A saturated map of common genetic variants associated with human height.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies.

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium. METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction. RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P=0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions. CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

Assessment of Subclinical Atherosclerosis in Asymptomatic People In Vivo: Measurements Suitable for Biomarker and Mendelian Randomization Studies.

BACKGROUND: One strategy to reduce the burden of cardiovascular disease is the early detection and treatment of atherosclerosis. This has led to significant interest in studies of subclinical atherosclerosis, using different phenotypes, not all of which are accurate reflections of the presence of asymptomatic atherosclerotic plaques. The aim of part 2 of this series is to provide a review of the existing literature on purported measures of subclinical disease and recommendations concerning which tests may be appropriate in the prevention of incident cardiovascular disease. METHODS: We conducted a critical review of measurements used to infer the presence of subclinical atherosclerosis in the major conduit arteries and focused on the predictive value of these tests for future cardiovascular events, independent of conventional cardiovascular risk factors, in asymptomatic people. The emphasis was on studies with >10 000 person-years of follow-up, with meta-analysis of results reporting adjusted hazard ratios (HRs) with 95% CIs. The arterial territories were limited to carotid, coronary, aorta, and lower limb arteries. RESULTS: In the carotid arteries, the presence of plaque (8 studies) was independently associated with future stroke (pooled HR, 1.89 [1.04-3.44]) and cardiac events (7 studies), with a pooled HR, 1.77 (1.19-2.62). Increased coronary artery calcium (5 studies) was associated with the risk of coronary heart disease events, pooled HR, 1.54 (1.07-2.07) and increasing severity of calcification (by Agaston score) was associated with escalation of risk (13 studies). An ankle/brachial index (ABI) of <0.9, the pooled HR for cardiovascular death from 7 studies was 2.01 (1.43-2.81). There were insufficient studies of either, thoracic or aortic calcium, aortic diameter, or femoral plaque to synthesize the data based on consistent reporting of these measures. CONCLUSIONS: The presence of carotid plaque, coronary artery calcium, or abnormal ankle pressures seems to be a valid indicator of the presence of subclinical atherosclerosis and may be considered for use in biomarker, Mendelian randomization and similar studies.

Health Disparities in Peripheral Artery Disease: A Scientific Statement From the American Heart Association.

Peripheral artery disease (PAD) affects 200 million individuals worldwide. In the United States, certain demographic groups experience a disproportionately higher prevalence and clinical effect of PAD. The social and clinical effect of PAD includes higher rates of individual disability, depression, minor and major limb amputation along with cardiovascular and cerebrovascular events. The reasons behind the inequitable burden of PAD and inequitable delivery of care are both multifactorial and complex in nature, including systemic and structural inequity that exists within our society. Herein, we present an overview statement of the myriad variables that contribute to PAD disparities and conclude with a summary of potential novel solutions.

Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study.

Progressive dilation of the infrarenal aortic diameter is a consequence of the ageing process and is considered the main determinant of abdominal aortic aneurysm (AAA). We aimed to investigate the genetic and clinical determinants of abdominal aortic diameter (AAD). We conducted a meta-analysis of genome-wide association studies in 10 cohorts (n = 13 542) imputed to the 1000 Genome Project reference panel including 12 815 subjects in the discovery phase and 727 subjects [Partners Biobank cohort 1 (PBIO)] as replication. Maximum anterior-posterior diameter of the infrarenal aorta was used as AAD. We also included exome array data (n = 14 480) from seven epidemiologic studies. Single-variant and gene-based associations were done using SeqMeta package. A Mendelian randomization analysis was applied to investigate the causal effect of a number of clinical risk factors on AAD. In genome-wide association study (GWAS) on AAD, rs74448815 in the intronic region of LDLRAD4 reached genome-wide significance (beta = -0.02, SE = 0.004, P-value = 2.10 × 10-8). The association replicated in the PBIO1 cohort (P-value = 8.19 × 10-4). In exome-array single-variant analysis (P-value threshold = 9 × 10-7), the lowest P-value was found for rs239259 located in SLC22A20 (beta = 0.007, P-value = 1.2 × 10-5). In the gene-based analysis (P-value threshold = 1.85 × 10-6), PCSK5 showed an association with AAD (P-value = 8.03 × 10-7). Furthermore, in Mendelian randomization analyses, we found evidence for genetic association of pulse pressure (beta = -0.003, P-value = 0.02), triglycerides (beta = -0.16, P-value = 0.008) and height (beta = 0.03, P-value < 0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases.

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

The association between reproductive history and abdominal adipose tissue among postmenopausal women: results from the Women's Health Initiative.

STUDY QUESTION: What is the association between reproductive health history (e.g. age at menarche, menopause, reproductive lifespan) with abdominal adiposity in postmenopausal women? SUMMARY ANSWER: Higher visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) tissue levels were observed among women with earlier menarche, earlier menopause, and greater parity. WHAT IS KNOWN ALREADY: Postmenopausal women are predisposed to accumulation of VAT and SAT. Reproductive health variables are known predictors of overall obesity status in women, defined by BMI. STUDY DESIGN, SIZE, DURATION: This study is a secondary analysis of data collected from the baseline visit of the Women's Health Initiative (WHI). The WHI is a large prospective study of postmenopausal women, including both a randomized trial and observational study. There were 10 184 women included in this analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were collected from a reproductive health history questionnaire, dual-energy x-ray absorptiometry scans, and anthropometric measures at WHI baseline. Reproductive history was measured via self-report, and included age at menarche, variables related to pregnancy, and age at menopause. Reproductive lifespan was calculated as age at menopause minus age at menarche. Statistical analyses included descriptive analyses and multivariable linear regression models to examine the association between reproductive history with VAT, SAT, total body fat, and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: Women who reported early menarche (<10 years) or early menopause (<40 years) had the highest levels of VAT. Adjusted multivariable linear regression results demonstrate women who experienced menarche >15 years had 23 cm2 less VAT (95% CI: -31.4, -14.4) and 47 cm2 less SAT (95% CI: -61.8, -33.4) than women who experienced menarche at age 10 years or earlier. A similar pattern was observed for age at menopause: compared to women who experienced menopause <40 years, menopause at 50-55 years was associated with 19.3 cm2 (95% CI: -25.4, -13.3) less VAT and 27.4 cm2 (-29.6, 10.3) less SAT. High parity (>3 pregnancies) was also associated with VAT and SAT. For example, adjusted beta coefficients for VAT were 8.36 (4.33, 12.4) and 17.9 (12.6, 23.2) comparing three to four pregnancies with the referent, one to two pregnancies. LIMITATIONS, REASONS FOR CAUTION: The WHI reproductive health history questionnaire may be subject to poor recall owing to a long look-back window. Residual confounding may be present given lack of data on early life characteristics, such as maternal and pre-menarche characteristics. WIDER IMPLICATIONS OF THE FINDINGS: This study contributes to our understanding of reproductive lifespan, including menarche and menopause, as an important predictor of late-life adiposity in women. Reproductive health has also been recognized as a sentinel marker for chronic disease in late life. Given established links between adiposity and cardiometabolic outcomes, this research has implications for future research, clinical practice, and public health policy that makes use of reproductive health history as an opportunity for chronic disease prevention. STUDY FUNDING/COMPETING INTEREST(S): HRB and AOO are supported by the National Institute of Health National Institute of Aging (R01AG055018-04). JWB reports royalties from 'ACSM'S Body Composition Assessment Book' and consulting fees from the WHI. The remaining authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Omega-3 Polyunsaturated Fatty Acids are not associated with Peripheral Artery Disease in a Meta-Analysis from the Multi-Ethnic Study of Atherosclerosis and Atherosclerosis Risk in Communities Study Cohorts.

BACKGROUND: Research suggests omega-3 polyunsaturated fatty acids (PUFAs) exert favorable effects on several biological processes involved in the development and progression of atherosclerotic cardiovascular disease (ASCVD). However, studies examining the relationship between omega-3 PUFAs and peripheral artery disease (PAD) are scarce. OBJECTIVES: We evaluated the associations between omega-3 PUFAs and incident PAD in a meta-analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and Atherosclerosis Risk in Communities (ARIC) study cohorts. METHODS: Omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were measured at baseline for all MESA (n = 6495) and Minnesota ARIC participants (n = 3612). Incident clinical PAD events (MESA n = 106; ARIC n = 149) identified primarily through ICD discharge codes were assessed through follow-up of each cohort. Associations between omega-3 PUFAs (EPA, DHA, and EPA+DHA) and incident PAD were modeled in MESA and ARIC as quartiles and continuously using Cox proportional hazards regression, respectively. A fixed-effects meta-analysis was conducted to evaluate associations in the 2 cohorts combined. RESULTS: In the fully adjusted model, in 10,107 participants, no significant associations were observed between EPA, DHA, or EPA+DHA, and incident PAD modeled as quartiles or continuously for either MESA or ARIC cohorts separately or in the meta-analysis after a follow-up of approximately 15 y. CONCLUSION: This study is consistent with previous literature indicating that the beneficial effects of omega-3 PUFAs on the markers of ASCVD may not translate to a clinically meaningful decrease in PAD risk.

Risk of Adverse Cardiovascular Outcomes in Postmenopausal Women with Inflammatory Bowel Disease.

BACKGROUND: Individuals with inflammatory bowel disease (IBD) who lack traditional cardiovascular disease (CVD) risk factors, such as young females, are observed to experience adverse CVD outcomes. Whether women with IBD have increased CVD risk after the menopause transition is unclear. METHODS: We conducted a survival analysis of Women's Health Initiative (WHI) participants and excluded those with missing IBD diagnosis, model covariate data, follow-up data, or a baseline history of the following CVD outcomes: coronary heart disease (CHD), ischemic stroke, venous thromboembolism (VTE), peripheral arterial disease (PAD). Risk of outcomes between IBD and non-IBD women was performed using Cox proportional hazard models, stratified by WHI trial and follow-up. Models were adjusted for age, socio-demographics, comorbidities (e.g., hypertension, diabetes, hypercholesterolemia, etc.), family history, and lifestyle factors (e.g., smoking, alcohol, physical activity, body mass index, etc.). RESULTS: Of 134,022 WHI participants meeting inclusion criteria, 1367 (1.0%) reported IBD at baseline. Mean baseline age was 63.4 years. After adjusting for age and other confounders, no significant difference was observed between IBD and non-IBD women for the risk of CHD (HR 0.96, 95% CI 0.73-1.24), VTE (HR 1.11, 95% CI 0.81-1.52) or PAD (HR 0.64, 95% CI 0.28-1.42). After adjusting for age, risk of ischemic stroke was significantly higher (HR 1.41, 95% CI 1.06-1.88) in IBD than non-IBD women. With further adjustment, the excess risk of ischemic stroke among IBD women was attenuated and no longer statistically significant (HR 1.31, 95% CI 0.98-1.76). CONCLUSIONS: Among postmenopausal women with IBD, risk of ischemic stroke may be higher than in non-IBD women.

Association between Statin use and Incident Peripheral Artery Disease According to Race, Age, and Presence of Depression in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Peripheral artery disease (PAD) is associated with high morbidity and mortality and has been commonly described as a coronary heart disease equivalent. Statin medications are recommended for primary prevention of atherosclerotic cardiovascular disease (CVD) among other indications. Therefore, understanding the longitudinal relationship of incident PAD is necessary to inform future research on how to prevent the disease. Depression complicates CVD patients' ability to properly adhere to their medications, yet the effect of depression on the relationship between statin use and incident PAD is understudied. People with PAD have a higher incidence of depressive symptoms than people without PAD. Black American and Hispanic populations are disproportionately affected by both PAD and depression yet research on the modifying effect of either race or depression on the relationship between statin use and onset of PAD is minimal. While statin utilization is highest for ages 75-84 years, there is minimal evidence of favorable risk-benefit balance. Consequently, in this project, we examined the relationship between statin use and incident PAD and whether this relationship is modified by race/ethnicity, depressive symptoms, or age. METHODS: We used data on participants from the Multi-Ethnic Study of Atherosclerosis from visit 1 (2000) through study visit 6 (2020) who had three separate measurements of the ankle-brachial index (ABI) taken at visit 1, visit 3, and visit 5. Incident PAD was defined as 1) incident lower extremity amputation or revascularization or 2) ABI less than 0.90 coupled with ABI decrease greater than 0.15 over the follow-up period. Statin use was noted on the study visit prior to incident PAD diagnosis while depressive symptoms were measured at exam 1, visit 3, and visit 5. Propensity score matching was implemented to create balance between the participants in the two treatment groups, that is, statin-treated and statin-untreated groups, to reduce the problem of confounding by indication. Propensity scores were calculated using multivariate logistic regression model to estimate the probability of receiving statin treatment. We used Cox proportional hazards regression to investigate the relationship between time-dependent statin use as well as other risk factors with incident PAD, overall and stratified by 1) race, 2) depression status, and 3) age. RESULTS: A total of 4,210 participants were included in the final matched analytic cohort. There were 810 incident cases (19.3%) of PAD that occurred over an average (mean) of 11.3 years (SD = 5.7) of follow-up time. In the statin-treated group, and with an average follow-up time of 12.5 years (SD = 5.6), there were 281 cases (13.4%) of incident PAD with the average follow-up time of 10.1 years (SD = 5.5), whereas in the statin-untreated group, there were 531 cases (25.2%) (P < 0.001). Results demonstrate a lower risk of PAD event in the statin-treated group compared to the untreated group (hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.33-0.62) over the span of 18.5 years. The interactions between 1) depression and 2) race with statin use for incident PAD were not significant. However, other risk factors which were significant included Black American race that had approximately 30% lower hazard of PAD compared to non-Hispanic White (HR = 0.70, 95% CI: 0.58-0.84); age-stratified models were also fitted, and stain use was still a significant treatment factor for ages 45-54 (HR = 0.45, 95% CI: 0.33-0.63), 55-64 (HR = 0.61, 95% CI: 0.46-0.79), and 65-74 years (HR = 0.61, 95% CI: 0.48-0.78) but not for ages 75-84 years. CONCLUSIONS: Statin use was associated with a decreased risk of incident PAD for those under the age of 75 years. Neither race nor depression significantly modified the relationship between statin use and incident PAD; however, the risk of incident PAD was lower among Black Americans. These findings highlight that the benefit of statin may wane for those over the age of 75 years. Findings also suggest that statin use may not be compromised in those living with depression.

Arriba por la Vida Estudio: a randomized controlled trial promoting standing behavior to reduce sitting time among postmenopausal Latinas.

Postmenopausal Hispanic/Latina (N = 254) women with a body mass index (BMI) ≥ 25 kg/m2 were randomized to an intervention to reduce sitting time or a comparison condition for 12 weeks. The standing intervention group received three in-person health-counseling sessions, one home visit, and up to eight motivational interviewing calls. The heart healthy lifestyle comparison group (C) received an equal number of contact hours to discuss healthy aging. The primary outcome was 12-week change in sitting time measured via thigh-worn activPAL. Group differences in outcomes were analyzed using linear mixed-effects models. Participants had a mean age of 65 (6.5) years, preferred Spanish language (89%), BMI of 32.4 (4.8) kg/m2, and sat for an average of 540 (86) minutes/day. Significant between-group differences were observed in reductions of sitting time across the 12-week period [Mdifference (SE): C - 7.5 (9.1), SI - 71.0 (9.8), p < 0.01]. Results demonstrate that coaching models to reduce sitting are feasible and effective.

Loneliness, social isolation, and cardiovascular disease among nonveteran and veteran women.

We examined the prospective associations of social isolation and loneliness with incident cardiovascular disease (CVD) among aging nonveteran and veteran women, and effect modification by veteran status. Participants with no history of myocardial infarction (MI), stroke, coronary heart disease (CHD), or coronary heart failure from the Women's Health Initiative Extension Study II self-reported social isolation, loneliness, health behaviors, health status, and veteran status. CVD and CVD subevents were physician adjudicated. Hazard ratios (HR) and 95% confidence intervals (CI) for the Interquartile Range (IQR) in social isolation (IQR = 1) and loneliness (IQR=.33) were calculated using Cox proportional hazard models adjusting for sociodemographic, health behavior, and health status characteristics. Veteran status was tested as an effect modifier. Among 52,442 women (Mean age = 79 ± 6.1; veterans n = 1023; 89.2% non-Hispanic White), 3579 major CVD events occurred over an average 5.8 follow-up years. Compared to nonveterans, veteran women reported higher levels of social isolation (p < .01) and loneliness (p < .01). The CVD HR was 1.07 (95% CI, 1.04-1.10) for the IQR in social isolation and 1.03 (95% CI, 1.10-1.06) for the IQR in loneliness. The HR for the IQR in both social isolation and loneliness was 1.10 (95% CI, 1.05-1.15). Social isolation was associated with CHD (HR = 1.12; 95% CI, 1.03-1.21). The CHD HR for the IQR in social isolation was 1.12 (95% CI, 1.03-1.21). Associations did not differ by veteran status (all p-interactions > 0.08). Findings suggest that the adverse associations of social isolation and loneliness with CVD are similar among veteran and nonveteran women.

Genome-wide association study of body fat distribution traits in Hispanics/Latinos from the HCHS/SOL.

Central obesity is a leading health concern with a great burden carried by ethnic minority populations, especially Hispanics/Latinos. Genetic factors contribute to the obesity burden overall and to inter-population differences. We aimed to identify the loci associated with central adiposity measured as waist-to-hip ratio (WHR), waist circumference (WC) and hip circumference (HIP) adjusted for body mass index (adjBMI) by using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL); determine if differences in associations differ by background group within HCHS/SOL and determine whether previously reported associations generalize to HCHS/SOL. Our analyses included 7472 women and 5200 men of mainland (Mexican, Central and South American) and Caribbean (Puerto Rican, Cuban and Dominican) background residing in the USA. We performed genome-wide association analyses stratified and combined across sexes using linear mixed-model regression. We identified 16 variants for waist-to-hip ratio adjusted for body mass index (WHRadjBMI), 22 for waist circumference adjusted for body mass index (WCadjBMI) and 28 for hip circumference adjusted for body mass index (HIPadjBMI), which reached suggestive significance (P < 1 × 10-6). Many loci exhibited differences in strength of associations by ethnic background and sex. We brought a total of 66 variants forward for validation in cohorts (N = 34 161) with participants of Hispanic/Latino, African and European descent. We confirmed four novel loci (P < 0.05 and consistent direction of effect, and P < 5 × 10-8 after meta-analysis), including two for WHRadjBMI (rs13301996, rs79478137); one for WCadjBMI (rs3168072) and one for HIPadjBMI (rs28692724). Also, we generalized previously reported associations to HCHS/SOL, (8 for WHRadjBMI, 10 for WCadjBMI and 12 for HIPadjBMI). Our study highlights the importance of large-scale genomic studies in ancestrally diverse Hispanic/Latino populations for identifying and characterizing central obesity susceptibility that may be ancestry-specific.

Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction.

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.

The Association between Inflammation, Testosterone and SHBG in men: A cross-sectional Multi-Ethnic Study of Atherosclerosis.

CONTEXT: Earlier studies have investigated the role of obesity-related inflammation and endogenous sex hormones in men. The role of interleukin-6 (IL-6) and C-reactive protein (CRP) with testosterone and sex hormone binding globulin (SHBG) levels in men is still debated. OBJECTIVE: To investigate the independent association between levels of high sensitivity CRP (hsCRP) and IL-6 with endogenous sex hormones in men. DESIGN: Cross-sectional observational study using data from the Multi-Ethnic Study of Atherosclerosis. PATIENTS OR OTHER PARTICIPANTS: A community-based sample of 3212 men aged 45-84 years was included. After exclusions, 3041 men remained for the analyses. MAIN OUTCOME MEASURE(S): Serum concentrations of testosterone, SHBG, hsCRP, IL-6, and sTNFR were measured from the baseline exam. Multivariable linear regressions were used to examine the association of inflammatory markers with sex hormones. RESULTS: An inverse association was found between levels of hsCRP and levels of testosterone and SHBG, even after adjustment for confounders and IL-6 (Total Testosterone; B = -0.14, Bioavailable Testosterone; B = -0.06, and SHBG; B = -0.66). Similar results were found for IL-6, although a positive association was found for SHBG (B = 0.95). Notably, an inverse association was found for IL-6 with bioavailable testosterone in African Americans and Hispanic Americans aged 45-54 years. No associations were found for sTNFR and endogenous sex hormones. CONCLUSION: Our results indicate that inflammatory markers have independent associations with levels of testosterone (total and bioavailable) and furthermore, appear to associate differently with SHBG levels.

Associations between Metabolomic Biomarkers of Avocado Intake and Glycemia in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Avocado consumption is linked to better glucose homeostasis, but small associations suggest potential population heterogeneity. Metabolomic data capture the effects of food intake after digestion and metabolism, thus accounting for individual differences in these processes. OBJECTIVES: To identify metabolomic biomarkers of avocado intake and to examine their associations with glycemia. METHODS: Baseline data from 6224 multi-ethnic older adults (62% female) included self-reported avocado intake, fasting glucose and insulin, and untargeted plasma proton nuclear magnetic resonance metabolomic features (metabolomic data were available for a randomly selected subset; N = 3438). Subsequently, incident type 2 diabetes (T2D) was assessed over an ∼18 y follow-up period. A metabolome-wide association study of avocado consumption status (consumer compared with nonconsumer) was conducted, and the relationship of these features with glycemia via cross-sectional associations with fasting insulin and glucose and longitudinal associations with incident T2D was examined. RESULTS: Three highly-correlated spectral features were associated with avocado intake at metabolome-wide significance levels (P < 5.3 ∗ 10-7) and combined into a single biomarker. We did not find evidence that these features were additionally associated with overall dietary quality, nor with any of 47 other food groups (all P > 0.001), supporting their suitability as a biomarker of avocado intake. Avocado intake showed a modest association only with lower fasting insulin (ß = -0.07 +/- 0.03, P = 0.03), an association that was attenuated to nonsignificance when additionally controlling for body mass index (kg/m2). However, our biomarker of avocado intake was strongly associated with lower fasting glucose (ß = -0.22 +/- 0.02, P < 2.0 ∗ 10-16), lower fasting insulin (ß = -0.17 +/- 0.02, P < 2.0 ∗ 10-16), and a lower incidence of T2D (hazard ratio: 0.68; 0.63-074, P < 2.0 ∗ 10-16), even when adjusting for BMI. CONCLUSIONS: Highly significant associations between glycemia and avocado-related metabolomic features, which serve as biomarkers of the physiological impact of dietary intake after digestion and absorption, compared to modest relationships between glycemia and avocado consumption, highlights the importance of considering individual differences in metabolism when considering diet-health relationships.

Mean affect and affect variability may interact to predict inflammation.

INTRODUCTION: Individuals with greater affect variability (i.e., moment-to-moment fluctuations possibly reflecting emotional dysregulation) are at risk for greater systemic inflammation, which is associated with cardiovascular disease. Some evidence suggests that affect variability is linked with poorer health indicators only among those with higher average levels of affect, particularly for positive affect (PA), and that associations may be non-linear. The present study sought to examine whether links between both PA and negative affect (NA) variability and inflammation are moderated by average level of affect. METHODS: Participants (N = 300, 50 % female, ages 21-70, 60 % non-Hispanic White, 19 % Hispanic, 15 % non-Hispanic Black) completed a lab assessment and provided a blood sample to measure systemic inflammation (i.e., TNF-α, IL-6, CRP). Affect was collected via a two-day ecological momentary assessment protocol where reports were collected about every 45-min during waking hours. Momentary affect ratings were averaged across both days (i.e., iM), separately for PA and NA, for each participant. Affect variability was calculated as the person-specific SD (i.e., iSD) of affect reports, separately for PA and NA. Linear and quadratic interactions were tested. Models included covariates for sex, race, and body mass index. RESULTS: There were significant interactions between NA iM and NA iSD predicting TNF-α (b = 6.54; p < 0.05) and between PA iM and PA iSD predicting IL-6 (b = 0.45; p < 0.05). Specifically, the association between these affect variability indicators and inflammatory markers were suggestive of a positive association among those with higher average affect but a negative association among those with lower average affect. There was no evidence of non-linear associations between affect and inflammation. DISCUSSION: Incorporating interactive effects between affect variability and average affect may be an important consideration in understanding affective-inflammatory associations.

CT-derived pectoralis composition and incident pneumonia hospitalization using fully automated deep-learning algorithm: multi-ethnic study of atherosclerosis.

BACKGROUND: Pneumonia-related hospitalization may be associated with advanced skeletal muscle loss due to aging (i.e., sarcopenia) or chronic illnesses (i.e., cachexia). Early detection of muscle loss may now be feasible using deep-learning algorithms applied on conventional chest CT. OBJECTIVES: To implement a fully automated deep-learning algorithm for pectoralis muscle measures from conventional chest CT and investigate longitudinal associations between these measures and incident pneumonia hospitalization according to Chronic Obstructive Pulmonary Disease (COPD) status. MATERIALS AND METHODS: This analysis from the Multi-Ethnic Study of Atherosclerosis included participants with available chest CT examinations between 2010 and 2012. We implemented pectoralis muscle composition measures from a fully automated deep-learning algorithm (Mask R-CNN, built on the Faster Region Proposal Network (R-) Convolutional Neural Network (CNN) with an extension for mask identification) for two-dimensional segmentation. Associations between CT-derived measures and incident pneumonia hospitalizations were evaluated using Cox proportional hazards models adjusted for multiple confounders which include but are not limited to age, sex, race, smoking, BMI, physical activity, and forced-expiratory-volume-at-1 s-to-functional-vital-capacity ratio. Stratification analyses were conducted based on baseline COPD status. RESULTS: This study included 2595 participants (51% female; median age: 68 (IQR: 61, 76)) CT examinations for whom we implemented deep learning-derived measures for longitudinal analyses. Eighty-six incident pneumonia hospitalizations occurred during a median 6.67-year follow-up. Overall, pectoralis muscle composition measures did not predict incident pneumonia. However, in fully-adjusted models, only among participants with COPD (N = 507), CT measures like extramyocellular fat index (hazard ratio: 1.98, 95% CI: 1.22, 3.21, p value: 0.02), were independently associated with incident pneumonia. CONCLUSION: Reliable deep learning-derived pectoralis muscle measures could predict incident pneumonia hospitalization only among participants with known COPD. CLINICAL RELEVANCE STATEMENT: Pectoralis muscle measures obtainable at zero additional cost or radiation exposure from any chest CT may have independent predictive value for clinical outcomes in chronic obstructive pulmonary disease patients. KEY POINTS: •Identification of independent and modifiable risk factors of pneumonia can have important clinical impact on patients with chronic obstructive pulmonary disease. •Opportunistic CT measures of adipose tissue within pectoralis muscles using deep-learning algorithms can be quickly obtainable at zero additional cost or radiation exposure. •Deep learning-derived pectoralis muscle measurements of intermuscular fat and its subcomponents are independently associated with subsequent incident pneumonia hospitalization.

Rare and low-frequency coding variants alter human adult height.

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Association between urinary phthalate biomarker concentrations and adiposity among postmenopausal women.

BACKGROUND: Obesity is a leading risk factor for chronic diseases, potentially related to excess abdominal adiposity. Phthalates are environmental chemicals that have been suggested to act as obesogens, driving obesity risk. For the associations between phthalates and adiposity, prior studies have focused primarily on body mass index. We hypothesize that more refined measures of adiposity and fat distribution may provide greater insights into these associations given the role of central adiposity in chronic disease risk. OBJECTIVES: To evaluate associations between urinary phthalate biomarkers and both visceral and subcutaneous adipose tissue (VAT and SAT) among postmenopausal women enrolled in the Women's Health Initiative (WHI). METHODS: We included 1125 WHI participants with available, coincident measurements of urinary phthalate biomarkers (baseline, year 3) and VAT and SAT (baseline, year 3, year 6). VAT and SAT measurements were estimated from DXA scans. Multilevel mixed-effects models estimated the prospective associations between urinary phthalate biomarkers at baseline and VAT and SAT three years later. RESULTS: In multivariable adjusted models, we observed positive associations between some phthalate biomarkers, including the sum of di-isobutyl phthalate (ΣDiBP) biomarkers, MCNP, and ΣDEHP, with VAT three years later. For example, we observed positive associations between concentrations of ΣDiBP and VAT (Q4 vs Q1 ß = 7.15, 95% CI -1.76-16.06; Q3 vs Q1 ß = 10.94, 95% CI 3.55-18.33). Associations were generally attenuated but remained significant after additional adjustment for SAT. MBzP was positively associated with SAT. Other phthalate biomarkers investigated (MEP, MCOP, MCPP, ΣDBP) were not significantly associated with VAT or SAT. DISCUSSION: Based on robust measures of adiposity, this study provides supportive evidence that higher urinary concentrations of select phthalate compounds were associated with higher VAT levels over time in postmenopausal women. Efforts to replicate these findings are needed.