Combination therapy as a potential risk factor for the development of type 2 diabetes in patients with schizophrenia: the GOMAP study.

BACKGROUND: Schizophrenia (SCZ) is associated with increased risk of type 2 diabetes (T2D). The potential diabetogenic effect of concomitant application of psychotropic treatment classes in patients with SCZ has not yet been evaluated. The overarching goal of the Genetic Overlap between Metabolic and Psychiatric disease (GOMAP) study is to assess the effect of pharmacological, anthropometric, lifestyle and clinical measurements, helping elucidate the mechanisms underlying the aetiology of T2D. METHODS: The GOMAP case-control study (Genetic Overlap between Metabolic and Psychiatric disease) includes hospitalized patients with SCZ, some of whom have T2D. We enrolled 1653 patients with SCZ; 611 with T2D and 1042 patients without T2D. This is the first study of SCZ and T2D comorbidity at this scale in the Greek population. We retrieved detailed information on first- and second-generation antipsychotics (FGA, SGA), antidepressants and mood stabilizers, applied as monotherapy, 2-drug combination, or as 3- or more drug combination. We assessed the effects of psychotropic medication, body mass index, duration of schizophrenia, number of hospitalizations and physical activity on risk of T2D. Using logistic regression, we calculated crude and adjusted odds ratios (OR) to identify associations between demographic factors and the psychiatric medications. RESULTS: Patients with SCZ on a combination of at least three different classes of psychiatric drugs had a higher risk of T2D [OR 1.81 (95% CI 1.22-2.69); p = 0.003] compared to FGA alone therapy, after adjustment for age, BMI, sex, duration of SCZ and number of hospitalizations. We did not find evidence for an association of SGA use or the combination of drugs belonging to two different classes of psychiatric medications with increased risk of T2D [1.27 (0.84-1.93), p = 0.259 and 0.98 (0.71-1.35), p = 0.885, respectively] compared to FGA use. CONCLUSIONS: We find an increased risk of T2D in patients with SCZ who take a combination of at least three different psychotropic medication classes compared to patients whose medication consists only of one or two classes of drugs

Evaluating the glucose raising effect of established loci via a genetic risk score.

Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with glucose levels. We tested the hypothesis here whether the cumulative effect of glucose raising SNPs, assessed via a score, is associated with glucose levels. A total of 1,434 participants of Greek descent from the THISEAS study and 1,160 participants form the GOMAP study were included in this analysis. We developed a genetic risk score (GRS), based on the known glucose-raising loci, in order to investigate the cumulative effect of known glucose loci on glucose levels. In the THISEAS study, the GRS score was significantly associated with increased glucose levels (mmol/L) (β ± SE: 0.024 ± 0.004, P = 8.27e-07). The effect of the genetic risk score was also significant in the GOMAP study (β ± SE: 0.011 ± 0.005, P = 0.031). In the meta-analysis of the two studies both scores were significantly associated with higher glucose levels GRS: β ± SE: 0.019 ± 0.003, P = 1.41e-09. Also, variants at the SLC30A8, PROX1, MTNR1B, ADRA2A, G6PC2, LPIN3 loci indicated nominal evidence for association with glucose levels (p < 0.05). We replicate associations of the established glucose raising variants in the Greek population and confirm directional consistency of effects (binomial sign test p = 6.96e-05). We also demonstrate that the cumulative effect of the established glucose loci yielded a significant association with increasing glucose levels

Screening for Familial Mediterranean Fever M694V and V726A Mutations in the Greek Population

Familial Mediterranean Fever (FMF) is an autosomal recessive genetic disease that primarily affects populations surrounding the Mediterranean basin. FMF patients suffer from recurrent episodes of fever accompanied by abdominal pain, pleuritis, and arthritis. Missense mutations in the gene for FMF (MEFV) have been shown to be responsible for the disease, while more than 70 mutations have been identified to date. The aim of the present study was to determine the carrier rates of two of the most common MEFV mutations, M694V and V726A, in the general Greek population. A cohort of 220 healthy and unrelated individuals of Greek descent was screened for the two MEFV mutations using the Amplification Refractory Mutation System. Our results showed that none of the healthy individuals tested were carriers of any of the two mutations. In conclusion, our study independently confirms that the carrier rate for the MEFV mutations M694V and V726A is extremely low in the general Greek population

Sites of differential DNA methylation between placenta and peripheral blood molecular markers for noninvasive prenatal diagnosis of aneuploidies

The use of epigenetic differences between maternal whole blood and fetal (placental) DNA is one of the main areas of interest for the development of noninvasive prenatal diagnosis of aneuploidies. However, the lack of detailed chromosome-wide identification of differentially methylated sites has limited the application of this approach. in this study, we describe an analysis of chromosome-wide methylation status using methylation DNA immunoprecipitation coupled with high-resolution tiling oligonucleotide array analysis specific for chromosomes 21, 18, 1.3, X, and Y using female whole blood and placental DNA. We identified more than 2000 regions of differential methylation between female whole blood and placental DNA on each of the chromosomes tested. A subset of the differentially methylated regions identified was validated by real-time quantitative polymerase chain reaction. Additionally, correlation of these regions with CpG islands, genes, and promoter regions was investigated. Between 56 to 83% of the regions were located within nongenic regions whereas only 1 to 11% of the regions overlapped with CpG islands; of these, up to 65% were found in promoter regions. In summary, we identified a large number of previously unreported fetal epigenetic molecular markers that have the potential to be developed into targets for noninvasive prenatal diagnosis of trisomy 21 mid other common aneuploidies. In addition, we demonstrated the effectiveness of the methylation DNA immunoprecipitation approach in the enrichment of hypermethylated fetal DNA. (Am J Pathol 2009, 174: 1609-1618 DOI: 10.2353/ajpath.2009.081038

Distribution of individuals in every genotype score group and cumulative effects of the risk alleles from the 36 SNPs for glucose levels.

<p>The bar plots show the average and standard error of glucose in mmol/L for each genotype score group distribution of the genetic risk score.</p

Associations of the unweighted Genetic Risk Score (GRS) and the weighted Genetic Risk Score (wGRS) with glucose levels for the meta-analysis of the GOMAP and THISEAS studies ^a.

<p>Associations of the unweighted Genetic Risk Score (GRS) and the weighted Genetic Risk Score (wGRS) with glucose levels for the meta-analysis of the GOMAP and THISEAS studies <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0186669#t001fn001" target="_blank">^a</a>.</p

Genetic Variation of DKK3 May Modify Renal Disease Severity in ADPKD

Significant variation in the course of autosomal dominant polycystic kidney disease ( ADPKD) within families suggests the presence of effect modifiers. Recent studies of the variation within families harboring PKD1 mutations indicate that genetic background may account for 32 to 42% of the variance in estimated GFR (eGFR) before ESRD and 43 to 78% of the variance in age at ESRD onset, but the genetic modifiers are unknown. Here, we conducted a high-throughput single-nucleotide polymorphism (SNP) genotyping association study of 173 biological candidate genes in 794 white patients from 227 families with PKD1. We analyzed two primary outcomes: (1) eGFR and (2) time to ESRD (renal survival). For both outcomes, we used multidimensional scaling to correct for population structure and generalized estimating equations to account for the relatedness among individuals within the same family. We found suggestive associations between each of 12 SNPs and at least one of the renal outcomes. We genotyped these SNPs in a second set of 472 white patients from 229 families with PKD1 and performed a joint analysis on both cohorts. Three SNPs continued to show suggestive/significant association with eGFR at the Dickkopf 3 (DKK3) gene locus; no SNPs significantly associated with renal survival. DKK3 antagonizes Wnt/β-catenin signaling, which may modulate renal cyst growth. Pending replication, our study suggests that genetic variation of DKK3 may modify severity of ADPKD resulting from PKD1 mutations

Associations of the unweighted Genetic Risk Score (GRS) and the weighted Genetic Risk Score (wGRS) with glucose levels for the meta-analysis of the GOMAP and THISEAS studies ^b.

<p>Associations of the unweighted Genetic Risk Score (GRS) and the weighted Genetic Risk Score (wGRS) with glucose levels for the meta-analysis of the GOMAP and THISEAS studies <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0186669#t002fn001" target="_blank">^b</a>.</p