Juha Sinisalo

A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium.

The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.

A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses.

Summary Background Comparison of patients with coronary heart disease and controls in genome-wide association studies has revealed several single nucleotide polymorphisms (SNPs) associated with coronary heart disease. We aimed to establish the external validity of these findings and to obtain more precise risk estimates using a prospective cohort design. Methods We tested 13 recently discovered SNPs for association with coronary heart disease in a case-control design including participants differing from those in the discovery samples (3829 participants with prevalent coronary heart disease and 48u2008897 controls free of the disease) and a prospective cohort design including 30u2008725 participants free of cardiovascular disease from Finland and Sweden. We modelled the 13 SNPs as a multilocus genetic risk score and used Cox proportional hazards models to estimate the association of genetic risk score with incident coronary heart disease. For case-control analyses we analysed associations between individual SNPs and quintiles of genetic risk score using logistic regression. Findings In prospective cohort analyses, 1264 participants had a first coronary heart disease event during a median 10·7 years follow-up (IQR 6·7–13·6). Genetic risk score was associated with a first coronary heart disease event. When compared with the bottom quintile of genetic risk score, participants in the top quintile were at 1·66-times increased risk of coronary heart disease in a model adjusting for traditional risk factors (95% CI 1·35–2·04, p value for linear trend=7·3×10−10). Adjustment for family history did not change these estimates. Genetic risk score did not improve C index over traditional risk factors and family history (p=0·19), nor did it have a significant effect on net reclassification improvement (2·2%, p=0·18); however, it did have a small effect on integrated discrimination index (0·004, p=0·0006). Results of the case-control analyses were similar to those of the prospective cohort analyses. Interpretation Using a genetic risk score based on 13 SNPs associated with coronary heart disease, we can identify the 20% of individuals of European ancestry who are at roughly 70% increased risk of a first coronary heart disease event. The potential clinical use of this panel of SNPs remains to be defined. Funding The Wellcome Trust; Academy of Finland Center of Excellence for Complex Disease Genetics; US National Institutes of Health; the Donovan Family Foundation.

Relation of inflammation to vascular function in patients with coronary heart disease.

Endothelium plays a pivotal role in the regulation of vascular relaxation. Inflammation may in turn induce endothelial dysfunction and thus increase the risk of atherothrombosis. We investigated 31 men with angiographically verified coronary heart disease, aged 57. 7+/-5.3 years, in regard to endothelium-dependent, acetylcholine-induced, and to endothelium-independent, sodium nitroprusside-induced vasodilatation in the forearm vasculature by strain-gauge plethysmography. Logistic regression analysis served to determine the relation between forearm vascular function and the inflammatory factors measured, concentration of C-reactive protein, subtypes of peripheral blood T-lymphocytes, and other factors potentially affecting endothelial function (lipoprotein and glucose levels). Concentration of C-reactive protein was an independent determinant of endothelium-dependent vascular function (P<0.001 for low dose acetylcholine, P=0.01 for high dose acetylcholine). Other determinants of endothelium-dependent vascular dysfunction were CD8-lymphocytes expressing ICAM-1 (P=0.001), antibodies to oxidized low-density lipoprotein (P<0.001), and body weight (P=0.007). The present data showed an association between inflammatory risk factors linked to atherothrombosis and endothelial dysfunction in coronary heart disease patients. It is possible that endothelial dysfunction in coronary heart disease patients is related to the chronic inflammation or infection coexisting with atherosclerosis.

Genetic Variability Overrides the Impact of Parental Cell Type and Determines iPSC Differentiation Potential

Summary Reports on the retention of somatic cell memory in induced pluripotent stem cells (iPSCs) have complicated the selection of the optimal cell type for the generation of iPSC biobanks. To address this issue we compared transcriptomic, epigenetic, and differentiation propensities of genetically matched human iPSCs derived from fibroblasts and blood, two tissues of the most practical relevance for biobanking. Our results show that iPSC lines derived from the same donor are highly similar to each other. However, genetic variation imparts a donor-specific expression and methylation profile in reprogrammed cells that leads to variable functional capacities of iPSC lines. Our results suggest that integration-free, bona fide iPSC lines from fibroblasts and blood can be combined in repositories to form biobanks. Due to the impact of genetic variation on iPSC differentiation, biobanks should contain cells from large numbers of donors.

Periodontitis is associated with angiographically verified coronary artery disease

INTRODUCTIONnWe investigated the association of periodontitis and severity of coronary artery disease (CAD) as verified using coronary angiography.nnnMATERIAL AND METHODSnParticipants were recruited among those attending coronary angiography at Helsinki University Central Hospital, Finland, in 2007 and 2008. Detailed clinical periodontal examination [number of teeth, bleeding on probing, periodontal probing depth (PPD)] and oral panoramic radiographs [alveolar bone loss (ABL), angular bone defects] were performed.nnnRESULTSnOf 506 patients, 123 (24.3%) had no significant CAD, whereas 184 (36.4%) had stable CAD and 169 (33.4%) acute coronary syndrome (ACS). Both stable CAD and ACS were associated with 8-17 missing teeth with ORs 4.33 (1.61-11.7, pxa0=xa00.020) and 5.24 (1.90-14.5, pxa0=xa00.014), and more than seven teeth with PPD ≥6xa0mm with ORs 2.44 (1.01-6.07, pxa0=xa00.049) and 2.75 (1.16-6.53, pxa0=xa00.022) respectively. Severe ABL was associated with ACS with an OR 5.39 (1.23-23.6, pxa0=xa00.025). Number of stenosed arteries was linearly associated with ABL (p for trend <0.001), number of missing teeth (pxa0<xa00.001), and pockets with probing depth ≥6xa0mm (pxa0=xa00.033).nnnCONCLUSIONSnCompared with patients with no significant stenosis, poor periodontal health including missing teeth, periodontal inflammation, and bone loss is associated with angiographically verified coronary artery narrowing in patients with stable CAD or ACS.

Salivary biomarkers of bacterial burden, inflammatory response, and tissue destruction in periodontitis

AIMnChronic periodontitis has an episodic and multifactorial character, with fluctuations in bacterial burden, inflammatory response, and tissue destruction. We investigated the association of selected salivary biomarkers with periodontal parameters and validated the use of a novel salivary diagnostic approach, the cumulative risk score (CRS), in detection of periodontitis in subjects with angiographically verified coronary artery disease diagnosis.nnnMATERIALS AND METHODSnThe concentrations of matrix metalloproteinase (MMP)-8, interleukin (IL)-1β, and Porphyromonas gingivalis were analysed from saliva of 493 subjects. The subjects participated in a detailed clinical and radiographic oral examination. The CRS index, combining the three salivary biomarkers, was calculated for each subject.nnnRESULTSnHigh salivary concentrations of MMP-8, IL-1β, and P. gingivalis were associated with deepened periodontal pockets and alveolar bone loss, and MMP-8 and IL-1β with bleeding on probing. The CRS index had a stronger association with moderate to severe periodontitis (OR 6.13; 95% CI 3.11-12.09) than any of the markers alone.nnnCONCLUSIONSnSalivary concentrations of MMP-8, IL-1β, and P. gingivalis are associated with various clinical and radiographic measures of periodontitis. The CRS index, combining the three salivary biomarkers, is associated with periodontitis more strongly than any of the markers alone regardless of the coronary artery disease status of the patients.

A common periodontal pathogen has an adverse association with both acute and stable coronary artery disease

OBJECTIVEnThe aim of this study was to investigate the association between angiographically verified coronary artery disease (CAD) and salivary levels of four major periodontal pathogens.nnnMETHODSnThe study population (nxa0=xa0492) was composed of 179 (36.4%) patients with stable CAD, 166 (33.7%) with acute coronary syndrome (ACS), and 119 (24.2%) showing no pathological findings by coronary angiography. All patients were subjected to a detailed oral health examination. The saliva samples were analyzed for lipopolysaccharide activity as well as for Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, and Tannerella forsythia by quantitative PCR. Serum antibodies levels against A.xa0actinomycetemcomitans were analyzed.nnnRESULTSnThe level of bacterial burden was linearly associated with alveolar bone loss (pxa0<xa00.001) and bleeding on probing (pxa0=xa00.015). The median salivary levels of A.xa0actinomycetemcomitans in pathogen-positive patients were significantly higher in the Stable CAD (pxa0=xa00.014) and the ACS (pxa0=xa00.044) groups when compared to No significant CAD patients. In logistic regression models, a 10-fold increase in the salivary A.xa0actinomycetemcomitans levels was associated with a risk for stable CAD and ACS with odds ratios (ORs) of 7.47 (95% confidence interval [CI]: 1.57-35.5, pxa0=xa00.012) and 4.31 (95% CI: 1.06-17.5, pxa0=xa00.041), respectively. The OR for the association of IgA-class antibody levels against A.xa0actinomycetemcomitans with ACS risk was 3.13 (95% CI: 1.38-7.12, pxa0=xa00.006)/log(10) unit increase.nnnCONCLUSIONSnHigh salivary levels of A.xa0actinomycetemcomitans and systemic exposure to the bacterium were associated with increased risk for CAD. These findings emphasize the importance of oral microbiota in cardiovascular risk assessment and therapeutics.

Chromosome X-Wide Association Study Identifies Loci for Fasting Insulin and Height and Evidence for Incomplete Dosage Compensation

The X chromosome (chrX) represents one potential source for the “missing heritability” for complex phenotypes, which thus far has remained underanalyzed in genome-wide association studies (GWAS). Here we demonstrate the benefits of including chrX in GWAS by assessing the contribution of 404,862 chrX SNPs to levels of twelve commonly studied cardiometabolic and anthropometric traits in 19,697 Finnish and Swedish individuals with replication data on 5,032 additional Finns. By using a linear mixed model, we estimate that on average 2.6% of the additive genetic variance in these twelve traits is attributable to chrX, this being in proportion to the number of SNPs in the chromosome. In a chrX-wide association analysis, we identify three novel loci: two for height (rs182838724 near FGF16/ATRX/MAGT1, joint P-valueu200a=u200a2.71×10−9, and rs1751138 near ITM2A, P-valueu200a=u200a3.03×10−10) and one for fasting insulin (rs139163435 in Xq23, P-valueu200a=u200a5.18×10−9). Further, we find that effect sizes for variants near ITM2A, a gene implicated in cartilage development, show evidence for a lack of dosage compensation. This observation is further supported by a sex-difference in ITM2A expression in whole blood (P-valueu200a=u200a0.00251), and is also in agreement with a previous report showing ITM2A escapes from X chromosome inactivation (XCI) in the majority of women. Hence, our results show one of the first links between phenotypic variation in a population sample and an XCI-escaping locus and pinpoint ITM2A as a potential contributor to the sexual dimorphism in height. In conclusion, our study provides a clear motivation for including chrX in large-scale genetic studies of complex diseases and traits.

Associations of reported bruxism with insomnia and insufficient sleep symptoms among media personnel with or without irregular shift work.

BackgroundThe aims were to investigate the prevalence of perceived sleep quality and insufficient sleep complaints, and to analyze whether self-reported bruxism was associated with perceptions of sleep, and awake consequences of disturbed sleep, while controlling confounding factors relative to poor sleep.MethodsA standardized questionnaire was mailed to all employees of the Finnish Broadcasting Company with irregular shift work (n = 750) and to an equal number of randomly selected controls in the same company with regular eight-hour daytime work.ResultsThe response rate in the irregular shift work group was 82.3% (56.6% men) and in the regular daytime work group 34.3% (46.7% men). Self-reported bruxism occurred frequently (often or continually) in 10.6% of all subjects. Altogether 16.8% reported difficulties initiating sleep (DIS), 43.6% disrupted sleep (DS), and 10.3% early morning awakenings (EMA). The corresponding figures for non-restorative sleep (NRS), tiredness, and sleep deprivation (SLD) were 36.2%, 26.1%, and 23.7%, respectively. According to logistic regression, female gender was a significant independent factor for all insomnia symptoms, and older age for DS and EMA. Frequent bruxism was significantly associated with DIS (p = 0.019) and DS (p = 0.021). Dissatisfaction with current work shift schedule and frequent bruxism were both significant independent factors for all variables describing insufficient sleep consequences.ConclusionSelf-reported bruxism may indicate sleep problems and their adherent awake consequences in non-patient populations.

Self-reported bruxism mirrors anxiety and stress in adults.

Objectives: The aims were to analyze whether the levels of self-reported bruxism and anxiety associate among otherwise healthy subjects, and to investigate the independent effects of anxiety and stress experience on the probability of self-reported bruxism. Study Design: As part of a study on irregular shift work, a questionnaire was mailed to all employees of the Finnish Broadcasting Company with irregular shift work (number of subjects: n=750) and to an equal number of randomly selected employees in the same company with regular eight-hour daytime work. Results: The response rates were 82.3% (56.6 % men) and 34.3 % (46.7 % men), respectively. Among the 874 respondents, those aware of more frequent bruxism reported significantly more severe anxiety (p<0.001). Adjusted by age and gender, frequent bruxers were more than two times more likely to report severe stress (odds ratio 2.5; 95% confidence interval 1.5-4.2) and anxiety (odds ratio 2.2; 95% confidence interval 1.3-3.6) than non-or-mild bruxers. Conclusions: Present findings suggest that self-reported bruxism and psychological states such as anxiety or stress may be related in working age subjects. Key words:Bruxism, self-report, anxiety, stress, adult.