A study paradigm integrating prospective epidemiologic cohorts and electronic health records to identify disease biomarkers.

Defining the full spectrum of human disease associated with a biomarker is necessary to advance the biomarker into clinical practice. We hypothesize that associating biomarker measurements with electronic health record (EHR) populations based on shared genetic architectures would establish the clinical epidemiology of the biomarker. We use Bayesian sparse linear mixed modeling to calculate SNP weightings for 53 biomarkers from the Atherosclerosis Risk in Communities study. We use the SNP weightings to computed predicted biomarker values in an EHR population and test associations with 1139 diagnoses. Here we report 116 associations meeting a Bonferroni level of significance. A false discovery rate (FDR)-based significance threshold reveals more known and undescribed associations across a broad range of biomarkers, including biometric measures, plasma proteins and metabolites, functional assays, and behaviors. We confirm an inverse association between LDL-cholesterol level and septicemia risk in an independent epidemiological cohort. This approach efficiently discovers biomarker-disease associations.

Genetic variation in SLC7A2 interacts with calcium and magnesium intakes in modulating the risk of colorectal polyps.

Solute carrier family 7, member 2 (SLC7A2) gene encodes a protein called cationic amino acid transporter 2, which mediates the transport of arginine, lysine and ornithine. l-Arginine is necessary for cancer development and progression, including an important role in colorectal cancer pathogenesis. Furthermore, previous studies found that both calcium and magnesium inhibit the transport of arginine. Thus, calcium, magnesium or calcium:magnesium intake ratio may interact with polymorphisms in the SLC7A2 gene in association with colorectal cancer. We conducted a two-phase case-control study within the Tennessee Colorectal Polyps Study. In the first phase, 23 tagging single-nucleotide polymorphisms in the SLC7A2 gene were included for 725 colorectal adenoma cases and 755 controls. In the second phase conducted in an independent set of 607 cases and 2113 controls, we replicated the significant findings in the first phase. We observed that rs2720574 significantly interacted with calcium:magnesium intake ratio in association with odds of adenoma, particularly multiple/advanced adenoma. In the combined analysis, among those with a calcium:magnesium intake ratio below 2.78, individuals who carried GC/CC genotypes demonstrated higher odds of adenoma [OR (95% CI):1.36 (1.11-1.68)] and multiple/advanced adenoma [OR (95% CI): 1.68 (1.28, 2.20)] than those who carried the GG genotype. The P values for interactions between calcium:magnesium intake ratio and rs2720574 were .002 for all adenomas and <.001 for multiple/advanced adenoma. Among those with the GG genotype, a high calcium:magnesium ratio was associated with increased odds of colorectal adenoma [OR (95% CI): 1.73 (1.27-2.36)] and advanced/multiple adenomas [1.62 (1.05-2.50)], whereas among those with the GC/CC genotypes, high calcium:magnesium ratio was related to reduced odds of colorectal adenoma [0.64 (0.42-0.99)] and advanced/multiple adenomas [0.55 (0.31-1.00)].

An association analysis of Alzheimer disease candidate genes detects an ancestral risk haplotype clade in ACE and putative multilocus association between ACE, A2M, and LRRTM3.

Alzheimer's disease (AD) is the most common form of progressive dementia in the elderly. It is a neurodegenerative disorder characterized by the neuropathologic findings of neurofibrillary tangles and amyloid plaques that accumulate in vulnerable brain regions. AD etiology has been studied by many groups, but since the discovery of the APOE epsilon4 allele, no further genes have been mapped conclusively to late-onset AD (LOAD). In this study, we examined genetic association with LOAD susceptibility in 738 Caucasian families (4,704 individuals) and an independent case-control dataset with 296 cases and 566 controls exploring 11 candidate genes (47 SNPs common to both samples). In addition to tests for main effects and haplotypes, the MDR-PDT was used to search for gene-gene interactions in the family data. We observed significant haplotype effects in ACE in family and case-control samples using standard and cladistic haplotype models. ACE was also part of significant 2 and 3-locus MDR-PDT joint effects models with Alpha-2-Macroglobulin (A2M), which mediates the clearance of Abeta, and Leucine-Rich Repeat Transmembrane-3 (LRRTM3), a nested gene in Alpha-3 Catenin (CTNNA3) which binds Presenilin-1. This result did not replicate in the case-control sample, and may not be a true positive. These genes are related to Abeta clearance; thus this constellation of effects might constitute an axis of susceptibility for LOAD. The consistent ACE haplotype result between independent family-based and unrelated case-control datasets is strong evidence in favor of ACE as a susceptibility locus for AD, and replicates results from several other studies in a large sample.