Juergen Wellmann

The glu298asp polymorphism in the nitric oxide synthase 3 gene is associated with the risk of ischemic stroke in two large independent case-control studies.

The search for genes involved in the pathogenesis of stroke has been highlighted as a field of needs. We followed the concept, that stroke represents a complex genetic disorder, and analyzed the contribution of 106 informative single nucleotide polymorphisms (SNPs) from 63 candidate genes for cardiovascular diseases for the risk of stroke. We conducted two independent case–control studies in two different German regions and recruited a total of 1,901 hospitalized stroke cases and 1,747 regional population controls. The smaller of both studies was used as the replication study. Multiplex PCR in combination with allele-specific hybridization was used for genotype determination. Descriptive statistics, permutations and multivariable logistic regression were used in the analyses. After permutation testing 5 SNPs, located in the nitric oxide synthase 3, the alpha 2 integrin, the interleukin 13, the selectin P and the chemokine receptor 2 genes, had a significant allele difference between cases and controls in the larger study. For one of these SNPs, the glu298asp polymorphism in the nitric oxide synthase 3 gene, an association with ischemic stroke was replicated in the second study and also in a combined analysis of both studies. This association was independent of age, gender, hypertension, diabetes and hypercholesterolemia in both studies. Using large sample sizes and a replication study approach, we found evidence for a role of a polymorphism in the nitric oxide synthase 3 gene in stroke onset.

Smoking history and the incidence of age-related macular degeneration - results from the Muenster Aging and Retina Study (MARS) cohort and systematic review and meta-analysis of observational longitudinal studies.

To compare the association of smoking with age-related macular degeneration (AMD) in the Muenster Aging and Retina Study (MARS) cohort with current evidence. Adjusted risk ratios for incident AMD in MARS were compared with findings of a systematic review and meta-analysis of observational prospective studies. 9.6% of MARS participants progressed to AMD over a median of 30.9 months. In MARS the adjusted risk ratio in current versus never smokers was 3.25 (95% confidence interval [1.50-7.06]), and 1.28 [0.70-2.33] in former smokers versus never smokers. The meta-analysis of previous studies showed a pooled adjusted risk ratio of 2.51 [1.09-5.76] in current versus never smokers. Inclusion of the MARS findings removed between-study heterogeneity and accentuated the pooled adjusted risk ratio for current smokers to 2.75 [1.52-4.98]. Specific analyses in MARS revealed a protective effect for time since smoking cessation in former smokers with an adjusted risk ratio=0.50 [0.29-0.89] per log(year). Current smoking nearly triples AMD incidence, while smoking cessation lowers AMD incidence in a non-linear fashion even in the elderly.

Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits

Persistent insomnia is among the most frequent complaints in general practice. To identify genetic factors for insomnia complaints, we performed a genome-wide association study (GWAS) and a genome-wide gene-based association study (GWGAS) in 113,006 individuals. We identify three loci and seven genes associated with insomnia complaints, with the associations for one locus and five genes supported by joint analysis with an independent sample (n = 7,565). Our top association (MEIS1, P < 5 × 10−8) has previously been implicated in restless legs syndrome (RLS). Additional analyses favor the hypothesis that MEIS1 exhibits pleiotropy for insomnia and RLS and show that the observed association with insomnia complaints cannot be explained only by the presence of an RLS subgroup within the cases. Sex-specific analyses suggest that there are different genetic architectures between the sexes in addition to shared genetic factors. We show substantial positive genetic correlation of insomnia complaints with internalizing personality traits and metabolic traits and negative correlation with subjective well-being and educational attainment. These findings provide new insight into the genetic architecture of insomnia.

LOC387715, smoking and their prognostic impact on visual functional status in age-related macular degeneration-The Muenster Aging and Retina Study (MARS) cohort.

Purpose: To prospectively evaluate the impact of homozygosity in the A69S-SNP of the LOC387715-gene, smoking history, and their interaction on visual functional status (v-FS) in age-related macular degeneration (AMD). Methods: The Muenster Aging and Retina Study (MARS) cohort (n = 656; 58.8% women, mean age 70.2 years) was followed over a mean of 2.5 years. AMD-status, genotype and smoking history were assessed at baseline. V-FS [from 0 (low) to 100 (unimpaired) points in general-, near- and far-vision], were AMD-status assessed at baseline and at follow-up. Linear models with stepwise adjustments for covariates were used to analyze decline of v-FS over time. Results: In initial models, homozygosity for the A69S-variant was negatively associated with all three dimensions of the v-FS. After including smoking history, ever smoking was negatively associated with declines in near and far vision (-4.82 and -5.12 points, respectively; each p < 0.05). In smokers homozygous for the A69S-variant the number of cigarettes smoked per day (smoking intensity) was negatively associated with all three dimensions of the v-FS (interaction term each p < 0.05). Time since smoking cessation in former smokers protected against declines in near and far vision. These effects were independent of the AMD-status at baseline. Conclusions: The interaction of homozygosity for the A69S-variant and smoking intensity had a negative impact on general-, near-, and far visual functional status independent of AMD-status. Quitting smoking seemed to have a time-dependent protective effect on near and far vision.