Objective:
Several genome–wide association studies (GWAS) have demonstrated that common genetic variants contribute to obesity. However, studies of this complex trait have focused on ancestrally ...European populations, despite the high prevalence of obesity in some minority groups.
Design and Methods:
As part of the “Population Architecture using Genomics and Epidemiology (PAGE)” Consortium, we investigated the association between 13 GWAS‐identified single‐nucleotide polymorphisms (SNPs) and BMI and obesity in 69,775 subjects, including 6,149 American Indians, 15,415 African‐Americans, 2,438 East Asians, 7,346 Hispanics, 604 Pacific Islanders, and 37,823 European Americans. For the BMI‐increasing allele of each SNP, we calculated β coefficients using linear regression (for BMI) and risk estimates using logistic regression (for obesity defined as BMI ≥ 30) followed by fixed‐effects meta‐analysis to combine results across PAGE sites. Analyses stratified by racial/ethnic group assumed an additive genetic model and were adjusted for age, sex, and current smoking. We defined “replicating SNPs” (in European Americans) and “generalizing SNPs” (in other racial/ethnic groups) as those associated with an allele frequency‐specific increase in BMI.
Results:
By this definition, we replicated 9/13 SNP associations (5 out of 8 loci) in European Americans. We also generalized 8/13 SNP associations (5/8 loci) in East Asians, 7/13 (5/8 loci) in African Americans, 6/13 (4/8 loci) in Hispanics, 5/8 in Pacific Islanders (5/8 loci), and 5/9 (4/8 loci) in American Indians.
Conclusion:
Linkage disequilibrium patterns suggest that tagSNPs selected for European Americans may not adequately tag causal variants in other ancestry groups. Accordingly, fine‐mapping in large samples is needed to comprehensively explore these loci in diverse populations.
Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk ...variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio OR >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (Pheterogeneity < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.
It is common in longitudinal studies for scheduled visits to be accompanied by as-needed visits due to medical events occurring between scheduled visits. If the timing of these as-needed visits is ...related to factors that are associated with the outcome but are not among the regression model covariates, naively including these as-needed visits in the model yields biased estimates. In this paper, the authors illustrate and discuss the key issues pertaining to inverse intensity rate ratio (IIRR)-weighted generalized estimating equations (GEE) methods in the context of a study of Kenyan mothers infected with human immunodeficiency virus type 1 (1999–2005). The authors estimated prevalences and prevalence ratios for morbid conditions affecting the women during a 1-year postpartum follow-up period. Of the 484 women under study, 62% had at least 1 as-needed visit. Use of a standard GEE model including both scheduled and unscheduled visits predicted a pneumonia prevalence of 2.9% (95% confidence interval: 2.3%, 3.5%), while use of the IIRR-weighted GEE predicted a prevalence of 1.5% (95% confidence interval: 1.2%, 1.8%). The estimate obtained using the IIRR-weighted GEE approach was compatible with estimates derived using scheduled visits only. These results highlight the importance of properly accounting for informative follow-up in these studies.
Context:
Microvascular disease is a leading cause of cognitive impairment. Approximately 50% of people with a hip fracture have cognitive impairment.
Objective:
We tested the hypothesis that ...microvascular diseases of the brain (lacunar infarcts and white matter disease WMD), kidney (albuminuria ≥ 30 mg/g creatinine and albumin creatinine ratio ACR), and eye (retinal vascular disorders) attenuate the association of cognitive impairment with hip fracture risk.
Setting:
The Cardiovascular Health Cognition Study.
Patients:
Three thousand, one-hundred six participants (mean age, ∼79 y; 8.84 y median follow-up) with cognitive testing. Subsets received ACR testing (n=2389), brain magnetic resonance imaging scans (n = 2094), and retinal photography (n = 1098).
Main Outcome Measure:
Incident hip fracture.
Results:
There were 488 participants (16%) with mild cognitive impairment (MCI) and 564 (18%) with dementia. There were 337 incident hip fractures, of which 19% occurred in participants with MCI and 26% in participants with dementia. Adjusted hazard ratios (HR) and 95% confidence interval for hip fracture in participants with MCI were 2.45 (1.67–3.61) and for dementia 2.35 (1.57–3.52). With doubling of ACR, the HR for fracture was attenuated in participants with dementia compared with participants with normal cognition interaction HR 0.70 (0.55–0.91). No such effect was found in participants with MCI. Albuminuria, lacunar infarcts, WMD, and retinal vascular disease (RVD) did not modify the association of dementia or MCI with hip fracture risk.
Conclusions:
ACR attenuates part of the risk of hip fracture in people with dementia, suggesting that these disorders share a common pathogenesis.
Cox regression is widely used to analyze discrete survival time data. Differential endpoint follow-up across sub-cohorts where distribution of a covariate varies may cause typical estimators to be ...biased or inefficient. We demonstrate that with Cardiovascular Health Study data for incident type 2 diabetes. Two cohorts with extremely different race distribution have differential follow-up for fasting glucose levels. We study various scenarios of Cox regression. We suggest an alternative approach, Poisson generalized estimating equations with an offset to accommodate the differential follow-up. We use simulations to contrast the methods.
In 5187 persons from the Cardiovascular Health Study, there was no significant association of dietary intakes of aromatic amino acids (AAA) with areal BMD of the hip or body composition. However, ...those who had the lowest dietary intakes of AAA were at increased risk for incident hip fractures. Prior studies of the association of protein intake with osteoporosis are conflicting and have not directly examined the relationship of aromatic amino acids (AAA) with fractures, areal bone mineral density (aBMD), and body composition. We sought to determine the relationship of dietary intakes of AAA with osteoporosis parameters in elderly men and women. 5187 men and women aged ≥ 65 years from the Cardiovascular Health Study (CHS) with dietary intakes of AAA (tryptophan, phenylalanine, tyrosine) estimated by food frequency questionnaire (FFQ) were included. We examined the relationship between a one-time estimate of daily dietary AAA intake with risk of incident hip fractures over a median of 13.2 years of fracture follow-up. A subset (
n
= 1336) who had dual energy X-ray absorptiometry (DXA) performed were included in a cross-sectional analysis of the association of dietary AAA intake with aBMD of the total hip and measurements of body composition. In multivariable models adjusted for demographic and clinical variables, medication use, and diet, higher dietary AAA intake was not significantly associated with incident hip fractures. All hazard ratios (HR) were less than one (tryptophan, HR 0.14, 95% CI 0.01 to 1.89; phenylalanine, HR 0.60, 95% CI 0.23 to 1.55; tyrosine, HR 0.59, 95% CI 0.27 to 1.32), but confidence intervals were wide and included no difference. However, in post hoc analyses, the lowest quartile of intake for each AAA was associated with an increased risk for hip fracture compared to higher quartiles (
p
≤ 0.047 for all). Dietary AAA intakes were not significantly associated with total hip aBMD or any measurements of body composition. Overall, there was no significant association of dietary AAA intake with hip fractures, aBMD of the hip, or body composition. However, there may be a subset of elderly individuals with low dietary intakes of AAA who are at increased for hip fractures.
Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. ...The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts.
The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 × 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 × 10(-6)), MTHFD1L (rs6922269, P=5.1 × 10(-10)), APOE (rs429358; P=2.7×10(-18)), ZNF627 (rs4804611; P=5.0 × 10(-8)), CXCL12 (rs501120; P=1.4 × 10(-6)) and LPL (rs268; P=2.7 × 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities.
Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.
Substantial progress has been made in identifying susceptibility variants for AMD in European populations; however, few studies have been conducted to understand the role these variants play in AMD ...risk in diverse populations. The present study aims to examine AMD risk across diverse populations in known and suspected AMD complement factor and lipid-related loci.
Targeted genotyping was performed across study sites for AMD and lipid trait-associated single nucleotide polymorphism (SNPs). Genetic association tests were performed at individual sites and then meta-analyzed using logistic regression assuming an additive genetic model stratified by self-described race/ethnicity. Participants included cases with early or late AMD and controls with no signs of AMD as determined by fundus photography. Populations included in this study were European Americans, African Americans, Mexican Americans, and Singaporeans from the Population Architecture using Genomics and Epidemiology (PAGE) study.
Index variants of AMD, rs1061170 (CFH) and rs10490924 (ARMS2), were associated with AMD at P=3.05×10(-8) and P=6.36×10(-6), respectively, in European Americans. In general, none of the major AMD index variants generalized to our non-European populations with the exception of rs10490924 in Mexican Americans at an uncorrected P value<0.05. Four lipid-associated SNPS (LPL rs328, TRIB1 rs6987702, CETP rs1800775, and KCTD10/MVK rs2338104) were associated with AMD in African Americans and Mexican Americans (P<0.05), but these associations did not survive strict corrections for multiple testing.
While most associations did not generalize in the non-European populations, variants within lipid-related genes were found to be associated with AMD. This study highlights the need for larger well-powered studies in non-European populations.
Background
Decline in serum androgens is common among older men and has been associated with cardiovascular disease, although its role in risk of atrial fibrillation (AF) has not been well defined.
...Hypothesis
Low serum androgens are associated with an increased risk of AF.
Methods
We examined the prospective associations between testosterone, its more active metabolite dihydrotestosterone (DHT), and sex hormone–binding globulin (SHBG) with risk of AF among 1019 otherwise healthy men with average age 76.3 ±4.9 years in the Cardiovascular Health Study.
Results
After median follow‐up of 9.5 years, 304 (30%) men developed AF. We detected a nonlinear association with risk of incident AF in both free and total DHT, in which subjects with the lowest levels had a higher risk of incident AF. After adjustment for demographics, clinical risk factors, left atrial diameter, and serum NT‐proBNP levels, men with free DHT <0.16 ng/dL were at increased risk compared with men with higher levels (hazard ratio: 1.48, 95% confidence interval: 1.01–2.17, P <0.05). Sensitivity analyses confirmed that the increased risk was not cutpoint‐specific, with a significant association noted up to cutpoints <~0.2 ng/dL. We also detected a complex nonlinear association between SHBG and incident AF, in which subjects in the middle quintile (52.9–65.3 nmol/L) had increased risk.
Conclusions
Among older men, low free DHT is associated with an increased risk of incident AF. Further studies are needed to explore mechanisms for this association.
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