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The human serotonin transporter (SERT) gene possesses a 43-base pair (bp) insertion-deletion promoter polymorphism, the h5-HTTLPR. Genotype at this locus correlates with variation in anxiety-related personality traits and risk for major depressive disorder in many studies. Yet, the complex effects of the h5-HTTLPR, in combination with closely associated single-nucleotide polymorphisms (SNPs), continue to be debated. Moreover, although SERT is of high clinical significance, transporter function in vivo remains difficult to assess. Rhesus express a promoter polymorphism related to the h5-HTTLPR. The rh5-HTTLPR has been linked to differences in stress-related behavior and cognitive flexibility, although allelic variations in serotonin uptake have not been investigated. We studied the serotonin system as it relates to the 5-HTTLPR in rhesus peripheral blood cells. Sequencing of the rh5-HTTLPR revealed a 23-bp insertion, which is somewhat longer than originally reported. Consistent with previous reports, no SNPs in the rh5-HTTLPR and surrounding genomic regions were detected in the individuals studied. Reductions in serotonin uptake rates, cell surface SERT binding, and 5-hydroxyindoleacetic acid/serotonin ratios, but not SERT mRNA levels, were associated with the rh5-HTTLPR short allele. Thus, serotonin uptake rates are differentiable with respect to the 5-HTTLPR in an easily accessible native peripheral tissue. In light of these findings, we foresee that primary blood cells, in combination with high sensitivity functional measurements enabled by chronoamperometry, will be important for investigating alterations in serotonin uptake associated with genetic variability and antidepressant responsiveness in humans.

BackgroundMutations in the peripherin/retinal degeneration slow (RDS) gene have been identified in patients with retinitis pigmentosa and pattern macular dystrophy. The authors initially examined a large family affected with both peripheral and macular degeneration, inherited as an autosomal dominant trait. Screening for peripherin/RDS mutations identified a previously unreported nucleotide alteration in all of the affected individuals. Two additional families later were found to have this same mutation.MethodsDNA samples from the members of three unrelated families were screened for peripherin/RDS mutations by denaturing gradient gel electrophoresis of the polymerase chain reaction-amplified peripherin/RDS coding sequences. The sequence change that was detected was further characterized by DNA sequencing. Family members were examined and evaluated with psychophysical and electrophysiologic methods.ResultsA proline to arginine mutation in codon 210 of peripherin/RDS was found in all clinically affected individuals. Macular changes included extensive geographic atrophy, pigment epithelial changes, and/or drusen. The proline to arginine mutation was not found among 100 healthy individuals, making it unlikely to be a nondisease-causing polymorphism.ConclusionsThe authors identified a novel peripherin/RDS gene mutation associated with autosomal dominant retinal degeneration in patients from three different families. The largest family showed a broad variability in the expressivity of the mutation. The overlap of clinical features with those of age-related maculopathy highlights the need to consider photoreceptor-specific genes as potential factors in the etiology of the latter condition.

Objective: The purpose of this study was to examine the association of the alpha-actinin-3 (ACTN3) R577X polymorphism on muscle function and physical performance in older adults.Methods: We measured knee extensor torque, midthigh muscle cross-sectional area, muscle quality, short physical performance battery score, and 400-meter walk time at baseline and after 5 years in white older adults aged 70-79 years in the Health, Aging and Body Composition Study cohort (n = 1367). Incident persistent lower extremity limitation (PLL) over 5 years was additionally assessed. We also examined white men in the Osteoporotic Fractures in Men Study, a longitudinal, observational cohort (n = 1152) of men 65 years old or older as a validation cohort for certain phenotypes.Results: There were no significant differences between genotype groups in men or women for adjusted baseline phenotypes. Male X-homozygotes had a significantly greater adjusted 5-year increase in their 400-meter walk time compared to R-homozygotes and heterozygotes (p =.03). In women, X-homozygotes had a approximately 35% greater risk of incident PLL compared to R-homozygotes (hazard ratio = 0.65, 95% confidence interval = 0.44-0.94). There were no other significant associations between any of the phenotypes and ACTN3 genotype with aging in either cohort.Conclusions: The ACTN3 polymorphism may influence declines in certain measures of physical performance with aging in older white adults, based on longitudinal assessments. However, the influence of the ACTN3 R577X polymorphism does not appear to have a strong effect on skeletal muscle-related phenotypes based on the strength and consistency of the associations and lack of replication with regard to specific phenotypes. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-1beta is a cytokine released as part of the innate immune response to Plasmodium falciparum. Because the role played by IL-1beta polymorphic variability in conditioning the immunopathogenesis of severe malarial anemia (SMA) remains undefined, relationships between IL-1beta promoter variants (-31C/T and -511A/G), SMA (hemoglobin [Hb] level <6.0 g/dL), and circulating IL-1beta levels were investigated in children with parasitemia (n= 566) from western Kenya. The IL-1beta promoter haplotype -31C/-511A (CA) was associated with increased risk of SMA (Hb level <6.0 g/dL; odds ratio [OR], 1.98 [95% confidence interval {CI}, 1.55-2.27]; P < .05) and reduced circulating IL-1beta levels (p <.05). The TA (-31T/-511A) haplotype was nonsignificantly associated with protection against SMA (OR, 0.52 [95% CI, 0.18-1.16]; p =.11) and elevated IL-1beta production ( p<.05). Compared with the non-SMA group, children with SMA had significantly lower IL-1beta levels and nonsignificant elevations in both IL-1 receptor antagonist (IL-1Ra) and the ratio of IL-1Ra to IL-1beta. The results presented demonstrate that variation in IL-1beta promoter conditions susceptibility to SMA and functional changes in circulating IL-1beta levels. [ABSTRACT FROM AUTHOR]

Objective: Haptoglobin is a plasma protein that binds free hemoglobin, thereby inhibiting hemoglobin-induced oxidative damage. We investigated the association between the haptoglobin genotype and the incidence of coronary artery disease (CAD) in a cohort of individuals with childhood-onset type 1 diabetes.Research Design and Methods: Participants from the Epidemiology of Diabetes Complications Study who were free of CAD at study entry and had DNA available were selected (n = 453, mean age 27.1 years, and diabetes duration 18.8 years). CAD was defined as angina, ischemic electrocardiogram, myocardial infarction confirmed by Q-waves on electrocardiogram or hospital records, angiographic stenosis >50%, or revascularization.Results: The proportions of the cohort with the haptoglobin 1/1, 2/1, and 2/2 genotypes were 11.5, 41.3, and 47.2%, respectively. During 18 years of follow-up, there were 135 (29.8%) incident CAD events. Univariately, the proportion of CAD events increased from 15.4 to 28.3 and 34.6% for haptoglobin 1/1, 2/1, and 2/2, respectively (P = 0.02, P-trend = 0.007). Cumulative incidence (including 33 baseline prevalent cases) also increased from 24.1 to 32.3 and 39.1%, respectively (P = 0.07, P-trend = 0.02). In Cox proportional hazards models adjusting for traditional CAD risk factors, the haptoglobin 2/2 genotype was associated with increased CAD incidence compared with the haptoglobin 1/1 genotype (hazard ratio [HR] 2.21, 95% CI 1.05-4.65, P = 0.04). Although the risk associated with the haptoglobin 2/1 genotype did not reach significance (1.78, 0.84-3.79, P = 0.13), there remained a significant trend across the three groups (P = 0.03).Conclusions: These data support the hypothesis that the haptoglobin genotype influences cardiovascular risk in type 1 diabetes. [ABSTRACT FROM AUTHOR]

AIMS: Mutations in the serine protease inhibitor (SPINK1) gene have been associated with all forms of chronic pancreatitis. Recently, an association of SPINK1 mutations with early-onset Type 2 diabetes mellitus has been reported in patients from Bangladesh. Therefore, we determined the frequency of SPINK1 N34S mutations in patients with Type 2 diabetes mellitus from the USA. METHODS: The study population of Hispanic and non-Hispanic white people consisted of 387 patients with Type 2 diabetes and familial clustering of the disease, 232 family members without diabetes, 259 patients with Type 2 diabetes without a family history, and 302 ethnically matched healthy controls as part of the San Luis Valley Diabetes Study. We performed linkage- and association-analysis in 82 multiplex families with Type 2 diabetes mellitus. RESULTS: No significant linkage or allele sharing was detected between Type 2 diabetes mellitus and the SPINK1 locus. The frequency of the N34S mutation was determined by fluorescence polarization and was similar between patients (n = 14/387 patients with familial clustering; n = 2/259 patients without family history) and controls (n = 5/232 family members without diabetes; n = 10/302 individuals). Variables such as ethnicity, age of diabetes onset and percentage of individuals with impaired glucose tolerance did not differ significantly between carriers and homozygous normal individuals. CONCLUSION: The SPINK1 N34S mutation appears not to predispose Hispanic or non-Hispanic white people from the USA to the development of Type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

BACKGROUND: We reported previously that the socio-economic status (SES) of individuals predicts variation in brain serotonergic responsivity, as assessed by neuropharmacological challenge in an adult community sample, and that this association is qualified by allelic variation in the serotonin transporter gene-linked polymorphic region (5-HTTLPR). Here we examine whether serotonergic responsivity covaries similarly with the SES of communities, as indexed by US Census data in the same study sample. METHOD: Community SES was defined by levels of income, economic disadvantage, housing costs, and educational attainment of census tracts in which 249 locally recruited study participants (54% male) resided. Serotonergic responsivity was assessed as the baseline-adjusted, peak plasma prolactin (Prl) concentration following acute administration of the serotonin-releasing agent, fenfluramine; tissue for DNA extraction and 5-HTTLPR genotyping was available on 131 participants. RESULTS: Subjects residing in census tracts of lower SES showed a blunted Prl response to fenfluramine (diminished serotonergic responsivity) relative to individuals living in more affluent neighborhoods. When adjusted for personal income and education, SES at the community level continued to predict fenfluramine-stimulated Prl responses and did so independently of 5-HTTLPR genotype. CONCLUSIONS: Area-level indices of relative social and economic disadvantage covary with individual differences in brain serotonergic responsivity, and this association is, in part, independent of individually defined SES. These findings may be relevant to reported effects of low community SES on the prevalence of psychiatric disorders or behaviors associated with dysregulation of central serotonergic function, such as depression, impulsive aggression, and suicide. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine the influence of angiotensinogen (AGT) A-20C, M235 T, and angiotensin II type 1 receptor (AGTR1) A1166C genotypes on resting blood pressure (BP) response to strength training (ST) in older men and women. DESIGN: Prospective intervention study with retrospective genotyping. SETTING: University of Maryland Exercise Physiology Laboratory. PARTICIPANTS: Seventy sedentary, healthy older men (n=34) and women (n=36). INTERVENTION: Approximately 23 weeks of ST performed 3 days per week. MEASUREMENTS: Resting BP was measured on six separate occasions before and after ST for each subject. AGT and AGTR1 genotyping was performed retrospectively from each subject's genomic deoxyribonucleic acid. RESULTS: Systolic BP decreased in C-allele carriers at the AGT A-20C locus with ST (122+/-1 to 116+/-2 mmHg, P<.05), which was significantly greater than the decrease in the A homozygotes (126+/-1 to 123+/-1 mmHg, P<.05). At the AGTR1 A1166C locus, diastolic BP decreased to a greater extent in the C-allele carriers (76+/-1 to 70+/-2 mmHg, P<.05) than in the A homozygotes (75+/-1 to 72+/-1 mmHg, P<.05). CONCLUSION: The AGT A-20C and AGTR1 A1166C genotypes may influence resting BP response to ST, such that C-allele carriers at each of these loci reduce their resting BP in response to ST to a greater extent than A homozygotes. [ABSTRACT FROM AUTHOR]

The heritability of substance dependence (SD) liability is based on polymorphisms at the genes that are likely to be related to the function of the central nervous systern. We have recently shown an association between the dopamine DS receptor gene and SD liability. We report herein a replication of this association in an independent case-control sample. [ABSTRACT FROM AUTHOR]

Context: Anatomical, physiological, and epidemiological data indicate that there may be a significant genetic component to prolonged time with and recurrent episodes of otitis media in children.Objective: To determine the genetic component of time with and episodes of middle ear effusion and acute otitis media (AOM) during the first 2 years of life.Design: Prospective twin and triplet cohort study with enrollment from 1982 through 1995.Setting: Otitis Media Research Center in the ear, nose, and throat clinic of Children's Hospital of Pittsburgh, Pittsburgh, Pa.Patients: A total of 168 healthy same-sex twin and 7 triplet sets were recruited within the first 2 months of life; zygosity results were available for 140 sets; 138 (99%) of these were followed up for 1 year and 126 (90%) for 2 years.Main Outcome Measures: Proportion of time with middle ear effusion, episodes of middle ear effusion, and episodes of AOM by zygosity status.Results: At the 2-year end point, the estimate of heritability of time with middle ear effusion was 0.73 (P<.001). The estimates of discordance for 3 or more episodes of middle ear effusion were 0.04 for monozygotic twins and 0.37 for dizygotic twins (P = .01). The estimate of discordance of an episode of AOM in monozygotic twins was 0.04 compared with 0.49 in dizygotic twins (P = .005).Conclusions: Our study suggests there is a strong genetic component to the amount of time with middle ear effusion and episodes of middle ear effusion and AOM in children. [ABSTRACT FROM AUTHOR]

Background: Leptin, a 16 kDa polypeptide hormone, implicated in various physiological processes, exerts its action through the leptin receptor, a member of the class I cytokine receptor family. Both leptin and leptin receptor have recently been implicated in processes leading to breast cancer initiation and progression in animal models and humans. An A to G transition mutation in codon 223 in exon 6 of the leptin receptor gene, resulting in glutamine to arginine substitution (Gln223Arg), lies within the first of two putative leptin-binding regions and may be associated with impaired signaling capacity of the leptin receptor. This study was designed to assess the role of this polymorphism in breast cancer susceptibility in Nigerian women.Methods: We utilized a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay to evaluate the association between the Gln223Arg polymorphism of the leptin receptor gene and breast risk in Nigeria in a case control study involving 209 women with breast cancer and 209 controls without the disease. Study participants were recruited from surgical outpatient clinics and surgical wards of four University Teaching Hospitals located in Midwestern and southeastern Nigeria between September 2002 and April 2004.Results: Premenopausal women carrying at least one LEPR 223Arg allele were at a modestly increased risk of breast cancer after adjusting for confounders (OR = 1.8, 95% confidence interval [CI] 1.0-3.2, p = 0.07). There was no association with postmenopausal breast cancer risk (OR = 0.9, 95% CI 0.4-1.8, p = 0.68).Conclusion: Our results suggest that the LEPR Gln223Arg polymorphism in the extracellular domain of the LEPR receptor gene is associated with a modestly increased risk of premenopausal breast cancer in Nigerian women. [ABSTRACT FROM AUTHOR]

Background: Because of the scarcity of data available from direct comparisons of age and gender groups using the same relative training stimulus, it is unknown whether older individuals can increase their muscle mass as much as young individuals and whether women can increase as much as men in response to strength training (ST). In addition, little is known about whether the hypertrophic response to ST is affected by myostatin genotype, a candidate gene for muscle hypertrophy.Methods: Eleven young men (25 +/- 3 years, range 21-29 years), 11 young women (26 +/- 2 years, range 23-28 years), 12 older men (69 +/- 3 years, range 65-75 years), and 11 older women (68 +/- 2 years, range 65-73 years) had bilateral quadriceps muscle volume measurements performed using magnetic resonance imaging (MRI) before and after ST and detraining. Training consisted of knee extension exercises of the dominant leg three times per week for 9 weeks. The contralateral limb was left untrained throughout the ST program. Following the unilateral training period, the subjects underwent 31 weeks of detraining during which no regular exercise was performed. Myostatin genotype was determined in a subgroup of 32 subjects, of which five female subjects were carriers of a myostatin gene variant.Results: A significantly greater absolute increase in muscle volume was observed in men than in women (204 +/- 20 vs 101 +/- 13 cm3, p < .01), but there was no significant difference in muscle volume response to ST between young and older individuals. The gender effect remained after adjusting for baseline muscle volume. In addition, there was a significantly greater loss of absolute muscle volume after 31 weeks of detraining in men than in women (151 +/- 13 vs 88 +/- 7 cm3, p < .05), but no significant difference between young and older individuals. Myostatin genotype did not explain the hypertrophic response to ST when all 32 subjects were assessed. However, when only women were analyzed, those with the less common myostatin allele exhibited a 68% larger increase in muscle volume in response to ST (p = .056).Conclusions: Aging does not affect the muscle mass response to either ST or detraining, whereas gender does, as men increased their muscle volume about twice as much in response to ST as did women and experienced larger losses in response to detraining than women. Young men were the only group that maintained muscle volume adaptation after 31 weeks of detraining. Although myostatin genotype may not explain the observed gender difference in the hypertrophic response to ST, a role for myostatin genotype may be indicated in this regard for women, but future studies are needed with larger subject numbers in each genotype group to confirm this observation. [ABSTRACT FROM AUTHOR]

Growing evidence links extremes of self-reported sleep duration with higher circulating markers of inflammatory disease risk, although not all findings are consistent. Extremes of sleep duration also associate with activation of the hypothalamic-pituitary-adrenocortical (HPA) system and the peripheral release of cortisol, a glucocorticoid (GC) important in downregulating transcription of pro-inflammatory molecules. Polymorphic variation in the gene encoding the GC receptor (GR; NR3C1) modulates cellular sensitivity to GC-mediated anti-inflammatory signaling, thereby affecting levels of pro-inflammatory molecules. Thus, we hypothesized that extremes of self-reported sleep duration may covary with circulating levels of inflammatory markers as a function of allelic variation in NR3C1. Specifically, we examine the possibility that a single nucleotide polymorphism of the GR gene-(rs6198), the minor (G) allele of which confers reduced GR sensitivity-moderates an association of sleep duration with interleukin (IL)-6 and C-reactive protein (CRP) among a large sample (IL-6: N = 857; CRP: N = 929) of midlife community volunteers of European ancestry. Findings showed that sleep duration varied inversely with IL-6 (β = -0.087, p = .012), and this association was stronger among individuals homozygous for the rs6198 G-allele compared to alternate genotypes (β = -0.071, p = .039). We also found that sleep duration showed a U-shaped association with CRP (polynomial term: β = 0.093, p = .006), which was not moderated by rs6198 genotype. In conclusion, we show that a common genetic variant in the GR moderates an inverse association of self-reported sleep duration with circulating IL-6, possibly contributing to the increased disease risk observed among some short sleepers., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Appendicitis affects 9% of Americans and is the most common diagnosis requiring hospitalization of both children and adults. We performed a genome-wide association study of self-reported appendectomy with 18,773 affected adults and 114,907 unaffected adults of European American ancestry. A significant association with appendectomy was observed at 4q25 near the gene PITX2 (rs2129979, p value = 8.82 × 10 -14 ) and was replicated in an independent sample of Caucasians (59 affected, 607 unaffected; p value = 0.005). Meta-analysis of the associated variant across our two cohorts and cohorts from Iceland and the Netherlands (in which this association had previously been reported) showed strong cumulative evidence of association (OR = 1.12; 95% CI 1.09-1.14; p value = 1.81 × 10 -23 ) and some evidence for effect heterogeneity (p value = 0.03). Eight other loci were identified at suggestive significance in the discovery GWAS. Associations were followed up by measuring gene expression across resected appendices with varying levels of inflammation (N = 75). We measured expression of 27 genes based on physical proximity to the GWAS signals, evidence of being targeted by eQTLs near the signals according to RegulomeDB (score = 1), or both. Four of the 27 genes (including PITX2) showed significant evidence (p values < 0.0033) of differential expression across categories of appendix inflammation. An additional ten genes showed nominal evidence (p value < 0.05) of differential expression, which, together with the significant genes, is more than expected by chance (p value = 6.6 × 10 -12 ). PITX2 impacts morphological development of intestinal tissue, promotes an anti-oxidant response, and its expression correlates with levels of intestinal bacteria and colonic inflammation. Further studies of the role of PITX2 in appendicitis are warranted.

Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA., Objective: To identify additional AAA risk loci using data from all available genome-wide association studies., Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9., Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease., (© 2016 The Authors.)

Despite HLA allele matching, significant acute GvHD remains a major barrier to successful unrelated donor BMT. We conducted a genome-wide association study (GWAS) to identify recipient and donor genes associated with the risk of acute GvHD. A case-control design (grade III-IV versus no acute GvHD) and pooled GWA approach was used to study European-American recipients with hematological malignancies who received myeloablative conditioning non-T-cell-depleted first transplantation from HLA-A, -B, -C, -DRB1, -DQB1 allele level (10/10) matched unrelated donors. DNA samples were divided into three pools and tested in triplicate using the Affymetrix Genome-wide SNP Array 6.0. We identified three novel susceptibility loci in the HLA-DP region of recipient genomes that were associated with III-IV acute GvHD (rs9277378, P=1.58E-09; rs9277542, P=1.548E-06 and rs9277341, P=7.718E-05). Of these three single nucleotide polymorphisms (SNPs), rs9277378 and rs9277542 are located in non-coding regions of the HLA-DPB1 gene and the two are in strong linkage disequilibrium with two other published SNPs associated with acute GvHD, rs2281389 and rs9277535. Eighteen other recipient SNPs and 3 donor SNPs with a high level of significance (8E-07 or lower) were found. Our report contributes to emerging data showing clinical significance of the HLA-DP region genetic markers beyond structural matching of DPB1 alleles., Competing Interests: The authors declare no conflict of interest

The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for "general" substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤ 10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95% C.I. [0.83-0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.

Objective: Elevated blood pressure and the Apolipoprotein ε4 allele (APOE ε4) are independent risk factors for Alzheimer's disease. We sought to determine whether the combined presence of the APOE ε4 allele and elevated blood pressure is associated with lower cognitive performance in cognitively healthy middle-aged adults., Methods: A total of 975 participants aged 30-54 (mean age = 44.47) were genotyped for APOE. Cardiometabolic risk factors including blood pressure, lipids, and glucose were assessed and cognitive function was measured using the Trail Making Test and the Visual Reproduction and Logical Memory subtests from the Wechsler Memory Scale., Results: Multivariable regression analysis showed that the association between APOE ε4 and episodic memory performance varied as a function of systolic blood pressure (SBP), such that elevated SBP was predictive of poorer episodic memory performance only in APOE ε4 carriers (β = -.092; t = -2.614; p = .009). Notably, this association was apparent at prehypertensive levels (≥130 mmHg), even after adjusting for physical activity, depression, smoking, and other cardiometabolic risk factors., Conclusions: The joint presence of APOE ε4 and elevated SBP, even at prehypertensive levels, is associated with lower cognitive performance in healthy, middle-aged adults. Results of this study suggest that the combination of APOE ε4 and elevated SBP may synergistically compromise memory function well before the appearance of clinically significant impairments. Interventions targeting blood pressure control in APOE ε4 carriers during midlife should be studied as a possible means to reduce the risk of cognitive decline in genetically susceptible samples., ((c) 2015 APA, all rights reserved).)