Publications

Nitric oxide (NO), a potent vasodilator, plays a pivotal role in blood pressure regulation. Endothelial NO synthase gene (NOS3) polymorphisms influence NO levels. Here, we investigated the role of the -922A/G, -786T/C, 4b/4a, and 894G/T polymorphisms of the NOS3 and NO(x) levels in 800 consecutive unrelated subjects comprising 455 patients of essential hypertension and 345 controls. The polymorphisms were investigated independently and as haplotypes. Plasma NO(x) levels (nitrate and nitrite) were estimated by the Griess method. Genotype frequencies for the -786T/C, 4b/4a, and 894G/T polymorphisms differed significantly (P<0.001) between patients and controls and were associated with an increased risk of hypertension (OR=2.0, OR=3.8, OR=1.6, respectively). The 4-locus haplotypes ATaG (H1), ATaT (H2), and GCaG (H3) were significantly associated with essential hypertension and served as susceptible haplotypes (P

One of the many obstacles to effective drug treatment is the efflux transporter P-glycoprotein (P-gp), which can restrict the plasma and intracellular concentrations of numerous xenobiotics. Variable drug response to P-gp substrates suggests that genetic differences in ABCB1 may affect P-gp transport. The current study examined how ABCB1 variants alter the P-gp-mediated transport of probe substrates in vitro. Nonsynonymous ABCB1 variants and haplotypes with an allele frequency >/=2% were transiently expressed in HEK293T cells, and the transport of calcein acetoxymethyl ester and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY-FL)-paclitaxel was measured in the absence or presence of the P-gp inhibitor cyclosporin A. The A893S, A893T, and V1251I variants and the N21D/1236C>T/A893S/3435C>T haplotype altered intracellular accumulation compared with reference P-gp in a substrate-dependent manner. It is interesting that certain variants showed altered sensitivity to cyclosporin A inhibition that was also substrate-specific. These functional data demonstrate that nonsynonymous polymorphisms in ABCB1 may selectively alter P-gp transport and drug-drug interactions in a substrate- and inhibitor-dependent manner.

BACKGROUND

Atrial fibrillation (AF) may be due to an inherited trait, particularly in lone AF patients. A family history of AF in lone AF patients has not previously been compared with a family history of patients with AF and established risk factors (non-lone AF).

OBJECTIVE

The purpose of this study was to compare the frequency of having a first-degree relative with AF in lone and non-lone AF patients.

METHODS

We performed a case-control study of consecutive subjects presenting to a single electrophysiology laboratory. A convenience sample of subjects with no known arrhythmias was also enrolled.

RESULTS

Four hundred twenty-nine subjects were enrolled: 136 had AF (54 with lone AF), 84 had atrial flutter, 158 had other supraventricular arrhythmias, and 51 had no known arrhythmias. Significantly more subjects with AF reported a first-degree family history of AF compared with the remainder of the cohort (25% vs. 5%; P <.001). In multivariable analysis adjusting for potential confounders, AF patients had a 6-fold greater odds of having a family member with AF (95% confidence interval [CI] 2.93-12.7; P <.001). Lone AF patients had a first-degree family member with AF substantially more often than those with non-lone AF (41% vs. 14%; P <.001). After adjusting for potential confounders, lone AF patients remained significantly more likely than other AF patients to have a first-degree relative with AF (OR 7.2; 95% CI 2.1-24.7; P = .002).

CONCLUSION

Lone AF patients have a first-degree family member with AF substantially more often than other AF patients. This suggests that an inherited trait may be particularly important in this subgroup of patients.