Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10−5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10−8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10−8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci Lisa de las Fuentes, Yun Ju Sung et al.

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Genomic testing is an important part of personalized oncology. This study explored testing patterns and results, as well as patient (pt) characteristics, in the BC setting. Data from the nationwide, de-identified Flatiron Health (FH)-Foundation Medicine, Inc. (FMI) BC clinico-genomic database were included; pts had to have been treated in a FH network oncology practice and tested with a FMI CGP test. Pts were &gt;18 years old and had a primary or metastatic BC (mBC) diagnosis between 1/1/2011 and 3/30/2020. Only pts with solid-tumor tissue of origin and solid-tumor assay tests were considered; pts whose tests occurred &gt;120 days after their last visit (based on report date) were excluded. Pt cohorts were classified by timing of test result receipt: cohort 1, between primary diagnosis and &lt;60 days after primary surgery, or &lt;120 days post-diagnosis if no surgery recorded; cohort 2, between 60 days post-primary surgery and 60 days prior to mBC diagnosis, or &gt;120 days post-diagnosis if no surgery recorded; cohort 3a, within 60 days prior to/after mBC diagnosis; and cohort 3b, &gt;60 days after mBC diagnosis. Pt characteristics and actionable mutations according to the FMI report only (associated with sensitivity or resistance to ≥1 therapy) were described by cohort and BC subtype, defined at primary diagnosis for cohorts 1/2 and at mBC diagnosis for cohorts 3a/3b. Pt characteristics were compared with those of the FH cohort (not tested with next-generation sequencing or received other next-generation sequencing tests). Overall, 4183 pts were included: 285 in cohort 1, 412 in cohort 2, and 3486 in cohorts 3a/3b. There was an overrepresentation of triple-negative BC (TNBC) among pts tested in the early setting (cohorts 1/2) vs the underlying population (33%/32% vs 10%), and an underrepresentation of hormone receptor (HR)-positive/HER2-negative BC (45%/48% vs 71%). TNBC remained overrepresented among pts tested at mBC diagnosis (cohort 3a; 30% vs 11%), but not during mBC follow-up (cohort 3b; 14% vs 11%), which followed the underlying FH distribution. The majority of patients were tested using samples collected within their respective test windows: 100% in cohort 1, 63% in cohort 2, and 78% and 46% in cohorts 3a/3b. For pts tested in the mBC setting, 22% and 15% in cohorts 3a and 3b, respectively, were tested using tissue collected &gt;60 days prior to mBC diagnosis. Percentages of pts with at least one FMI-report-actionable alteration ranged from 94% (n = 601) in HER2-positive samples to 75% (n = 668) in pts with TNBC. Among this BC cohort, FMI-CGP predominantly occurred in the mBC setting, and use of archival tissue for CGP occurred in later lines of treatment. Testing, in particular prior to mBC diagnosis, reflected a disproportionately higher prevalence of pts with TNBC, potentially due to there being fewer satisfactory treatment options in this setting. The distribution of actionable alterations varied by HER2 and HR status. Citation Format: Achim Rody, Nayan Chaudhary, Christopher Craggs, Marcio Debiasi, Gilles Erb, Virginia Fisher, Margaret McCusker, Tamara Snow, Maria Vidal Losada, Patricia Luhn. Comprehensive genomic profiling (CGP) in breast cancer (BC): Patterns and results from a clinico-genomic database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 437.