Emmi Tikkanen

Causal Relationship Between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts

A mendelian randomization study based on data from multiple cohorts conducted by Karani Santhanakrishnan Vimaleswaran and colleagues re-examines the causal nature of the relationship between vitamin D levels and obesity.

Genome-wide association study identifies multiple loci influencing human serum metabolite levels

Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10−10) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.

Genome-Wide Screen for Metabolic Syndrome Susceptibility Loci Reveals Strong Lipid Gene Contribution But No Evidence for Common Genetic Basis for Clustering of Metabolic Syndrome Traits

Background— Genome-wide association (GWA) studies have identified several susceptibility loci for metabolic syndrome (MetS) component traits, but have had variable success in identifying susceptibility loci to the syndrome as an entity. We conducted a GWA study on MetS and its component traits in 4 Finnish cohorts consisting of 2637 MetS cases and 7927 controls, both free of diabetes, and followed the top loci in an independent sample with transcriptome and nuclear magnetic resonance-based metabonomics data. Furthermore, we tested for loci associated with multiple MetS component traits using factor analysis, and built a genetic risk score for MetS. Methods and Results— A previously known lipid locus, APOA1/C3/A4/A5 gene cluster region (SNP rs964184), was associated with MetS in all 4 study samples (P=7.23×10−9 in meta-analysis). The association was further supported by serum metabolite analysis, where rs964184 was associated with various very low density lipoprotein, triglyceride, and high-density lipoprotein metabolites (P=0.024–1.88×10−5). Twenty-two previously identified susceptibility loci for individual MetS component traits were replicated in our GWA and factor analysis. Most of these were associated with lipid phenotypes, and none with 2 or more uncorrelated MetS components. A genetic risk score, calculated as the number of risk alleles in loci associated with individual MetS traits, was strongly associated with MetS status. Conclusions— Our findings suggest that genes from lipid metabolism pathways have the key role in the genetic background of MetS. We found little evidence for pleiotropy linking dyslipidemia and obesity to the other MetS component traits, such as hypertension and glucose intolerance.

Genetic Risk Prediction and a 2-Stage Risk Screening Strategy for Coronary Heart Disease

Objective—Genome-wide association studies have identified several genetic variants associated with coronary heart disease (CHD). The aim of this study was to evaluate the genetic risk discrimination and reclassification and apply the results for a 2-stage population risk screening strategy for CHD. Approach and Results—We genotyped 28 genetic variants in 24 124 participants in 4 Finnish population-based, prospective cohorts (recruitment years 1992–2002). We constructed a multilocus genetic risk score and evaluated its association with incident cardiovascular disease events. During the median follow-up time of 12 years (interquartile range 8.75–15.25 years), we observed 1093 CHD, 1552 cardiovascular disease, and 731 acute coronary syndrome events. Adding genetic information to conventional risk factors and family history improved risk discrimination of CHD (C-index 0.856 versus 0.851; P=0.0002) and other end points (cardiovascular disease: C-index 0.840 versus 0.837, P=0.0004; acute coronary syndrome: C-index 0.859 versus 0.855, P=0.001). In a standard population of 100 000 individuals, additional genetic screening of subjects at intermediate risk for CHD would reclassify 2144 subjects (12%) into high-risk category. Statin allocation for these subjects is estimated to prevent 135 CHD cases over 14 years. Similar results were obtained by external validation, where the effects were estimated from a training data set and applied for a test data set. Conclusions—Genetic risk score improves risk prediction of CHD and helps to identify individuals at high risk for the first CHD event. Genetic screening for individuals at intermediate cardiovascular risk could help to prevent future cases through better targeting of statins.

Detailed metabolic and genetic characterization reveals new associations for 30 known lipid loci

Almost 100 genetic loci are known to affect serum cholesterol and triglyceride levels. For many of these loci, the biological function and causal variants remain unknown. We performed an association analysis of the reported 95 lipid loci against 216 metabolite measures, including 95 measurements on lipids and lipoprotein subclasses, obtained via serum nuclear magnetic resonance metabolomics and four enzymatic lipid traits in 8330 individuals from Finland. The genetic variation in the loci was investigated using a dense set of 440 807 directly genotyped and imputed variants around the previously identified lead single nucleotide polymorphisms (SNPs). For 30 of the 95 loci, we identified new metabolic or genetic associations (P < 5 × 10(-8)). In the majority of the loci, the strongest association was to a more specific metabolite measure than the enzymatic lipids. In four loci, the smallest high-density lipoprotein measures showed effects opposite to the larger ones, and 14 loci had associations beyond the individual lipoprotein measures. In 27 loci, we identified SNPs with a stronger association than the previously reported markers and 12 loci harboured multiple, statistically independent variants. Our data show considerable diversity in association patterns between the loci originally identified through associations with enzymatic lipid measures and reveal association profiles of far greater detail than from routine clinical lipid measures. Additionally, a dense marker set and a homogeneous population allow for detailed characterization of the genetic association signals to a resolution exceeding that achieved so far. Further understanding of the rich variability in genetic effects on metabolites provides insights into the biological processes modifying lipid levels.

Genomic prediction of coronary heart disease

Aims Genetics plays an important role in coronary heart disease (CHD) but the clinical utility of genomic risk scores (GRSs) relative to clinical risk scores, such as the Framingham Risk Score (FRS), is unclear. Our aim was to construct and externally validate a CHD GRS, in terms of lifetime CHD risk and relative to traditional clinical risk scores. Methods and results We generated a GRS of 49 310 SNPs based on a CARDIoGRAMplusC4D Consortium meta-analysis of CHD, then independently tested it using five prospective population cohorts (three FINRISK cohorts, combined n = 12 676, 757 incident CHD events; two Framingham Heart Study cohorts (FHS), combined n = 3406, 587 incident CHD events). The GRS was associated with incident CHD (FINRISK HR = 1.74, 95% confidence interval (CI) 1.61–1.86 per S.D. of GRS; Framingham HR = 1.28, 95% CI 1.18–1.38), and was largely unchanged by adjustment for known risk factors, including family history. Integration of the GRS with the FRS or ACC/AHA13 scores improved the 10 years risk prediction (meta-analysis C-index: +1.5–1.6%, P < 0.001), particularly for individuals ≥60 years old (meta-analysis C-index: +4.6–5.1%, P < 0.001). Importantly, the GRS captured substantially different trajectories of absolute risk, with men in the top 20% of attaining 10% cumulative CHD risk 12–18 y earlier than those in the bottom 20%. High genomic risk was partially compensated for by low systolic blood pressure, low cholesterol level, and non-smoking. Conclusions A GRS based on a large number of SNPs improves CHD risk prediction and encodes different trajectories of lifetime risk not captured by traditional clinical risk scores.

A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism

Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on the rate of nicotine metabolism. Our objective was to use nicotine metabolite ratio (NMR), an established biomarker of nicotine metabolism rate, in a genome-wide association study (GWAS) to identify novel genetic variants influencing nicotine metabolism. A heritability estimate of 0.81 (95% CI 0.70–0.88) was obtained for NMR using monozygotic and dizygotic twins of the FinnTwin cohort. We performed a GWAS in cotinine-verified current smokers of three Finnish cohorts (FinnTwin, Young Finns Study, FINRISK2007), followed by a meta-analysis of 1518 subjects, and annotated the genome-wide significant SNPs with methylation quantitative loci (meQTL) analyses. We detected association on 19q13 with 719 SNPs exceeding genome-wide significance within a 4.2 Mb region. The strongest evidence for association emerged for CYP2A6 (min p = 5.77E-86, in intron 4), the main metabolic enzyme for nicotine. Other interesting genes with genome-wide significant signals included CYP2B6, CYP2A7, EGLN2, and NUMBL. Conditional analyses revealed three independent signals on 19q13, all located within or in the immediate vicinity of CYP2A6. A genetic risk score constructed using the independent signals showed association with smoking quantity (p = 0.0019) in two independent Finnish samples. Our meQTL results showed that methylation values of 16 CpG sites within the region are affected by genotypes of the genome-wide significant SNPs, and according to causal inference test, for some of the SNPs the effect on NMR is mediated through methylation. To our knowledge, this is the first GWAS on NMR. Our results enclose three independent novel signals on 19q13.2. The detected CYP2A6 variants explain a strikingly large fraction of variance (up to 31%) in NMR in these study samples. Further, we provide evidence for plausible epigenetic mechanisms influencing NMR.

Pain in 1,000 women treated for breast cancer: a prospective study of pain sensitivity and postoperative pain.

Background:This article describes the methods and results of the early part (experimental pain tests and postoperative analgesia) of a study that assesses genetic and other factors related to acute pain and persistent pain after treatment of breast cancer in a prospective cohort of 1,000 women. Methods:One thousand consenting patients were recruited to the study. Before surgery (breast resection or mastectomy with axillary surgery), the patients filled in questionnaires about health, life style, depression (Beck Depression Inventory), and anxiety (State-Trait Anxiety Inventory). They were also exposed to experimental tests measuring heat (43° and 48°C, 5 s) and cold (2-4°C) pain intensity and tolerance. Anesthesia was standardized with propofol and remifentanil, and postoperative analgesia was optimized with i.v. oxycodone. Results:The patients showed significant interindividual variation in heat and cold pain sensitivity and cold pain tolerance. There was a strong correlation between the experimental pain measures across the tests. Presence of chronic pain, the number of previous operations, and particularly state anxiety were related to increased pain sensitivity. Previous smoking correlated with decreased heat pain sensitivity. These factors explained 4–5% of the total variance in pain sensitivity in these tests. Oxycodone consumption during 20 h was significantly higher in patients who had axillary clearance. Oxycodone consumption had only a weak correlation with the experimental pain measures. Conclusions:Contact heat and cold pressure tests identify variability in pain sensitivity which is modified by factors such as anxiety, chronic pain, previous surgery, and smoking. High levels of anxiety are connected to increased pain sensitivity in experimental and acute postoperative pain.In a study of 1,000 women undergoing breast surgery for cancer, a small portion of the variance in preoperative response to noxious heat and cold testing could be explained by anxiety, the presence of chronic pain, and the number of previous operations. There was a weak correlation between response to experimental pain testing and acute postoperative pain, with largely similar predictive factors across both.

Genetic Variants and Blood Pressure in a Population-Based Cohort: The Cardiovascular Risk in Young Finns Study

Clinical relevance of a genetic predisposition to elevated blood pressure was quantified during the transition from childhood to adulthood in a population-based Finnish cohort (N=2357). Blood pressure was measured at baseline in 1980 (age 3–18 years) and in follow-ups in 1983, 1986, 2001, and 2007. Thirteen single nucleotide polymorphisms associated with blood pressure were genotyped, and 3 genetic risk scores associated with systolic and diastolic blood pressures and their combination were derived for all of the participants. Effects of the genetic risk score were 0.47 mm Hg for systolic and 0.53 mm Hg for diastolic blood pressures (both P<0.01). The combination genetic risk score was associated with diastolic blood pressure from age 9 years onward (&bgr;=0.68 mm Hg; P=0.015). Replications in 1194 participants of the Bogalusa Heart Study showed essentially similar results. The participants in the highest quintile of the combination genetic risk score had a 1.82-fold risk of hypertension in adulthood (P<0.0001) compared with the lowest quintile, independent of a family history of premature hypertension. These findings show that genetic variants are associated with preclinical blood pressure traits in childhood; individuals with several susceptibility alleles have, on average, a 0.5-mm Hg higher blood pressure, and this trajectory continues from childhood to adulthood.

Transition From Microscopic to Endoscopic Transsphenoidal Surgery for Nonfunctional Pituitary Adenomas

OBJECTIVE At our institution, a total of 320 patients were operated on between 2000 and 2010 for a newly diagnosed pituitary adenoma. In an attempt to improve quality of tumor resection, the transsphenoidal microscopic technique was replaced by the endoscopic technique in June 2008. This retrospective single center study compares the outcomes after microscopic (n = 144) and endoscopic (n = 41) tumor surgery of all patients operated on for a nonfunctional pituitary adenoma. METHODS Tumor size and location, Knosp grade, prevalence of anterior hypopituitarism, diabetes insipidus, visual acuity/fields, complication rates, and operation time were compared between the groups. RESULTS At the 3-month follow-up, hypopituitarism had improved in 7% of patients in the microscopic group and in 9% in the endoscopic group, and had further impaired in 13% and 9%, respectively. At the 3-month follow-up magnetic resonance imaging, a total tumor removal was achieved in 45% versus 56% of patients, respectively (P = not significant [NS]). Visual fields had normalized or improved in 90% versus 88% of patients, respectively (P = NS). Postoperative cerebrospinal fluid leak occurred in 3.5% versus 2.4% (P = NS), and diabetes insipidus (transient or permanent) in 7.6% versus 4.9% (P = NS) of cases, respectively. Larger tumor size (P < 0.0005) and endoscopic technique (P = 0.03) were independent predictors of increased mean operative time. CONCLUSIONS Initial results with the endoscopic technique were statistically similar to those achieved with the microscopic technique. However, there was a trend toward improved outcomes and fewer complications in the endoscopic group.