👤 T A McAllister

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that increases risk for premature coronary artery disease and has accessible and effective interventions. The Dutch lipid clinic network is currently the most used diagnostic criterion; however, genetic sequencing provides a definitive diagnosis of FH. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify individuals who were genotype positive for FH. Participants were recruited from 3 geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; and Jacksonville, FL). Participants underwent Exome+ sequencing (dba Helix, San Mateo, CA) and return of results for specific genetic findings in At the time of the study, 84 413 participants were enrolled in the Tapestry study. Annotation and interpretation of all variants in genes for FH resulted in the identification of 419 likely pathogenic and pathogenic variants (prevalence, 0.50%), which included 116 Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have familial hypercholesterolemia. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05212428. Show less

To execute a large-scale, decentralized, clinical-grade whole exome sequencing study, coined Tapestry, for clinical practice, research discovery, and genomic education. Between July 1, 2020, and May 31, 2024, we invited 1,287,608 adult Mayo Clinic patients to participate in Tapestry. Of those contacted, 114,673 patients were consented and 98,222 (65.2% women) are currently enrolled: 62,495 (63.6%) were recruited from Minnesota-, 18,353 (18.7%) from Florida- and 17,374 (17.7%) from Arizona-based practices. Saliva from participants was used to extract DNA, and whole exome sequencing plus ∼300,000 single nucleotide polymorphisms (ie, Exome+ assay) were sequenced by a clinical lab. Results for the Centers for Disease Control and Prevention Tier 1 genes (eg, hereditary breast, ovarian cancer syndrome: BRCA1/2; Lynch syndrome: MLH1, MSH2, MSH6, PMS2, and EPCAM; and familial hypercholesterolemia: APOB, LDLR, PCSK9, and LDLRAP1) were interpreted and entered into the electronic health record. The median age of participants was 59.1 years and ∼11% were from racial/ethnic groups under-represented in research. One thousand eight hundred nineteen (1.9%) participants had actionable pathogenic or likely pathogenic variants (50.0% BRCA1/2, 28.4% familial hypercholesterolemia, and 22.2% Lynch syndrome). Positive results were communicated by genetic counselors who educated patients and providers. Thus far, 62,758 patients' Exome+ assays are stored for research, and the Tapestry Data Access Committee has received 118 requests from investigators, of which 82 have been approved, resulting in the delivery of 1,117,410 Exome+ assays to researchers. A large, decentralized, clinical Exome+ assay study in a tertiary medical center detects actionable germline variants, educates patients as well as providers, and offers access to big data for discovery that advances human health. clinicaltrials.gov Identifier: NCT05212428. Show less

Fat deposition influences both meat quality and animal productivity. However, it is not clear how fat development is regulated in growing and fattening beef cattle. This study characterized proteomic changes in subcutaneous adipose tissue from steers fed a high-grain diet in an effort to understand the molecular mechanisms of fat development during feedlot production. Eight British-Continental crossbred steers had two subcutaneous adipose tissue biopsies at 12 and 15 mo of age. Protein expression in fat samples was profiled using liquid chromatography-tandem mass spectrometry (LC-MS/MS). During the finishing period, steers increased subcutaneous adipose tissue mass with concomitant changes in the proteome profile, but the nature of these changes varied among steers. The expression of 123 out of 627 identified proteins differed (P <: 0.05) between 2 ages. Functional analyses on differentially expressed proteins revealed that 20.2% of them were associated with cellular growth and proliferation of adipose tissue. There were 17 out of 108 differentially expressed proteins associated with lipid metabolism, which were acyl-CoA synthetase medium-chain family member 1 (ACSM1), annexin A1 (ANXA1), apolipoprotein C-III (APOC3), apolipoprotein H (beta-2-glycoprotein I; APOH), EH-domain containing 1 (EHD1), coagulation factor II (thrombin; F2), gelsolin (GSN), lamin A/C (LMNA), mitogen-activated protein kinase kinase 1 (MAP2K1), myosin, heavy chain 9, non-muscle (MYH9), orosomucoid 1 (ORM1), protein disulfide isomerase family A, member 3 (PDIA3), retinol binding protein 4, plasma (RBP4), renin binding protein (RENBP), succinate dehydrogenase complex, subunit A, flavoprotein (Fp; SDHA), serpin peptidase inhibitor, clade C (antithrombin), member 1 (SERPINC1), and serpin peptidase inhibitor, clade G (C1 inhibitor), member 1 (SERPING1). Further analysis of the expression levels of proteins associated with lipid metabolism indicated a downregulation in the synthesis of fatty acids at the cellular level at 15 compared to 12 mo of age. These results suggest that even though adipose tissue expanded, fat anabolism was reduced in adipocytes during growth, revealing a coordinated balance between subcutaneous fat mass and the cellular abundance of lipogenic proteins to control the rate of fat deposition in growing beef cattle. The findings observed in this study expand our understanding on how proteome of bovine adipose tissue is regulated during growth, which might help the development in the future of new strategies to manipulate adiposity in beef cattle in a manner that improves meat quality and animal productivity. Show less

Two previously reported DNA polymorphisms of sterol regulatory element binding transcription factor 1 (SREBP-1) and liver X receptor alpha (LXRα) and two DNA polymorphisms of fatty acid desaturase 1 (FADS1) were evaluated for associations with fatty acids in brisket adipose tissue of Canadian crossbred beef steers. The polymorphism of 84 bp insert/deletion in intron 5 of SREBP-1 was significantly associated with the concentration of 9c C17:1 (P=0.013). The G>A single nucleotide polymorphism (SNP) in the exon 4 of LXRα gene was associated with the concentration of 9c, 11t C18:2 (P=0.04), sum of conjugated linoleic acids (CLA) (P=0.025) and 11c C20:1(P=0.042). Two DNA polymorphisms in the promoter region of FADS1, deletion/insertion of →GTG in rs133053720 and SNP A>G in rs42187276, were significantly associated with concentrations of C17:0 iso, C17:0 ai, total branched chain fatty acids (BFA), 12t C18:1, 13t/14t C18:1, 15t C18:1, and 13c C18:1 (P<0.05). Further studies are needed to validate the associations and to delineate the roles of the gene polymorphisms in determining the fatty acid composition in beef tissues. Show less

Genetic studies carried out mainly in European and European-derived populations have shown that common polymorphisms in genes coding for apolipoproteins are significant determinants of serum lipoprotein-lipid levels variation. However, except for a few sporadic studies, the distribution of apolipoprotein polymorphisms and their association with serum lipoprotein-lipid levels have not been evaluated systematically in African or African-derived populations. In this investigation we have studied five apolipoprotein polymorphisms, including APOA1/MspI-75 bp, APOA1/MspI+83 bp, APOC3/PvuII, APOE, and APOH in 786 Africans (493 men, 293 women) from Nigeria. The sample is comprised of Nigerian civil servants consisting of 462 junior staff (less affluent) and 324 senior staff (more affluent) where staff status is a correlate of their socioeconomic status. We first examined genetic associations in the total sample stratified by gender to determine the role of apolipoprotein polymorphisms in affecting serum lipid profile in the general population, and then by staff status to evaluate possible gene-environment interactions. In the total sample, the APOC3/PvuII polymorphism showed significant effect on HDL-cholesterol (P = 0.029) and HDL3-cholesterol (P = 0.009) in women, and the APOE polymorphism was significantly associated with total cholesterol (P = 0.031) and LDL-cholesterol (P = 0.0006) in women. Multiple regression analyses showed that the APOC3/PvuII polymorphism accounts for about 2 and 3% of the variation in HDL-cholesterol and HDL3-cholesterol, respectively, in women; while the APOE polymorphism accounted for about 5 and 6% of the variation in total- and LDL-cholesterol, respectively, in women. Whereas the association of the APOE polymorphism was independent of the staff status, the significant affect of the APOC3/PvuII polymorphism on HDL- and HDL3-cholesterol was confined to senior staff women where it explained about 7% of their variation. We also observed an interaction between staff and the APOH polymorphism in affecting cholesterol levels. The APOH polymorphism showed significant association with total cholesterol (P = 0.010) and LDL-cholesterol (P = 0.016) in senior staff women and explained about 7 and 5% of their phenotypic variations, respectively. These data indicate that gene-environment interaction may play an important role in affecting serum lipid profile in African populations. Show less