Citations

Background— Whether knowledge of genetic risk for coronary heart disease (CHD) affects health-related outcomes is unknown. We investigated whether incorporating a genetic risk score (GRS) in CHD risk estimates lowers low-density lipoprotein cholesterol (LDL-C) levels. Methods and Results— Participants (n=203, 45–65 years of age, at intermediate risk for CHD, and not on statins) were randomly assigned to receive their 10-year probability of CHD based either on a conventional risk score (CRS) or CRS + GRS ( + GRS). Participants in the + GRS group were stratified as having high or average/low GRS. Risk was disclosed by a genetic counselor followed by shared decision making regarding statin therapy with a physician. We compared the primary end point of LDL-C levels at 6 months and assessed whether any differences were attributable to changes in dietary fat intake, physical activity levels, or statin use. Participants (mean age, 59.4±5 years; 48% men; mean 10-year CHD risk, 8.5±4.1%) were allocated to receive either CRS (n=100) or + GRS (n=103). At the end of the study period, the + GRS group had a lower LDL-C than the CRS group (96.5±32.7 versus 105.9±33.3 mg/dL; P =0.04). Participants with high GRS had lower LDL-C levels (92.3±32.9 mg/dL) than CRS participants ( P =0.02) but not participants with low GRS (100.9±32.2 mg/dL; P =0.18). Statins were initiated more often in the + GRS group than in the CRS group (39% versus 22%, P <0.01). No significant differences in dietary fat intake and physical activity levels were noted. Conclusions— Disclosure of CHD risk estimates that incorporated genetic risk information led to lower LDL-C levels than disclosure of CHD risk based on conventional risk factors alone. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01936675.

The legacy of human-Neandertal interbreeding Non-African humans are estimated to have inherited on average 1.5 to 4% of their genomes from Neandertals. However, how this genetic legacy affects human traits is unknown. Simonti et al. combined genotyping data with electronic health records. Individual Neandertal alleles were correlated with clinically relevant phenotypes in individuals of European descent. These archaic genetic variants were associated with medical conditions affecting the skin, the blood, and the risk of depression. Science , this issue p. 737

We investigated whether family history (FHx) of atherosclerotic cardiovascular disease (ASCVD) was associated with presence of abdominal aortic aneurysm (AAA). The study cohort comprised of 696 patients with AAA (70±8 years, 84% men) and 2686 controls (68±10 years, 61% men) recruited from noninvasive vascular and stress electrocardiogram (ECG) laboratories at Mayo Clinic. AAA was defined as a transverse diameter of abdominal aorta ⩾ 3 cm or history of AAA repair. Controls were not known to have AAA. FHx was defined as having at least one first-degree relative with aortic aneurysm or with onset of ASCVD (coronary, cerebral or peripheral artery disease) before age 65 years. FHx of aortic aneurysm or ASCVD were each associated with presence of AAA after adjustment for age, sex, conventional risk factors and ASCVD: adjusted odds ratios (OR; 95% confidence interval): 2.17 (1.66–2.83, p < 0.01) and 1.31 (1.08–1.59, p < 0.01), respectively. FHx of ASCVD remained associated with AAA after additional adjustment for FHx of aortic aneurysm: adjusted OR: 1.27 (1.05–1.55, p = 0.01). FHx of ASCVD in multiple arterial locations was associated with higher odds of having AAA: the adjusted odds were 1.23 times higher for each additionally affected arterial location reported in the FHx (1.08–1.40, p = 0.01). Our results suggest both unique and shared environmental and genetic factors mediating susceptibility to AAA and ASCVD.

SummaryBackgroundObesity in children is associated with vitamin D deficiency and endothelial dysfunction. It is not known if treatment with vitamin D improves endothelial function in obese adolescents.ObjectiveThis study aimed to determine whether treatment with vitamin D3 improves endothelial function in obese adolescents.MethodsNineteen obese adolescents, 13–18 years of age, with 25‐hydroxy vitamin D (25[OH]D) levels <75 nmol L−1 were treated with 100 000 IU vitamin D3 orally once a month for 3 months in an open‐label, single‐centre prospective trial. Endothelial function was assessed by flow‐mediated dilatation (FMD) of the brachial artery at study entry and 1 month after the third dose of vitamin D3. Biochemical parameters, including calcium, fasting lipids, glucose, insulin and high‐sensitivity C‐reactive protein, were also obtained.ResultsMean 25(OH)D levels increased from 55.9 ± 12.2 to 86.9 ± 16.7 nmol L−1 (P < 0.01). There was no correlation between 25(OH)D levels and brachial artery FMD. The brachial artery FMD (%) did not change significantly following vitamin D3 treatment (9.5 ± 3.53 vs. 10.3 ± 3.83, P = 0.83). Serum parathyroid hormone declined from 3.8 ± 1.5 to 3.1 ± 1 pmol L−1 (P = 0.01). The remainder of biochemical measurements did not show a significant change.ConclusionsTreatment with vitamin D3, 100 000 IU once a month for 3 months was effective in increasing 25(OH)D levels in obese adolescents but did not impact endothelial function.

ObjectiveTo examine associations between circulating levels of the bone‐derived protein osteocalcin (OC) and type 2 diabetes (T2D) risk in Latino children and adults.MethodsSerum OC was measured in 136 children and 531 adults who had the following T2D risk factors assessed, body mass index (BMI), Hemoglobin A1c (HbA1c), fasting and 2‐hour glucose during an oral glucose tolerance test.ResultsOC was significantly higher in children than adults (209.0 ± 12.1 vs. 41.0 ± 0.9 ng/ml, p<0.0001). In adults, OC was inversely associated (all p<0.001) with BMI (r=‐0.2), HbA1c (r=‐0.2), fasting glucose (r=‐0.16), and 2‐hour glucose (r=‐0.21), while there were no significant associations in children. There was a stepwise decrease in OC with increasing dysglycemia in adults, normoglycemic (44.1 ± 1.3 ng/ml), prediabetic (39.3 ± 1.3 ng/ml), and T2D (31.8 ± 1.2 ng/ml), (p<0.0001), whereas there were no differences between normal and prediabetic youth (195.7 ± 16.1 vs. 194.7 ± 25.8 ng/ml, p=0.3).ConclusionsOC was inversely associated with T2D risk in Latino adults; however, this pattern was not observed in children. Am. J. Hum. Biol. 27:859–861, 2015. © 2015 Wiley Periodicals, Inc.

Several risk factors for atherosclerotic peripheral arterial disease (PAD), such as dyslipidemia, diabetes mellitus, and hypertension, are heritable. However, predisposition to PAD may be influenced by genetic variants acting independently of these risk factors. Identification of such genetic variants will provide insights into underlying pathophysiologic mechanisms and facilitate the development of novel diagnostic and therapeutic approaches. In contrast to coronary heart disease, relatively few genetic variants that influence susceptibility to PAD have been discovered. This may be, in part, because of greater clinical and genetic heterogeneity in PAD. In this review, we (1) provide an update on the current state of knowledge about the genetic basis of PAD, including results of family studies and candidate gene, linkage as well as genome-wide association studies; (2) highlight the challenges in investigating the genetic basis of PAD and possible strategies to overcome these challenges; and (3) discuss the potential of genome sequencing, RNA sequencing, differential gene expression, epigenetic profiling, and systems biology in increasing our understanding of the molecular genetics of PAD.

We investigated whether disclosure of coronary heart disease (CHD) genetic risk influences perceived personal control (PPC) and genetic counseling satisfaction (GCS). Participants (n = 207, age: 45–65 years) were randomized to receive estimated 10‐year risk of CHD based on a conventional risk score (CRS) with or without a genetic risk score (GRS). Risk estimates were disclosed by a genetic counselor who also reviewed how GRS altered risk in those randomized to CRS+GRS. Each participant subsequently met with a physician and then completed surveys to assess PPC and GCS. Participants who received CRS+GRS had higher PPC than those who received CRS alone although the absolute difference was small (25.2 ± 2.7 vs 24.1 ± 3.8, p = 0.04). A greater proportion of CRS+GRS participants had higher GCS scores (17.3 ± 5.3 vs 15.9 ± 6.3, p = 0.06). In the CRS+GRS group, PPC and GCS scores were not correlated with GRS. Within both groups, PPC and GCS scores were similar in patients with or without family history (p = NS). In conclusion, patients who received their genetic risk of CHD had higher PPC and tended to have higher GCS. Our findings suggest that disclosure of genetic risk of CHD together with conventional risk estimates is appreciated by patients. Whether this results in improved outcomes needs additional investigation.

Objectives To examine associations between specific inflammatory biomarkers and cognitive function in African Americans (AAs) and European Americans (EAs) with prevalent vascular risk factors. Design Cross‐sectional analysis using generalized estimating equations to account for familial clustering; standardized β‐coefficients, adjusted for age, sex, and education are reported. Setting Community cohort study in Jackson, Mississippi, and Rochester, Minnesota. Participants Genetic Epidemiology Network of Arteriopathy (GENOA)–Genetics of Microangiopathic Brain Injury (GMBI) Study participants. Measurements Associations between inflammation (high‐sensitivity C‐reactive protein (CRP), interleukin (IL)‐6, soluble tumor necrosis factor (TNF) receptor 1 and 2 (sTNFR1, sTNFR2)) and cognitive function (global, processing speed, language, memory, and executive function) were examined in AAs and EAs (N = 1,965; aged 26–95, 64% women, 52% AA, 75% with hypertension). Results In AAs, higher sTNFR2 was associated with poorer cognition in all domains (global: −0.11, P = .009; processing speed: −0.11, P < .001; language: −0.08, P = .002; memory: −0.09, P = .008; executive function: −0.07, P = .03); sTNFR1 was associated with slower processing speed (−0.08, P < .001) and poorer executive function (−0.08, P = .008); higher CRP was associated with slower processing speed (−0.04, P = .024), and higher IL6 was associated with poorer executive function (−0.07, P = .02). In EA, only higher sTNFR1 was associated with slower processing speed (−0.05, P = .007). Associations were not found between cognition and sTNFR2, CRP, or IL6 in EA. Conclusion In a population with high vascular risk, adverse associations between inflammation and cognitive function were especially apparent in AAs, primarily involving markers of TNFα activity.

Background— Massively parallel, high-throughput sequencing technology is helping to generate new insights into the genetic basis of human diseases. We used whole exome sequencing to identify the mutation underlying a syndrome affecting 2 siblings with aortic hypoplasia, calcific atherosclerosis, systolic hypertension, and premature cataract. Methods and Results— Exonic regions were captured and sequenced using a next-generation sequencing platform to generate 100 bases paired-end reads. A computational genomic data analysis pipeline was used to perform quality control, align reads to a reference genome, and identify genetic variants; findings were confirmed using a different exome analyses pipeline. The 2 siblings were homozygous for a rare missense mutation (Ser818Cys) in INO80D , a subunit of the human INO80 chromatin remodeling complex. Homozygosity mapping and Sanger sequencing confirmed that the mutation is located in one of the runs of homozygosity on chromosome 2. INO80D encodes a key subunit of the human IN080 complex, a multiprotein complex involved in DNA binding, chromatin modification, organization of chromosome structure, and ATP-dependent nucleosome sliding. By introducing a new disulphide-bond in the protein product and also disrupting the composition of low-complexity regions, the Ser818Cys mutation may affect INO80D function, protein–protein interactions, and chromatin remodeling. Conclusions— Our findings suggest a link between the Ser818Cys mutation in INO80D , a subunit of the human INO80 chromatin remodeling complex, and accelerated arterial aging.