases' (CVDs) processes. The aim of our study was then to investigate a possible sex-specific effect of the GNB3 C825T polymorphism on serum soluble cell adhesion molecules such as E, P and L-selectins (sE, sP and sL-selectins). RESULTS:Participants were from the STANISLAS Family Study and were free of chronic disease as CVDs or cancer. We included in total 771 subjects aged 6 to 58 years (391 males (50.71%) and 380 females (49.29%)). No significant association of rs5443 was observed in the whole population with serum sE, sP and sL-selectins after adjusting for age, sex, body mass index, systolic blood pressure, anti-inflammatory drugs and hormonal drugs consumption. A significant interaction of rs5443 was observed with sex for sE-selectin (p?<?0.001), but not for sP and sL-selectins. After adjusting for covariables, the T allele was significantly associated with an additive increase effect on serum sE-selectin levels in males (??=?5.03?±?2.18; p?=?0.020), while a significant additive decrease effect was observed in females (??=-4.46?±?2.06; p?=?0.030). These associations stayed significant after correction for multiple tests (p?=?0.045 in males and in females). The additive phenotypic variance was 21.54% in males versus 1.91% in females. CONCLUSIONS:In our Caucasian population, the GNB3 C825T polymorphism showed a significant sex-specific effect on serum sE-selectin levels, with a disadvantage for males, as increased sE-selectin levels has been associated with CVDs outcomes. The T allele has been previously associated with the same CVDs as increased sE-selectin, but more often in males. The link we observed between this polymorphism and E-selectin is then consistent with previous findings, and helps to better understand the deleterious effect of the GNB3 825 T allele on CVDs outcomes in males. We revealed in this study an important pathway through which the GNB3 gene induces CVDs' outcomes.

Dataset Information

GNB3 C825T Polymorphism and Myocardial Recovery in Peripartum Cardiomyopathy: Results of the Multicenter Investigations of Pregnancy-Associated Cardiomyopathy Study.

Publications

GNB3 C825T Polymorphism and Myocardial Recovery in Peripartum Cardiomyopathy: Results of the Multicenter Investigations of Pregnancy-Associated Cardiomyopathy Study.

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