Exome Variant Analysis of Chronic Periodontitis in 2 Large Cohort Studies.

Periodontitis is characterized by inflammation of the gingival tissue. The main risk factors are socioeconomic factors, sex, age, smoking, and diabetes, but periodontal disease has also a genetic background. Previous genome-wide association studies failed to reveal genome-wide significant associations of single common single-nucleotide polymorphisms with chronic periodontitis. Using the Illumina ExomeChip data of 6,576 participants of the German population-based cohort studies Study of Health in Pomerania (SHIP) and SHIP-Trend, the authors performed single variant and also gene-based association studies of rare and common exonic variations on different periodontal case definitions. Although our study comprised the largest sample size to date to assess genetic predisposition for chronic periodontitis, the authors found no significant association. This study emphasizes that for chronic periodontitis, large sample sizes will be necessary to find genetic associations, even when examining rare genetic variants.

Mendelian randomization suggests non-causal associations of testosterone with cardiometabolic risk factors and mortality.

Prospective studies showed that low serum testosterone concentrations are associated with various cardiometabolic risk factors and mortality. However, the causal nature of these associations is controversial. We studied 1 882 men aged 20-79 years with serum testosterone concentrations and genotyping data from the longitudinal population-based Study of Health in Pomerania. Testosterone concentrations were cross-sectionally associated with cardiometabolic risk factors, including anthropometric, lipid, blood pressure and glycaemic parameters; and prospectively with all-cause mortality (277 deaths, 14.7%) during the 10-year follow-up. To overcome problems of residual confounding, reverse causation, or regression dilution bias in the investigated testosterone-outcome associations, we used two-stage least square regression models with previously identified polymorphisms at the SHBG gene (rs12150660) and X chromosome (rs5934505) as multiple genetic instruments in an instrumental variable (IV) approach, also known as Mendelian randomization. In standard regression analyses, testosterone was robustly associated with a wide range of cardiometabolic risk factors. In subsequent IV analyses, no such significant associations were observed. Similarly, prospective analyses showed a consistent association of low testosterone concentrations with increased all-cause mortality risk, which was not apparent in subsequent IV analyses. The present Mendelian randomization analyses did not detect any evidence for causal associations of testosterone concentrations with cardiometabolic risk factors and mortality, suggesting that previously reported associations might largely result from residual confounding or reverse causation. Although testosterone assessment might improve risk prediction, implementation of testosterone replacement therapy requires further evidence of a direct effect on cardiometabolic outcomes from double-blinded randomized controlled trials and large-scale Mendelian randomization meta-analyses.

Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM.

Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10(-11) and 2.7 × 10(-11)), which were also in strong linkage disequilibrium (r(2)=0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10(-05)) and Parkinson's disease pathways (P-value=3.6 × 10(-05)).