A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

Objective: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy.Methods: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum.Results: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found.Significance: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.</p

Genomic and clinical predictors of lacosamide response in refractory epilepsies

Objective: Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real-world clinical setting.Methods: We tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome-wide association studies and exome studies, comprising 281 candidate genes.Results: Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders (Significance: No genetic predictor of lacosamide response was identified. Patients with refractory GGE might benefit from treatment with lacosamide.</p

Family trees depicting transmission of 15q11.2-q13.3 duplications and neuropsychiatric phenotypes.

<p>Red fill indicates maternal duplications, blue indicates paternal duplications, and grey indicates no duplications. Samples where no DNA was available have no fill. Where DNA samples were available, parent of origin was determined using methylation-sensitive high-resolution melt curve analysis, or methylation-sensitive Southern Blot. Neuropsychiatric phenotype (detailed in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005993#pgen.1005993.s004" target="_blank">S1 Table</a>) is indicated as follows: SZ—schizophrenia; SZA—schizoaffective; DD—developmental delay; UA—unaffected. In addition, one individual was reported to have epilepsy and another ADHD.</p

Demographic properties of the study subjects in participant studies.

<p>Demographic properties of the study subjects in participant studies.</p

Prevalence of 15q11-q13 duplications in disease and control cohorts.

<p>Prevalence of 15q11-q13 duplications in disease and control cohorts.</p

Penetrance estimates for the 15q11.2-q13.3 duplication.

<p>In brackets are shown the 95%CI, calculated with the methods described in [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005993#pgen.1005993.ref024" target="_blank">24</a>].</p

Selection coefficient estimates for 15q11.2-q13.3 duplications.

<p>Selection coefficients are approximated as the proportion of <i>de novo</i> CNV out of the total number of CNVs: <i>de novo</i>/(<i>de novo</i> + inherited).</p

Genotype score associated with the risk of androgenetic alopecia.

<p>Abbreviations: OR, odds ratio; CI, confidence interval.</p>a<p>-The top SNPs from each genome-wide significant loci as shown in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002746#pgen-1002746-t002" target="_blank">Table 2</a> are used in risk score analysis.</p

Genome-wide meta-analysis results for AGA in MAAN.

<p>(A) Manhattan plot showing the −log₁₀ p value of SNPs against their chromosomal positions. The genome-wide significant SNPs are green (p value<5×10⁻⁸). The points with p value <1×10⁻⁴⁰ were truncated; the smallest p value was 2.4×10⁻⁹¹ at AR gene. (B–I) Regional association plots for eight loci associated with AGA. In each panel, the lead SNP is denoted in purple with its rs ID and association p value. The color of other SNPs indicates the LD with the lead SNP as red (0.8≤<i>r</i>²≤1), orange (0.6≤<i>r</i>²<0.8), green (0.4≤<i>r</i>²<0.6), light blue (0.2≤<i>r</i>²<0.4), and dark blue (<i>r</i>²<0.2). Estimated recombination rates are in light blue.</p

CNVs on chromosome 15.

<p>The image depicts the region on chromosome 15 that is affected by deletions and duplications caused by a number of low copy repeats. These form five recognised breakpoints (BPs) which cause the formation of deletions and duplications of different sizes. Several of them result in recognised syndromes: PWS/AS, 15q11.2 deletion and 15q13.3 deletion and duplication. The black bars at the top show the positions of the SZ/SZA probands in the current study (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005993#pgen.1005993.s004" target="_blank">S1 Table</a>). All four combinations of duplications between BP1 and BP4 are represented. They all intersect the regions of maternally and paternally expressed genes and the GABA receptors gene cluster.</p