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Despite early predictions and rapid progress in research, the introduction of personal genomics into clinical practice has been slow. Several factors contribute to this translational gap between knowledge and clinical application. The evidence available to support genetic test use is often limited, and implementation of new testing programs can be challenging. In addition, the heterogeneity of genomic risk information points to the need for strategies to select and deliver the information most appropriate for particular clinical needs. Accomplishing these tasks also requires recognition that some expectations for personal genomics are unrealistic, notably expectations concerning the clinical utility of genomic risk assessment for common complex diseases. Efforts are needed to improve the body of evidence addressing clinical outcomes for genomics, apply implementation science to personal genomics, and develop realistic goals for genomic risk assessment. In addition, translational research should emphasize the broader benefits of genomic knowledge, including applications of genomic research that provide clinical benefit outside the context of personal genomic risk. [ABSTRACT FROM AUTHOR]

Bronchodilator response (BDR) is an important asthma phenotype thatmeasures reversibility of airway obstruction by comparing ung function (i.e. FEV1) before and after the administration of a short-acting β2-agonist, the most common rescue medications sed for the treatment of asthma. BDR also serves as a test of β2-agonist efficacy. BDR is a complex trait that is partly under enetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV1 after dministration of a b2-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: AMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide olymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting or age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects rom DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. he lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary nalysis, those with rs295137 TT genotype had amedian BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased β2-adrenergic receptor levels. Our results uggest that SPATS2L may be an important regulator of β2-adrenergic receptor down-regulation and that there is promise in aining a better understanding of the biological mechanisms of differential response to b2-agonists through GWAS. [ABSTRACT FROM AUTHOR]

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium(NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components .We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df =10-6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P =6x10-7) but not in light coffee-drinkers. The apriori Replication hypothesis that "Among heavy coffee-drinkers, rs4998386&lowbar;T carriers have lower PD risk than rs4998386&lowbar;CC carriers" was confirmed: ORReplication = 0.59, PReplication =10-3; ORPooled =0.51 , PPooled =7x10-8. Compared to light coffee-drinkers with rs4998386&lowbar;CC genotype, heavy coffee-drinkers with rs4998386&lowbar;CC genotype had 18%lower risk (P = 3x10-3), whereas heavy coffee-drinkers with rs4998386&lowbar;TC genotype had 59% lower risk (P = 6x10-13). Imputation revealed a block of SNPs that achieved P2df < 5x10-8 in GWAIS, and OR = 0.41, P = 3x10-8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients. [ABSTRACT FROM AUTHOR]