Association of mitochondrial DNA copy number with metabolic syndrome and type 2 diabetes in 14 176 individuals.

BACKGROUND: Mitochondria play an important role in cellular metabolism, and their dysfunction is postulated to be involved in metabolic disturbances. Mitochondrial DNA is present in multiple copies per cell. The quantification of mitochondrial DNA copy number (mtDNA-CN) might be used to assess mitochondrial dysfunction. OBJECTIVES: We aimed to investigate the cross-sectional association of mtDNA-CN with type 2 diabetes and the potential mediating role of metabolic syndrome. METHODS: We examined 4812 patients from the German Chronic Kidney Disease (GCKD) study and 9364 individuals from the Cooperative Health Research in South Tyrol (CHRIS) study. MtDNA-CN was measured in whole blood using a plasmid-normalized qPCR-based assay. RESULTS: In both studies, mtDNA-CN showed a significant correlation with most metabolic syndrome parameters: mtDNA-CN decreased with increasing number of metabolic syndrome components. Furthermore, individuals with low mtDNA-CN had significantly higher odds of metabolic syndrome (OR = 1.025; 95% CI = 1.011-1.039, P = 3.19 × 10-4 , for each decrease of 10 mtDNA copies) and type 2 diabetes (OR = 1.027; 95% CI = 1.012-1.041; P = 2.84 × 10-4 ) in a model adjusted for age, sex, smoking and kidney function in the meta-analysis of both studies. Mediation analysis revealed that the association of mtDNA-CN with type 2 diabetes was mainly mediated by waist circumference in the GCKD study (66%) and by several metabolic syndrome parameters, especially body mass index and triglycerides, in the CHRIS study (41%). CONCLUSIONS: Our data show an inverse association of mtDNA-CN with higher risk of metabolic syndrome and type 2 diabetes. A major part of the total effect of mtDNA-CN on type 2 diabetes is mediated by obesity parameters.

Autosomal dominant Parkinson's disease in a large German pedigree.

OBJECTIVE: While several genes have been identified to cause Parkinson's disease (PD), monogenic forms explain only a small proportion of cases. We report clinical and genetic results in a large family with late-onset autosomal dominant PD. METHODS: Thirty-eight family members of a five-generation Northern German PD family underwent a detailed neurologic examination, and transcranial sonography was performed in fifteen of them. Comprehensive mutation analysis of known PD-causing genes and a genome-wide linkage analysis were performed. RESULTS: Late-onset definite PD was found in five subjects with a mean age at onset of 63 years. Another six individuals presented either with probable/possible PD or with subtle parkinsonian signs. Six members with a mean age of 79 years had an essential tremor phenotype. Mode of PD inheritance was compatible with autosomal dominant transmission. One of three examined patients with definite PD demonstrated an increased area of substantia nigra hyperechogenicity upon transcranial sonography. Comprehensive linkage and mutational analysis excluded mutations in known PD-causing genes. Genome-wide linkage analysis suggested a putative disease gene in an 11.3-Mb region on chromosome 7p15-21.1 with a multipoint LOD score of 2.0. CONCLUSIONS: The findings in this family further demonstrate genetic heterogeneity in familial autosomal dominant late-onset PD.

Viral hepatitis, HIV, human herpes virus and Treponema pallidum infection in haemodialysis patients from Kosovo, 2005.

The serological status of hepatitis viruses and other infectious diseases in the 66 dialysed patients of one haemodialysis unit in Kosovo were studied, comparing the data with a large group of blood donors and out-patients. All dialysed patients were hepatitis A virus (HAV) positive. Prevalence of hepatitis B surface antigen (HBsAg), hepatitis B surface antibodies (anti-HBs), and hepatitis B core antibodies (anti-HBc) was 14 of 66, 21% (95% confidence interval (CI): 12-33%), 5 of 66, 8% (95%CI: 5-22%), and 50 of 66, 76% (95%CI: 64-85%), respectively. Antibodies to hepatitis C virus (anti-HCV) prevalence was 57 of 66, 86% (95%CI: 76-94%). No human immunodeficiency virus (HIV) positive case was found. Prevalence of past herpes simplex virus type 2 (HSV-2) infection was 29% (95%CI: 18-41%). Two patients (3%, 95%CI: 0-10%) were positive for Treponema pallidum and 18% (95%CI: 10-30%) were human herpesvirus 8 (HHV-8) antibody positive. Four hundred and fifty-two subjects were recruited for comparison. Markers of past HAV infection was associated with haemodialysis (Fisher s exact test p-value=0.037). Dialysed patients were at a higher risk of being HBsAg positive than others: the sex- and age-adjusted odds ratio (OR) was 5.18 (95%CI: 1.87-14.32). Anti-HBc positivity was strongly associated with haemodialysis: the sex- and age-adjusted OR was 6.43 (95%CI: 3.22-12-85). Anti-HCV positivity was 86% and 1% in presence and absence of haemodialysis, respectively. The Fisher s exact test for association proved a strong association between haemodialysis and HCV (p-value<0.0001). The OR for association between haemodialysis and HSV-2 positivity was 3.20 (95%CI: 1.46-7.00). Significant associations were also observed between haemodialysis status and antibodies to Treponema pallidum (Fisher s exact test p-value=0.044). In Kosovo, the prevalence of viral hepatitis infection and other viral infections and Treponema pallidum among dialysed patients is high, indicating major ongoing nosocomial transmission.

Adapted Finnish Migraine-Specific Questionnaire for family studies (FMSQ(FS)): a validation study in two languages.

BACKGROUND AND PURPOSE: The hypothesis of a genetic component in the etiology of migraine is getting a foothold. However, to explore genetic associations, precision in clinical phenotypization is crucial. For this reason, migraine-specific questionnaires, well discriminating between primary headaches, are required when large numbers of individuals need to be assessed. METHODS: We adapted and translated in two languages, German and Italian, the Finnish Migraine-Specific Questionnaire for use in family studies. RESULTS AND CONCLUSIONS: This adaptation proved to be reliable when differentiating from primary headaches, and to be in very good agreement with the standard for comparison. However, discriminating between migraine with and without aura still relays on a specialist evaluation. This article describes the validation of this questionnaire.

ZAP-70 expression, as detected by immunohistochemistry on bone marrow biopsies from early-phase CLL patients, is a strong adverse prognostic factor.

Zeta-associated protein-70 (ZAP-70), mostly assessed by flow-cytometry (FC), recently emerged as reliable prognostic factor in chronic lymphocytic leukaemia (CLL) at presentation. We evaluated ZAP-70 expression in 156 CLL patients by immunohistochemistry (IHC) on formalin-fixed bone marrow (BM) biopsies at diagnosis. At presentation, 117 patients (75%) were with Binet stage A, 27 (17%) stage B and 12 (8%) stage C. Median follow-up was 61 months (range 6-242). ZAP-70 was expressed in neoplastic lymphocytes of 69 patients (44%). Concordance between ZAP-70 by IHC and ZAP-70 by FC, immunoglobulin heavy chain variable genes (IGHV) mutational status and CD38 expression was found in 41/46 (89%), 41/49 (80%) and in 60/88 (68%) tested cases, respectively. ZAP-70 expression significantly correlated with advanced Binet stage (B-C), diffuse BM infiltration, increased lactate dehydrogenase (LDH) and beta2-microglobulin serum levels and lymphocyte doubling time <12 months. ZAP-70 positivity was significantly related to poorer time to progression (median 16 months vs 158 of ZAP-70-negative cases) (P<0.0001) and overall survival (median 106 months vs not reached) (P=0.0002); this correlation was confirmed at multivariate analysis. ZAP-70 expression correlated with poorer outcome also when evaluated only in the 117 stage A patients. In conclusion, immunohistological detection of ZAP-70 on formalin-fixed BM biopsies at diagnosis appears a useful methodological approach to identify patients with poor prognosis in CLL.

Isolation and marriage patterns in four South Tyrolean villages (Italy) during the nineteenth century.

No information is currently available on the marriage patterns of German-speaking communities of the South Tyrol area. The aim of this study is to investigate the reproductive isolation of four South Tyrolean mountain villages during the 19th century. Data about 3953 marriages were drawn from existing pedigrees and completed with data from the parish registers of the studied villages to calculate the following indicators: age at marriage, endogamy, inbreeding from dispensations and from isonymy and repeated pairs of surnames among couples. The results show high levels of endogamy (78-87%) and an elevated age at marriage in all the studied villages. The percentages of consanguineous marriages (10-33%) vary considerably but result overall in relatively low inbreeding values (alpha 0.0015-0.0036; Ft 0.0098-0.0138). Levels of endogamy are consistent with the geographic characteristics of the area, while inbreeding values are lower than those observed in previous studies on Alpine communities. This is due to a low frequency of marriages between close relatives, probably related to the peculiar demographic and cultural characteristics of the studied populations that differentiate them from neighbouring Italian-speaking villages.

Association between interleukin-1 receptor antagonist gene and asthma-related traits in a German adult population.

BACKGROUND: A recent study in German and Italian families associated variants in the interleukin-1 receptor antagonist (IL1RA) gene with asthma. The aim of the present study was to further investigate the role of single nucleotide polymorphisms (SNPs) in the IL1RA gene in the development of atopy and lifelong asthma in a population-based study. METHODS: DNA samples from the German centres of the European Community Respiratory Health Survey were analysed for genetic variants in the IL1RA gene and the development of asthma, atopy and bronchial hyperreactivity. RESULTS: Carriers of the rare G allele of SNP rs447713 had a significantly increased risk of developing asthma (P = 0.0013) and allergic sensitization (P = 0.0119). Carriers of the rare C allele of SNP rs3087271 had an increased risk of asthma (P = 0.0227) and high immunoglobulin E (IgE) levels (P = 0.0232). A haplotype built from eight SNPs in the IL1RA gene (A-C-A-G-A-C-G-A) was associated with a higher prevalence of asthma (P = 0.007) and high total IgE (P = 0.02). Bronchial hyperreactivity was positively associated with the haplotype A-C-G-G-A-C-G-C (P = 0.02) and negatively with the A-C-G-G-A-C-T-C (P = 0.03). CONCLUSION: A previously described association between IL1RA and asthma in families could be reproduced in a population-based sample. The genetic variants of IL1RA gene do not to seem to affect asthma alone, but to act as modulators of asthma-related traits as well, where different haplotypes drive the development of different phenotypes.

The role of climate on the geographic variability of asthma, allergic rhinitis and respiratory symptoms: results from the Italian study of asthma in young adults.

BACKGROUND: Variations in the prevalence of respiratory symptoms according to geo-climatic factors could provide important clues to the knowledge of the aetiology of asthma. METHODS: Geo-climatic variations in the prevalence of current asthma, allergic rhinitis and chronic cough, and phlegm were assessed on a random sample of 18 873 subjects (response rate = 72.7%) from different climatic regions of Italy. An ecological analysis, supported by robust statistical methods, was employed to investigate potential trends. RESULTS: The prevalence of all symptoms was significantly heterogeneous throughout the peninsula. Only asthma-like symptoms showed a north-south trend: the prevalence increased at a decreasing latitude [odds ratio (OR) varies from 0.92 to 0.96, P < 0.05], at a decreasing distance from the sea (OR: 0.90-0.93 for 30 km distance, P < 0.05), at higher annual mean temperatures (OR: 1.11-1.14, P < 0.05) and at smaller annual temperature ranges (OR: 0.94-0.95, P < 0.05). Of the geo-climatic variables considered, temperature range had the greatest influence on most asthma-like symptoms. No association was found between geo-climatic variables and allergic rhinitis or chronic cough and phlegm. CONCLUSIONS: Asthma prevalence seems to be significantly affected by climate as asthma-like symptoms were more common in central-southern Italy, with a Mediterranean climate, than in areas with a continental climate (northern Italy).