Objective: Restenosis is the main drawback of percutaneous coronary intervention (PCI). Inherited factors may explain part of the risk of restenosis. Recently, the vitamin D receptor (VDR) has been shown to be involved not only in bone metabolism but also in modulating immune responses and cell proliferation. Since the inflammatory response is implicated in restenosis, VDR-gene variants could therefore contribute to the risk of restenosis. Methods/results: Systematic genotyping for 15 haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene was performed with the high throughput TaqMan allelic discrimination assays in the Genetic Determinants of Restenosis (GENDER) population. A haplotype-based survival analysis revealed an association of haplotypes in blocks 2, 3 and 4 of the VDR-gene with the risk of clinical restenosis (p-values 0.01, 0.04 and 0.02 respectively). After adjustment for clinical risk factors for restenosis, the individual effect of the block 2 AA haplotype (p = 0.011) persisted. Conclusions: The present study indicates that VDR plays a role in restenosis after PCI. Therefore, VDR genotype may be used as risk marker for restenosis and may contribute to individual patient screening prior to PCI in clinical practice.

OBJECTIVE: To investigate the co-occurrence of migraine and depression and assess whether shared genetic factors may underlie both diseases. METHODS: Subjects were 2,652 participants of the Erasmus Rucphen Family genetic isolate study. Migraine was diagnosed using a validated 3-stage screening method that included a telephone interview. Symptoms of depression were assessed using the Center for Epidemiologic Studies Depression scale and the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). The contribution of shared genetic factors in migraine and depression was investigated by comparing heritability estimates for migraine with and without adjustment for symptoms of depression, and by comparing the heritability scores of depression between migraineurs and controls. RESULTS: We identified 360 migraine cases: 209 had migraine without aura (MO) and 151 had migraine with aura (MA). Odds ratios for depression in patients with migraine were 1.29 (95% confidence interval [CI] 0.98-1.70) for MO and 1.70 (95% CI 1.28-2.24) for MA. Heritability estimates were significant for all migraine (0.56), MO (0.77), and MA (0.96), and decreased after adjustment for symptoms of depression or use of antidepressant medication, in particular for MA. Comparison of the heritability scores for depression between patients with migraine and controls showed a genetic correlation between HADS-D score and MA. CONCLUSIONS: There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors.

Objective: Adiponectin, a hormone secreted by adipose tissue is of particular interest to metabolic syndrome (MetS), since it is inversely correlated with obesity and insulin sensitivity. However, it is unknown to what extent the genetics of plasma adiponectin and the genetics of obesity and insulin sensitivity are interrelated. We aimed to evaluate the heritability of plasma adiponectin and its genetic correlation with the MetS and MetS related traits and the association between these traits and ten ADIPOQ SNPs. Research Design and Methods: We made use of a family-based population, the Erasmus Rucphen family (ERF) study (1258 women and 967 men). Heritability analysis was performed using a polygenic model. Genetic correlations were estimated using bivariate heritability analyses. Genetic association analysis was performed using a mixed model. Results: Plasma adiponectin showed a heritability of 55.1%. Genetic correlation between plasma adiponectin HDL-C and plasma insulin ranged from 15% to 24% but were not significant for fasting glucose, TG, blood pressure, HOMA-IR and CRP. Significant association with plasma adiponectin was found for ADIPOQ variants rs17300539 and rs182052. Nominally significant association was found with plasma insulin and HOMA-IR and ADIPOQ variant rs17300539 after adjusting for plasma adiponectin. Conclusions: The significant genetic correlation between plasma adiponectin and HDL-C, and plasma insulin should be taken into account in the interpretation of genome wide association studies. Association of ADIPOQ SNPs with plasma adiponectin was replicated and we showed association between one ADIPOQ SNP and plasma insulin and HOMA-IR.

OBJECTIVE: Plasma adiponectin is strongly associated with various components of metabolic syndrome, type 2 diabetes and cardiovascular outcomes. Concentrations are highly heritable and differ between men and women. We therefore aimed to investigate the genetics of plasma adiponectin in men and women. METHODS: We combined genome-wide association scans of three population-based studies including 4659 persons. For the replication stage in 13795 subjects, we selected the 20 top signals of the combined analysis, as well as the 10 top signals with p-values less than 1.0x10(-4) for each the men- and the women-specific analyses. We further selected 73 SNPs that were consistently associated with metabolic syndrome parameters in previous genome-wide association studies to check for their association with plasma adiponectin. RESULTS: The ADIPOQ locus showed genome-wide significant p-values in the combined (p=4.3x10(-24)) as well as in both women- and men-specific analyses (p=8.7x10(-17) and p=2.5x10(-11), respectively). None of the other 39 top signal SNPs showed evidence for association in the replication analysis. None of 73 SNPs from metabolic syndrome loci exhibited association with plasma adiponectin (p>0.01). CONCLUSIONS: We demonstrated the ADIPOQ gene as the only major gene for plasma adiponectin, which explains 6.7% of the phenotypic variance. We further found that neither this gene nor any of the metabolic syndrome loci explained the sex differences observed for plasma adiponectin. Larger studies are needed to identify more moderate genetic determinants of plasma adiponectin.

Abstract. Henneman P, Janssens ACJW, Carola Zillikens M, Frolich M, Frants RR, Oostra BA, van Duijn CM, van Dijk KW (Leiden University Medical Center, Leiden; Erasmus Medical Center, Rotterdam, The Netherlands). Menopause impacts the relation of plasma adiponectin levels with the metabolic syndrome. J Intern Med 2009; doi: 10.1111/j.1365-2796.2009.02162.xObjective. Plasma adiponectin is negatively correlated with metabolic syndrome (MetS) components obesity and insulin sensitivity. Here, we set out to evaluate the effect of menopause on the association of plasma adiponectin with MetS. Design. Data on plasma adiponectin and MetS were available from 2256 individuals participating in the Erasmus Rucphen Family study. Odds ratios for MetS were calculated by logistic regression analysis using plasma adiponectin quartiles. The discriminative accuracy of plasma adiponectin for MetS was determined by calculating the area under the curve (AUC) of receiver operator. Analyses were performed in women and men, pre- and postmenopausal women and younger and older men. Results. Virtually all determinants of MetS differed significantly between groups. Low plasma adiponectin showed the highest risk for MetS in postmenopausal women (odds ratio = 18.6, 95% CI = 7.9-44.0). We observed a high discriminative accuracy of age and plasma adiponectin for MetS not only in postmenopausal women (AUC = 0.76) but also in other subgroups (AUC from 0.67 to 0.87). However, in all groups, the discriminative accuracy of age and body mass index (BMI) for MetS was similar to the discriminative accuracy of age and plasma adiponectin. Conclusions. Low plasma levels of adiponectin are associated with increased prevalence of MetS, especially in postmenopausal women. Age and BMI have similar discriminatory accuracies for presence of MetS when compared with age and plasma adiponectin. Thus, we conclude that the association of plasma adiponectin with MetS is significantly affected by menopause but challenge the additional value of adiponectin for the discriminatory accuracy for presence of MetS.

Facioscapulohumeral muscular dystrophy (FSHD), caused by partial deletion of the D4Z4 macrosatellite repeat on chromosome 4q, has a complex genetic and epigenetic etiology. To develop FSHD, D4Z4 contraction needs to occur on a specific genetic background. Only contractions associated with the 4qA161 haplotype cause FSHD. In addition, contraction of the D4Z4 repeat in FSHD patients is associated with significant D4Z4 hypomethylation. To date, however, the methylation status of contracted repeats on nonpathogenic haplotypes has not been studied. We have performed a detailed methylation study of the D4Z4 repeat on chromosome 4q and on a highly homologous repeat on chromosome 10q. We show that patients with a D4Z4 deletion (FSHD1) have D4Z4-restricted hypomethylation. Importantly, controls with a D4Z4 contraction on a nonpathogenic chromosome 4q haplotype or on chromosome 10q also demonstrate hypomethylation. In 15 FSHD families without D4Z4 contractions but with at least one 4qA161 haplotype (FSHD2), we observed D4Z4-restricted hypomethylation on chromosomes 4q and 10q. This finding implies that a genetic defect resulting in D4Z4 hypomethylation underlies FSHD2. In conclusion, we describe two ways to develop FSHD:(1) contraction-dependent or (2) contraction-independent D4Z4 hypomethylation on the 4qA161 subtelomere. Hum Mutat 30:1-11, 2009.(c) 2009 Wiley-Liss, Inc.

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscular dystrophy in which no mutation of pathogenic gene(s) has been identified. Instead, the disease is, in most cases, genetically linked to a contraction in the number of 3.3 kb D4Z4 repeats on chromosome 4q. How contraction of the 4qter D4Z4 repeats causes muscular dystrophy is not understood. In addition, a smaller group of FSHD cases are not associated with D4Z4 repeat contraction (termed "phenotypic" FSHD), and their etiology remains undefined. We carried out chromatin immunoprecipitation analysis using D4Z4-specific PCR primers to examine the D4Z4 chromatin structure in normal and patient cells as well as in small interfering RNA (siRNA)-treated cells. We found that SUV39H1-mediated H3K9 trimethylation at D4Z4 seen in normal cells is lost in FSHD. Furthermore, the loss of this histone modification occurs not only at the contracted 4q D4Z4 allele, but also at the genetically intact D4Z4 alleles on both chromosomes 4q and 10q, providing the first evidence that the genetic change (contraction) of one 4qD4Z4 allele spreads its effect to other genomic regions. Importantly, this epigenetic change was also observed in the phenotypic FSHD cases with no D4Z4 contraction, but not in other types of muscular dystrophies tested. We found that HP1gamma and cohesin are co-recruited to D4Z4 in an H3K9me3-dependent and cell type-specific manner, which is disrupted in FSHD. The results indicate that cohesin plays an active role in HP1 recruitment and is involved in cell type-specific D4Z4 chromatin regulation. Taken together, we identified the loss of both histone H3K9 trimethylation and HP1gamma/cohesin binding at D4Z4 to be a faithful marker for the FSHD phenotype. Based on these results, we propose a new model in which the epigenetic change initiated at 4q D4Z4 spreads its effect to other genomic regions, which compromises muscle-specific gene regulation leading to FSHD pathogenesis.

OBJECTIVE: To study the clinical spectrum of CACNA1A S218L mutation carriers with special attention for ''early seizures and cerebral edema after trivial head trauma''(ESCEATHT), a combination of symptoms which resembles ''the juvenile head trauma syndrome''. PATIENTS AND METHODS: We sequenced all exons of CACNA1A in two patients with ESCEATHT. Both patients also had hemiplegic migraine and ataxia. Subsequently, we screened the literature for S218L mutation carriers. RESULTS: In both patients we found a de novo S218L mutation in the CACNA1A gene. In addition, we identified 11 CACNA1A S218L carriers from literature. From these 13 S218L mutation carriers, twelve (92%) patients had ataxia or cerebellar symptoms. Nine (69%) had hemiplegic migraine that could be triggered by trivial head trauma. Three mutation carriers had the complete ESCEATHT phenotype. Seven (54 %) had seizures (four had early post traumatic seizures) and five (38%) had edema as detected by MRI/CT. CONCLUSIONS: The CACNA1A S218L mutation is associated with FHM, ataxia and/or ESCEATHT. A minority of S218L mutation carriers have the complete ESCEATHT phenotype, but a high percentage of patients had one or more ESCEATHT symptoms. As the S218L mutation enhances the propensity for cortical spreading depression (CSD), we postulate a role for CSD not only in hemiplegic migraine, but also in early seizures and cerebral edema after trivial head trauma. As this combination of symptoms is part of the unexplained ''juvenile head trauma syndrome'', a similar molecular mechanism may underlie this disorder.

Migraine is a severely debilitating episodic disorder affecting up to 12% of the general population. Migraine arises from both genetic and environmental factors, complicating our understanding of what makes the migraine brain susceptible to attacks. In recent years, powerful genetic screening tools have revealed several single genes linked to migraine. One example of a monogenic subtype of migraine is familial hemiplegic migraine (FHM), a rare form of migraine with aura. The fact that FHM and common multifactorial migraine have many overlapping clinical features indicates that they likely share underlying pathophysiological pathways. In addition, the identification of monogenic subtypes has made it possible to generate suitable animal models for migraine. The purpose of this review is to present an overview of the clinical features of migraine and discuss the continuing highway of migraine gene discovery. The genes associated with FHM will be discussed, including what we have learned from studying the functional consequences of FHM mutations in cellular and animal models.