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 >or=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-beta1 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 (FEV( 1)), inspiratory vital capacity (IVC) and FEV(1)/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 FEV(1)/IVC in subjects with GOLD stage >or=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 FEV(1)/IVC in subjects with GOLD stage >or=2 COPD. The TGFB1 associations were replicated in GOLD stage >or=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.

Familial clustering of multiple sclerosis in a Dutch genetic isolate.

Multiple sclerosis (MS) is a complex disease with a substantial, yet poorly identified, genetic influence. We estimated the pattern of familial aggregation of MS in a recent genetically isolated population in The Netherlands. Forty-eight MS patients were identified. Their relationship was evaluated by tracing extended pedigrees, making use of municipal and church records. Of the 48 MS patients, 24 could be linked to a common ancestor in 14 generations. However, multiple relationships exist between patients and, to take these into account, we calculated inbreeding and kinship coefficients. We found that MS patients from the isolate were significantly more often related to each other and significantly more often inbred than a non-MS control group, drawn from the same isolate. There was no clustering of Type 1 diabetes and autoimmune thyroid diseases in families of MS patients from this isolate. Finally, HLA typing was performed. Although there was a trend towards a higher prevalence of the HLA DRB1*15 allele in patients compared to controls, differences did not reach significance. This study suggests familial aggregation in the genetically isolated population. The high level of inbreeding makes this population valuable for finding novel genes involved in MS.

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.

PET neuroimaging and mutations in the DJ-1 gene.

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.

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.

A clinical-genetic study of Parkinson's disease in a genetically isolated community.

The role of genetic factors in idiopathic, late-onset Parkinson's disease (PD) remains unclear, in spite of the recent advances in the genetics of early-onset forms of familial parkinsonism. There is increasing interest in using genetically isolated populations to unravel the genetics of complex diseases such as late-onset PD. We have studied genetic and clinical features of 109 patients with parkinsonism from an area comprising a genetically isolated population in the South-West of the Netherlands. Of the 109 patients with ascertained parkinsonism, 41 patients were diagnosed with PD and could be linked to a common founder 14 generations ago. The distribution of ages at onset of PD in the genetically isolated population was significantly bimodal, showing two peaks (one with a mean at age 67 years and another with a mean at 44 years, the former peak being significantly larger than that in a population-based study, the Rotterdam Study). In other clinical features, the only statistically significant difference between early-onset and late-onset PD was a decreased motor and cognitive function in patients with late-onset PD. Involvement of other PD genes including DJ-1, a gene implicated in a kindred with early-onset parkinsonism from the same genetic isolate, was excluded in other PD patients in the population. The finding of a common ancestor in 41 idiopathic-PD patients along with the exclusion of known PD genes and loci suggests the presence of at least one other, yet unknown, susceptibility gene involved in PD in this population.