Alizadeh, B.Z.

Association of two DRD2 gene polymorphisms with acute and tardive antipsychotic-induced movement disorders in young Caucasian patients (Article)

2012-02-01T00:00:00Z

Rationale: Pharmacogenetic studies on antipsychotic-induced movement disorders (MD) in schizophrenia so far have focused mainly on tardive dyskinesia. Only a few examined the more acute antipsychotic-induced MD such as parkinsonism and akathisia. Notably, all MD relate to deregulation of the dopamine system. Objective: This study aimed to replicate previously reported associations in candidate genes for acute and tardive antipsychotic-induced MD in a young Caucasian sample. Methods: In 402 patients (median age 26 years), a total of 13 polymorphisms were genotyped in eight dopamine-related candidate genes selected a priori from the literature (regarding dopamine and serotonin receptors, dopamine degradation, and free radicals scavenging enzymes pathways). Results: Patients with MD used on average a higher haloperidol dose equivalent when compared to those without MD. The prevalence of MD was high and did not differ between first- and second-generation antipsychotics. Significant associations were found between (a) the TaqI-D polymorphism and akathisia (OR = 2.3, p = 0.001 for each extra C-allele) and (b) the -141C polymorphism and tardive dyskinesia (OR = 0.20, p = 0.001 for each extra Del allele). The other polymorphisms were not significantly associated with an MD. Conclusions: Two associations were found between genetic variation TaqI-D and the -141C polymorphisms in the DRD2 gene and antipsychotic-induced MD; one with acute akathisia and one with tardive dyskinesia. These were previously reported to be associated with tardive dyskinesia and acute parkinsonism, respectively. These results suggest that the contribution of these DRD2 gene variants in the vulnerability of antipsychotic-induced MD takes place in a more general or pleiotropic way.

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma (Article)

2011-11-01T00:00:00Z

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10-8to P = 10-190). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.

Genetic correlates of early accelerated infant growth associated with juvenile-onset type 1 diabetes (Article)

2011-10-06T00:00:00Z

Objective: We previously showed that accelerated growth predisposing to development of childhood-onset type 1 diabetes (T1D) is restricted to the first year after birth. We assessed whether this phenomenon of increased early growth is associated with variants of two genes, insulin-like growth factor-1 (IGF1) and insulin variable number of tandem repeats (INS-VNTR), whose products are components of the growth axis. Patients and methods: Patients and their siblings were genotyped for the INS-VNTR and for an IGF1 microsatellite. We tested for difference in first year growth, i.e., increased weight standard deviation score (SDS), a reliable measure of especially first year growth, between carriers and non-carriers of these gene variants, using a repeated measurement and regression analysis. Results: In patients, growth did not differ between carriers and non-carriers of the INS-VNTR*III allele, while carriership of this allele in siblings was positively associated with increased first year growth. In both patients and siblings, non-carriership of the IGF1*194 allele was positively associated with growth. Birth size was not associated with either variant. Conclusions/discussion: Non-carriership of the IGF1*194 allele was positively associated with accelerated first year growth in both patients and siblings, independent of disease. This IGF1 variant may therefore contribute to increased first year growth, but cannot explain the association of first year growth with diabetes. An effect on growth of the INS-VNTR was detected in healthy siblings, but not in patients, suggesting that disease supersedes a growth effect of INS-VNTR.

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure (Article)

2011-10-01T00:00:00Z

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10 -8 to P = 2.3 × 10 -13) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

HFE gene mutations increase the risk of coronary heart disease in women (Article)

2010-09-01T00:00:00Z

he purpose of the present study is to examine HFE gene mutations in relation to newly diagnosed (incident) coronary heart disease (CHD). In a population-based follow-up study of 7,983 individuals aged 55 years and older, we compared the risk of incident CHD between HFE carriers and non-carriers, overall and stratified by sex and smoking status. HFE mutations were significantly associated with an increased risk of incident CHD in women but not in men (hazard ratio [HR] for women = 1.7, 95% confidence interval [CI] 1.2-2.4 versus HR for men = 0.9, 95% CI 0.7-1.2). This increased CHD risk associated with HFE mutations in women was statistically significant in never smokers (HR = 1.8, 95% CI 1.1-2.8) and current smokers (HR = 3.1, 95% CI 1.4-7.1), but not in former smokers (HR = 1.3, 95% CI 0.7-2.4). HFE mutations are associated with increased risk of incident CHD in women.

Association analysis of myosin IXB and type 1 diabetes (Article)

2010-06-01T00:00:00Z

To date, seven studies have provided evidence for an association between the gene encoding for myosin IXB (MYO9B) and celiac disease (CD), and inflammatory bowel diseases, including single nucleotide polymorphisms (SNPs) rs2305767, rs1457092, and rs2305764. We investigated whether MYO9B is associated with T1D. The three SNPs were genotyped in Dutch samples from 288 T1D patients and 1615 controls. The A allele of SNP rs2305767A>G showed some evidence of association with T1D (nominal p for genotype = 0.06; OR carrier = 1.51, 95% CI = 1.04-2.19), but not in British samples from 4301 case patients and 4706 controls (p = 0.53), or when the Dutch and UK data were pooled (N patients = 4582, N controls= 6224; Mantel-Hansel p = 0.83). Furthermore, the nonsynonymous rs1545620 C>A SNP that has been associated with the inflammatory bowel disease, showed no association with T1D in British case-control set (p = 0.57). We conclude that MYO9B might not be a strong determinant of T1D, although there was some association in our initial Dutch study. Further studies are needed to evaluate the role of MYO9B in T1D.

HFE variants, APOE and Alzheimer's disease: Findings from the population-based Rotterdam Study (Article)

2009-02-01T00:00:00Z

Iron is a reactive oxygen species and has been implicated in the pathogenesis of Alzheimer's disease (AD). In a population-based cohort study, including 268 incident AD patients and 2079 control individuals, we investigated the influence of the HFE C282Y and H63D variants and the apolipoprotein E4 (APOEε4) allele on the incidence, and age at onset of AD. There was no significant difference in the frequency of HFE variants in AD patients compared to controls. There was no significant effect modification by the APOEε4 allele. The mean age at onset was earlier in H63D homozygotes compared to non-carriers of this variant, in men (76.9 ± 3.2 compared to 82.2 ± 1.7) and women (82.1 ± 3.9 compared to 84.5 ± 1.7). In addition, in APOEε4 carriers, the mean age at onset of AD was earlier in men homozygous for the H63D variant (73.2 ± 2.1 versus 78.7 ± 1.6, p = 0.05). Our results suggest that HFE variants are not strong determinants of AD in the general population but may modify the age of onset.

Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes (Article)

2008-07-01T00:00:00Z

Th1 related chemokines CCL3 and CCL5 and Th2 related CCL4 as ligands of the receptor CCR5 contribute to disease development in animal models of type 1 diabetes. In humans, no data are available addressing the role of these chemokines regarding disease progression and remission. We investigated longitudinally circulating concentrations of CCR5 ligands of 256 newly diagnosed patients with type 1 diabetes. CCR5 ligands were differentially associated with β-cell function and clinical remission. CCL5 was decreased in remitters and positively associated with HbA1c suggestive of a Th1 associated progression of the disease. Likewise, CCL3 was negatively related to C-peptide and positively associated with the β-cell stress marker proinsulin but increased in remitters. CCL4 associated with decreased β-cell stress shown by negative association with proinsulin. Blockage of chemokines or antagonism of CCR5 by therapeutic agents such as maraviroc may provide a new therapeutic target to ameliorate disease progression in type 1 diabetes.

The H63D variant in the HFE gene predisposes to arthralgia, chondrocalcinosis and osteoarthritis (Article)

2007-11-01T00:00:00Z

Objectives: To investigate the relation between the HFE C282Y and H63D variants with arthralgia and joint pathology in the population-based Rotterdam Study. Methods: From a cohort of 7983 people aged 55 years and over, 2095 randomly drawn subjects were genotyped for C282Y and H63D variants. We compared the frequency of arthralgia, and the presence of chondrocalcinosis, osteophytes, joint space narrowing and radiographic osteoarthritis in hand, hip and knee joints, and Heberden's nodes in carriers of HFE variants with that in non-carriers. Results: Overall, there was a significantly higher frequency of arthralgia (odds ratio 1.6; 95% CI 1.0 to 2.6), oligoarthralgia (2.3; 1.2 to 4.4) and Heberden's nodes (2.0; 1.1 to 3.8) in H63D homozygotes compared with non-carriers. In subjects aged 65 years or younger, H63D homozygotes had significantly more often polyarthralgia (3.1; 1.3 to 7.4), chondrocalcinosis in hip or knee joints (4.7; 1.2 to 18.5), and more hand joints with osteophytes (6.1±1.0 vs 4.4±0.3), space narrowing (2.8±0.5 vs 1.0±0.1), radiographic osteoarthritis (4.4±0.7 vs 2.0±0.2) and Heberden's nodes (3.1; 1.3 to 12.8) than non-carriers. We found no relation of arthralgia or joint pathology to C282Y, but compound heterozygotes had a significantly higher frequency of arthralgia (2.9; 1.0 to 9.3), chondrocalcinosis in hip joints (6.5; 1.8 to 22.3), and an increased number of osteophytes in knee (6.9±1.2, n = 5 vs 2.4±0.1) joints at a later age (>65 years). Conclusions: The HFE H63D variant may explain, at least in part, the prevalence of arthralgia in multiple joints sites, chondrocalcinosis, and hand osteoarthritis in the general population.

MICA marks additional risk factors for Type 1 diabetes on extended HLA haplotypes: An association and meta-analysis (Article)

2007-04-01T00:00:00Z

The association of the HLA complex on chromosome 6 does not explain total linkage of the HLA region to Type 1 Diabetes (T1D), leading to the hypothesis that there may be additional causal genes in the HLA region for immune-related disorders. Reports on the MHC Class I chain-related A (MICA) gene as candidate for association with T1D are contradicting. We investigated whether variation in MICA is associated to T1D in a cohort of 350 unrelated individuals with juvenile-onset T1D and 540 control subjects, followed by a meta-analysis of 14 studies. We also investigated an HLA-independent association for MICA with T1D. In our case-control study, we found that the MICA*A5 variant was significantly associated with an increased risk for T1D, while MICA*A6 was significantly associated with a decreased risk that was confirmed by our meta-analysis. However, the meta-analysis did not show an association of MICA*A5 T1D. Analysis of MICA alleles conditional on T1D-associated high-risk MHC class II haplotypes revealed that MICA*A6 was associated with an increased risk for T1D when this marker co-occurred with HLA DQ2DR17 T1D-risk-haplotypes. In contrast, MICA*A6 reduced the risk from the HLA DQ8DR4 T1D-risk haplotype. Moreover, MICA*A9 showed a significant association to increased risk for T1D on DQ8DR4 haplotypes. Co-inheritance of MICA*A6 with the HLA DQ2DR17 haplotype in T1D indicates this haplotype may carry the additional genetic factors for T1D, but our study does not support an independent association between MICA variants and T1D.

Osteoarthritis and Hemochromatosis: A genetic epidemiologic study (Doctoral Thesis)

2005-03-23T00:00:00Z

Osteoarthritis (OA) refers to a heterogeneous group of distinct diseases which express a common radiographic and clinical phenotype at diarthrodial joints.It is the leading cause of pain and disability in the elderly with a prevalence of 75 percent in the population aged 70 years. There is a substantial genetic component in the etiology of osteoarthritis. It is expected that genetic heterogeneity, the extent of which is unknown yet, contributes to a spectrum of osteoarthritis related phenotypes. Linkage as well as candidate gene studies are being performed to identify the genes involved.The overall aim of our research project is to identify genes that contribute to osteoarthritis. The aim of the present thesis was to understand the relation between hemochromatosis and osteoarthritis. As a part of this project, candidate osteoarthritis genes were analysed. These include the gene encoding the alpha domain of collagen type IX (COL9A1) and the HFE gene involved in hereditary hemochromatosis, a disorder that coincides with arthropathy. This thesis, therefore, brings together two related complex diseases, that share related phenotypes and possibly some of the underlying genetic components.

Polymorphisms in the prion protein gene and in the doppel gene increase susceptibility for Creutzfeldt-Jakob disease (Article)

2004-05-01T00:00:00Z

The prion protein gene (PRNP) plays a central role in the origin of Creutzfeldt-Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion-like doppel gene (PRND) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of PRNP and three polymorphisms in PRND (T26M, P56L and T174M) in CJD. The study included a population-based sample of 52 patients with sporadic CJD and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on PRND T174M comparing the data of the four studies conducted to date. For SNP 1368 and PRNP M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to CJD independent of PRNP M129V. We further found a significant increased prevalence of M homozygotes at PRND T174M among sporadic CJD patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for PRNP 129M and PRND 174M (odds ratio 4.35, 95% confidence interval 1.05-8.09; P=0.04). The meta-analysis on the PRND T174M polymorphism did not show a consistent effect across studies, raising the question as to whether PRND 174M is causally related to CJD, or whether the PRND allele is in linkage disequilibrium with another polymorphism related to CJD.

Does Bilirubin protect against hemochromatosis gene (HFE) related mortality? (Article)

2004-01-01T00:00:00Z

Serum bilirubin is an important antioxidant that is found at increased levels in hereditary hemochromatosis patients. We hypothesized that increased levels of serum bilirubin may play a protective role against oxidative stress induced by iron overload in carriers of mutations in the hereditary hemochromatosis gene (HFE). We studied the relation between serum total bilirubin, serum iron levels, the HFE C282Y and H63D mutations, and mortality. The study was conducted in 2,332 randomly selected subjects from the Rotterdam Study, a population-based follow-up study of people aged 55 years or over. Serum bilirubin levels were significantly correlated with serum iron (Pearson's correlation coefficient (r) = 0.4, P < 0.001), transferrin saturation (r = 0.4, P < 0.001), and serum ferritin (r = 0.2, P < 0.05). Carriers of the HFE mutations had higher levels of bilirubin compared to wild-type homozygotes. The relation was the strongest in H63D heterozygotes or homozygotes and C282Y heterozygotes. High levels of serum bilirubin were associated with a 2.8 (95% CI 0.9-8.8) fold reduction in mortality in H63D homozygotes and a 2.2 (1.0-4.7) fold reduction in mortality in C282Y heterozygotes. Taken together, our data suggest that the high levels of the antioxidant bilirubin may counteract the adverse effect of oxidative stress induced by iron overload. This may explain in part the reduced penetrance of the HFE mutations.

The role of hemochromatosis C282Y and H63D gene mutations in type 2diabetes: findings from the Rotterdam Study and meta-analysis (Letter To Editor)

2002-01-01T00:00:00Z

Letter