Blood concentrations of lipoproteins and lipids are heritable risk factors for cardiovascular disease. Using genome-wide association data from three studies (n = 8,816 that included 2,758 individuals from the Diabetes Genetics Initiative specific to the current paper as well as 1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables reported in a companion paper in this issue) and targeted replication association analyses in up to 18,554 independent participants, we show that common SNPs at 18 loci are reproducibly associated with concentrations of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and/or triglycerides. Six of these loci are new (P < 5 x 10(-8) for each new locus). Of the six newly identified chromosomal regions, two were associated with LDL cholesterol (1p13 near CELSR2, PSRC1 and SORT1 and 19p13 near CILP2 and PBX4), one with HDL cholesterol (1q42 in GALNT2) and five with triglycerides (7q11 near TBL2 and MLXIPL, 8q24 near TRIB1, 1q42 in GALNT2, 19p13 near CILP2 and PBX4 and 1p31 near ANGPTL3). At 1p13, the LDL-associated SNP was also strongly correlated with CELSR2, PSRC1, and SORT1 transcript levels in human liver, and a proxy for this SNP was recently shown to affect risk for coronary artery disease. Understanding the molecular, cellular and clinical consequences of the newly identified loci may inform therapy and clinical care.

A genome-wide association study of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent SNPs are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (R2 ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈ 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

Rapidly declining biodiversity may be a contributing factor to another global megatrend—the rapidly increasing prevalence of allergies and other chronic inflammatory diseases among urban populations worldwide. According to the “biodiversity hypothesis,” reduced contact of people with natural environmental features and biodiversity may adversely affect the human commensal microbiota and its immunomodulatory capacity. Analyzing atopic sensitization (i.e., allergic disposition) in a random sample of adolescents living in a heterogeneous region of 100 × 150 km, we show that environmental biodiversity in the surroundings of the study subjects’ homes influenced the composition of the bacterial classes on their skin. Compared with healthy individuals, atopic individuals had lower environmental biodiversity in the surroundings of their homes and significantly lower generic diversity of gammaproteobacteria on their skin. The functional role of the Gram-negative gammaproteobacteria is supported by in vitro measurements of expression of IL-10, a key anti-inflammatory cytokine in immunologic tolerance, in peripheral blood mononuclear cells. In healthy, but not in atopic, individuals, IL-10 expression was positively correlated with the abundance of the gammaproteobacterial genus Acinetobacter on the skin. These results raise fundamental questions about the consequences of biodiversity loss for both allergic conditions and public health in general.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.

The 80% decline in coronary mortality in Finland mainly reflects a great reduction of the risk factor levels; these in turn have been associated with long-term comprehensive chronic disease prevention and health promotion interventions.

Substituting sitostanol-ester margarine for part of the daily fat intake in subjects with mild hypercholesterolemia was effective in lowering serum total cholesterol and LDL cholesterol.

Blood pressure is a heritable trait, but no common genetic variants contributing to blood pressure in humans have been definitively established. Natriuretic peptides (NP) have blood pressure-lowering properties. Genotyping SNPs at the NPPA/NPPB locus in 14,743 individuals of European ancestry identified associations of plasma atrial natriuretic peptide with rs5068 (P=8×10−70), rs198358 (P=8×10−30), and rs632793 (P=2×10−10), and of plasma B-type natriuretic peptide with rs5068 (P=3×10−12), rs198358 (P=1×10−25), and rs632793 (P=2×10−68). In 29,717 individuals, the alleles of rs5068 and rs198358 related to increased circulating NP concentrations were associated with lower systolic (P=2×10−6 and 6×10−5, respectively) and diastolic blood pressure (P=1×10−6 and 5×10−5), and reduced odds of hypertension (odds ratio 0.85, 95% confidence interval, 0.79–0.92, P=4×10−5; odds ratio 0.90, 95% confidence interval, 0.85–0.95, P=2×10−4, respectively). Common genetic variants related to circulating NP concentrations contribute to inter-individual variation in blood pressure and hypertension.

Study objective: The validity of self reported smoking in population surveys remains an important question. An associated question is what would be the value of measuring serum cotinine concentrations in such surveys to obtain validated smoking data. Design: Cross sectional analysis of data on self reported smoking and serum cotinine among a random population sample of 5846 persons aged 25 to 64 years, who participated in the FINRISK-92 survey. Main results: Among self reported regular smokers, 97.2% of men and 94.9% of women had a cotinine concentration of 10 ng/ml or higher in serum. Of those participants who reported to have smoked at any time during their life but not during the previous month, 6.3% of men and 5.2% of women had a serum cotinine concentration of at least 10 ng/ml. Among never smokers 2.5% of men and 2.7% of women had detectable level of cotinine in their serum. The validity of self reporting was similar among subjects from different areas, ages, and socioeconomic groups. Conclusions: In a sample of the general population in Finland the validity of self reported smoking is high, and most of the few self reported non-smokers who had cotinine in their serum had only low or moderate levels.B oth in clinical and in community settings there has been a concern about the validity of self reported smoking. Mainly, three biological measurements have been used to validate self reported smoking: carbon monoxide, thiocyanate, and cotinine. 3 The aim of our paper is to study the validity of self reported smoking in a cardiovascular risk factor population survey by comparing self reports with results of measurements of cotinine levels in serum.Nicotine metabolises rapidly and extensively, primarily in the liver. N-oxidation of nicotine to nicotine-1'-N-oxide occurs in humans. This metabolite has been shown to convert back to nicotine. In humans, the urinary elimination phase of the metabolite parallels that of the parent nicotine, indicating a formation rate limited excretion. It has been estimated that approximately 4% of the nicotine dose is excreted as nicotine-1'-N-oxide. Furthermore, it has been estimated that the quantitative disposition of nicotine is as follows: an average of 9% of the dose seems to be excreted as intact nicotine, and about 70% of nicotine seems to be converted to cotinine. Cotinine is the major plasma metabolite of nicotine and persists for a considerable time period in plasma, with a half life of approximately 16 hours. Only a minor fraction of the generated cotinine is excreted by the kidneys, but cotinine is further metabolised to more polar water soluble substances. According to recent human data the major metabolite found in urine is hydroxylated cotinine.