Pieter J.L.M. Snijders

A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis

Hereditary hemochromatosis (HH) is a very common disorder characterized by iron overload and multi-organ damage. Several genes involved in iron metabolism have been implicated in the pathology of HH (refs. 1–4). We report that a mutation in the gene encoding Solute Carrier family 11, member A3 (SLC11A3), also known as ferroportin, is associated with autosomal dominant hemochromatosis.

PARK7, a Novel Locus for Autosomal Recessive Early-Onset Parkinsonism, on Chromosome 1p36

Although the role of genetic factors in the origin of Parkinson disease has long been disputed, several genes involved in autosomal dominant and recessive forms of the disease have been localized. Mutations associated with early-onset autosomal recessive parkinsonism have been identified in the Parkin gene, and recently a second gene, PARK6, involved in early-onset recessive parkinsonism was localized on chromosome 1p35-36. We identified a family segregating early-onset parkinsonism with multiple consanguinity loops in a genetically isolated population. Homozygosity mapping resulted in significant evidence for linkage on chromosome 1p36. Multipoint linkage analysis using MAPMAKER-HOMOZ generated a maximum LOD-score of 4.3, with nine markers spanning a disease haplotype of 16 cM. On the basis of several recombination events, the region defining the disease haplotype can be clearly separated, by > or =25 cM, from the more centromeric PARK6 locus on chromosome 1p35-36. Therefore, we conclude that we have identified on chromosome 1 a second locus, PARK7, involved in autosomal recessive, early-onset parkinsonism.

Clinical features and neuroimaging of PARK7-linked parkinsonism

We recently reported linkage to chromosome 1p36 (the PARK7‐locus) in a family with early‐onset parkinsonism. Linkage to this locus has since been confirmed in an independent data set. We describe clinical and neuroimaging features of the 4 patients in the original PARK7‐linked kindred. Age at onset of parkinsonism varied from 27 to 40 years. Clinical progression was slow, and response to dopaminergic therapy good. The clinical spectrum ranged from mild hypokinesia and rigidity, to severe parkinsonism with levodopa‐induced dyskinesias and motor fluctuation. Three of four patients with PARK7‐linked parkinsonism exhibited psychiatric disturbances. Structural neuroimaging was unremarkable, but functional imaging of the brain, carried out in 3 patients, showed significant evidence for a presynaptic dopamine deficit, and assessment of cerebral glucose metabolism, as carried out in 1 patient, showed possible cerebellar involvement.

Familial aggregation, the PDE4D gene, and ischemic stroke in a genetically isolated population

Objective: The purpose of this investigation was to study the familial aggregation of ischemic stroke and the association between the PDE4D gene and ischemic stroke. Methods: The study was performed in an isolated population in The Netherlands, where the authors identified 91 patients with ischemic stroke. Ischemic stroke was subclassified in large- and small-vessel infarction. The authors calculated kinship and inbreeding coefficients and genotyped all patients for three single-nucleotide polymorphisms (SNPs) in the PDE4D gene. Results: The proportion of related pairs was higher in patients with ischemic stroke (68.8%) compared with controls (30.7%; p < 0.001). For large-vessel infarction, the proportion of related pairs was higher (71%) compared with small-vessel infarction (62.8%; p < 0.001). Familial aggregation was strongest for patients with early onset (age at onset <45 years). All stroke groups were significantly more inbred compared with controls. In inbred individuals, the C allele of SNP45 increased the risk of small-vessel infarction 4.8 times (95% CI 1.1 to 22.3) compared with controls (p = 0.04). The T allele of SNP39 increased the risk of small-vessel infarction 6.3 times (95% CI 1.4 to 28.7) compared with controls (p = 0.02). No associations were found for large-vessel stroke. Conclusions: There was familial aggregation of ischemic stroke and a difference in degree of familial clustering between stroke subtypes. The authors also found that the PDE4D gene is significantly associated with small-vessel infarction in inbred individuals.

LPIN2 Is Associated With Type 2 Diabetes, Glucose Metabolism, and Body Composition

OBJECTIVE—To identify the type 2 diabetes gene located at chromosome 18p11. RESEARCH DESIGN AND METHODS—We investigated the region in a young genetically isolated population by genotyping 34 single nucleotide polymorphisms (SNPs) in 78 case subjects and 101 control subjects. Two SNPs were selected and followed up in two cohorts. The first cohort came from a general Dutch population. In this cohort, association with type 2 diabetes was investigated using 616 type 2 diabetic case subjects and 2,890 control subjects; association with oral glucose tolerance test data was performed in 361 normoglycemic people. Association with fat distribution was studied in the second replication cohort, consisting of 836 people from the genetically isolated population. RESULTS—At the initial step, we found that the common C allele of SNP rs3745012 was associated with type 2 diabetes (odds ratio 2.01, P = 0.03). This SNP is located at the 3′ untranslated region of the LPIN2 gene, which is a plausible candidate for type 2 diabetes and obesity. In the cohort from the general Dutch population, we demonstrated that rs3745012 interacts with BMI in determination of type 2 diabetes: whereas in subjects with high BMI, the common C allele is associated with type 2 diabetes, the same allele exhibits a neutral or protective effect in lean subjects (P = 0.05 overall effect, P = 0.02 interaction). Most remarkably, rs3745012 strongly affected composite insulin sensitivity index (P = 0.006 for overall effect, P = 0.004 for interaction). In the second replication cohort, we found that the allele C of rs3745012 increases trunk-to-legs fat mass ratio (P = 0.001) and may affect other fat-related measurements. CONCLUSIONS—rs3745012 SNP of the LPIN2 gene is associated with type 2 diabetes and fat distribution.

PET neuroimaging and mutations in the DJ-1 gene

Summary.Mutations in the DJ-1 gene lead to autosomal recessive early-onset parkinsonism. We performed F-DOPA and FDG PET neuroimaging in two parkinsonism patients homozygous for DJ-1 mutations, three relatives heterozygous for a DJ-1 mutation and one non-carrier, all from the originally described kindred from The Netherlands. Their characteristics were compared to those of typical Parkinson’s disease patients and healthy controls. Both parkinsonism patients had reduced F-DOPA uptake concordant with typical Parkinson’s disease. In the, clinically unaffected, heterozygous relatives, F-DOPA metabolism was unremarkable, thus not suggesting a dosage effect of the DJ-1 gene.

Novel strategy to identify genetic risk factors for COPD severity: a genetic isolate

Studies using genetic isolates with limited genetic variation may be useful in chronic obstructive pulmonary disease (COPD) genetics, but are thus far lacking. The associations between single nucleotide polymorphisms (SNPs) in candidate genes and lung function in COPD were studied in a genetic isolate. In 91 subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage ≥1 COPD, who were members of an extended pedigree including 6,175 people from the Genetic Research in Isolated Populations study, 32 SNPs were analysed in 13 candidate genes: a disintegrin and metalloprotease domain 33 gene (ADAM33), transforming growth factor-β1 gene (TGFB1), matrix metalloprotease-1 gene (MMP1), MMP2, MMP9, MMP12, tissue inhibitor of metalloprotease-1 gene (TIMP1), surfactant protein A1 gene (SFTPA1), SFTPA2, SFTPB, SFTPD, glutathione S-transferase P1 gene (GSTP1), and haem oxygenase 1 gene (HMOX1). Their relation to forced expiratory volume in 1 s (FEV1), inspiratory vital capacity (IVC) and FEV1/IVC were studied using restricted maximum likelihood linear mixed modelling, accounting for pedigree structure. Significant associations were replicated in the general Vlagtwedde/Vlaardingen study. Six SNPs in TGFB1, SFTPA1, SFTPA2 and SFTPD were significantly associated with FEV1/IVC in subjects with GOLD stage ≥1 COPD. Two SNPs in TGFB1 (C to T substitution at nucleotide -509 and substitution of leucine 10 with proline (Leu10Pro)), Leu50Val in SFTPA1 and Ala160Thr in SFTPD showed evidence suggestive of association with FEV1/IVC in subjects with GOLD stage ≥2 COPD. The TGFB1 associations were replicated in GOLD stage ≥2 patients from the Vlagtwedde/Vlaardingen population, with similar effect sizes. It was shown that a genetic isolate can be used to determine the genetics of lung function, which can be replicated in COPD patients from an independent population.

Association between type 2 diabetes loci and measures of fatness

Background Type 2 diabetes (T2D) is a metabolic disorder characterized by disturbances of carbohydrate, fat and protein metabolism and insulin resistance. The majority of T2D patients are obese and obesity by itself may be a cause of insulin resistance. Our aim was to evaluate whether the recently identified T2D risk alleles are associated with human measures of fatness as characterized with Dual Energy X-ray Absorptiometry (DEXA). Methodology/Principal Findings Genotypes and phenotypes of approximately 3,000 participants from cross-sectional ERF study were analyzed. Nine single nucleotide polymorphisms (SNPs) in CDKN2AB, CDKAL1, FTO, HHEX, IGF2BP2, KCNJ11, PPARG, SLC30A8 and TCF7L2 were genotyped. We used linear regression to study association between individual SNPs and the combined allelic risk score with body mass index (BMI), fat mass index (FMI), fat percentage (FAT), waist circumference (WC) and waist to hip ratio (WHR). Significant association was observed between rs8050136 (FTO) and BMI (p = 0.003), FMI (p = 0.007) and WC (p = 0.03); fat percentage was borderline significant (p = 0.053). No other SNPs alone or combined in a risk score demonstrated significant association to the measures of fatness. Conclusions/Significance From the recently identified T2D risk variants only the risk variant of the FTO gene (rs8050136) showed statistically significant association with BMI, FMI, and WC.

Brachydactyly and short stature in a kindred with early-onset parkinsonism†

In a Dutch kindred we have identified a deletion of the DJ‐1 gene, leading to autosomal‐recessive parkinsonism. The parkinsonism patients also had short stature and brachydactyly. In the family and a control group from the same community, we used the DJ‐1 deletion as a marker for the originally linked PARK7 region and found a significant association with body height (P = 0.005), which suggests a gene in linkage disequilibrium with DJ‐1 to be implicated in short stature. Analysis of hand‐bone length showed incomplete segregation of the PARK7 region with brachydactyly, such that a gene in PARK7 is unlikely to fully explain the brachydactyly. Since the bone length reduction was more pronounced in the homozygous parkinsonism patients than in their heterozygous relatives, however, the PARK7 region may contain a modifier gene for growth.

Angiotensinogen M235T polymorphism and symptoms of depression in a population-based study and a family-based study.

Background Evidence suggests that the angiotensinogen (AGT) gene is involved in depression. The aim of this paper is to examine the association between the AGT M235T polymorphism and symptoms of depression in two independent populations; a population-based study, and a family-based study. Methods Symptoms of depression were scored using the Centre of Epidemiological Studies Depression Scale (CES-D) and compared between the MM, MT, and TT genotype groups. The extent to which AGT M235T explains the heritability of the scores was examined using a variance components analysis. Results A significant relationship between the AGT M235T polymorphism and CES-D scores was found in men in both populations. The heritability estimate was 32%. The AGT genotype contributed to 1% of the total variance of the CES-D scores. Conclusion Our findings suggest that the AGT gene is involved in the aetiology of symptoms of depression in men.