Genetic association studies and the effect of misclassification and selection bias in putative confounders

Genetic epidemiology studies often adjust for numerous potential confounders, yet the influences of confounder misclassification and selection bias are rarely considered. We used simulated data to evaluate the effect of confounder misclassification and selection bias in a case-control study of incident myocardial infarction. We show that putative confounders traditionally included in genetic association studies do not alter effect estimates, even when excessive levels of misclassification are incorporated. Conversely, selection bias resulting from covariates affected by the single-nucleotide polymorphism of interest can bias effect estimates upward or downward. These results support careful consideration of how well a study population represents the target population because selection bias may result even when associations are modest

Genetic association studies and the effect of misclassification and selection bias in putative confounders

Abstract Genetic epidemiology studies often adjust for numerous potential confounders, yet the influences of confounder misclassification and selection bias are rarely considered. We used simulated data to evaluate the effect of confounder misclassification and selection bias in a case-control study of incident myocardial infarction. We show that putative confounders traditionally included in genetic association studies do not alter effect estimates, even when excessive levels of misclassification are incorporated. Conversely, selection bias resulting from covariates affected by the single-nucleotide polymorphism of interest can bias effect estimates upward or downward. These results support careful consideration of how well a study population represents the target population because selection bias may result even when associations are modest

METABOLIC SYNDROME IN HEALTHY OBESE, OVERWEIGHT AND NORMAL WEIGHT INDIVIDUALS: THE ATHEROSCLEROSIS RISK IN COMMUNITIES STUDY

There is recent interest in characterizing the subset of obese individuals who have healthy metabolic profiles yet only two studies have examined this group prospectively but not in racially diverse populations. We analyzed factors associated with the prevalence and incidence of metabolic syndrome (MetSyn) among individuals grouped by body mass index (BMI) categories in a multi-center, community-based cohort of 14,663 African-American and white men and women aged 45-64 years at recruitment in 1987-1989, the Atherosclerosis Risk in Communities study. Logistic and proportional hazards regression were utilized to estimate odds ratios (OR) for the prevalence and hazard ratios (HR) for incidence of MetSyn with 95% confidence intervals (CI). At visit 1, MetSyn was positively associated with age, female gender, African-American race, and inversely related to education, associations being more pronounced among normal weight (NW) subjects. Among those without MetSyn at visit 1, obese (OB) subjects were more likely to develop MetSyn compared with NW [HR (95% CI): 4.53 (4.09-5.01)]. Several factors were associated with incident MetSyn among NW, including older age [per year: 1.05 (1.03-1.06)], female gender [vs. male: 1.29 (1.10-1.52)], heavy alcohol intake [vs. never: 0.75 (0.59-0.94)] and physical activity [tertile 3 vs. tertile 1: 0.71 (0.58-0.86)] but not OB. Weight gain (>5%) was also more highly associated with MetSyn in NW [1.61 (1.28-2.02)] compared with OB [1.01 (0.85-1.20)]. We conclude that lifestyle factors may play a stronger role in development of MetSyn in NW individuals compared with OB and that metabolically healthy obesity may not be a stable condition

China's transition: The effect of rapid urbanization on adult occupational physical activity

China has recently undergone rapid social and economic change. Increases in urbanization have led to equally rapid shifts toward more sedentary occupations through the acquisition of new technology and transitions away from a mostly agricultural economy. Our purpose was to utilize a detailed measure of urbanicity comprising 10 dimensions of urban services and infrastructure to examine its effects on the occupational physical activity patterns of Chinese adults. Longitudinal data were from individuals aged 18-55 from the years 1991-1997 of the China Health and Nutrition Survey (N = 4376 men and 4384 women). Logistic multilevel regression analyses indicated that men had 68% greater odds, and women had 51% greater odds, of light versus heavy occupational activity given the mean change in urbanization over the 6-year period. Further, simulations showed that light occupational activity increased linearly with increasing urbanization. After controlling for individual-level predictors, community-level urbanization explained 54% and 40% of the variance in occupational activity for men and women, respectively. This study provides empirical evidence of the reduction in intensity of occupational activity with modernization. It is likely that urbanization will continue unabated in China and this is liable to lead to further transitions in the labor market resulting in additional reductions in work-related activity. Because occupational activity remains the major source of energy expenditure for adults, unless alternative forms are widely adopted, the Chinese population is at risk of dramatic increases in the numbers of overweight and obese individuals

Role of BMI in the Association of the TCF7L2 rs7903146 Variant with Coronary Heart Disease: The Atherosclerosis Risk in Communities (ARIC) Study

We examined the association of variation in the type 2 diabetes risk-conferring TCF7L2 gene with the risk of incident coronary heart disease (CHD) among the lean, overweight, and obese members of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Cox proportional hazard regression analyses were performed using a general model, with the major homozygote as the reference category. For 9,865 whites, a significant increase in the risk of CHD was seen only among lean ( BMI < 25 kg/m2) individuals homozygous for the T allele of the TCF7L2 rs7903146 gene risk variant (hazard ratio 1.42; 95% CI 1.03,1.97; P = .01). No association was found among 3,631 blacks, regardless of BMI status. An attenuated hazard ratio was observed among the nondiabetic ARIC cohort members. This study suggests that body mass modifies the association of the TCF7L2 rs7903146 T allele with CHD risk

Interaction of FTO and Physical Activity Level on Adiposity in African-American and European-American Adults: The ARIC Study

Physical inactivity accentuates the association of variants in the FTO locus with obesity-related traits but evidence is largely lacking in non-European populations

Impact of long-term measures of glucose and blood pressure on the retinal microvasculature

Retinopathy and retinal microvascular abnormalities are common in adult populations, yet few long-term predictors have been identified. We therefore examined the association between systolic blood pressure (SBP) and fasting plasma glucose, assessed over 18 years, with retinopathy and retinal vascular caliber in 2,066 Carotid MRI participants, an Atherosclerosis Risk in Communities ancillary study

Association of the platelet GPIIb/IIIa polymorphism with atherosclerotic plaque morphology. The Atherosclerosis Risk in Communities (ARIC) Study

Platelet activation and aggregation play an important role in the pathogenesis of cardiovascular disease. We examined the association of a single nucleotide polymorphism (SNP) in the GPIIIa platelet glycoprotein (Leu33Pro) with carotid artery plaque morphology and with expression of platelet markers using data from the Atherosclerosis Risk in Communities (ARIC) Carotid MRI study

Fat mass and obesity gene and cognitive decline: The Atherosclerosis Risk in Communities Study

ABSTRACT Objective: To determine whether 4 genetic variants in the fat mass and obesity associated gene (FTO) identified in genome-wide association studies of diabetes and obesity are associated with cognitive change in midlife in the Atherosclerosis Risk in Communities (ARIC) Study.Methods: ARIC is a prospective cohort study of the development of atherosclerosis in 15,792 individuals aged 45 to 64 years at baseline from 1986 to 1989. FTO is highly expressed in human fetal and adult brain, and a single nucleotide polymorphism in FTO has previously been associated with reduced brain volume in cognitively normal subjects. Since a relationship between brain atrophy and diminished cognitive function has been demonstrated in ARIC participants, general linear models were used to evaluate the association between 6-year change in scores on 3 neuropsychological tests and FTO genotype.Results: In a sample of 8,364 white and 2,083 African American men and women with no clinical history of stroke, significantly greater mean change in performance on the Delayed Word Recall Test was associated with 2 of 4 FTO single nucleotide polymorphisms examined (rs9939609, rs805136, rs17817449, and rs1421085) in whites but not in African Americans (p ≤ 0.002). The association of the FTO polymorphisms with cognitive change was independent of potential confounding clinical and demographic variables including age, gender, education, diabetes, hypertension, and body mass index.Conclusions: Further studies will be needed to clarify the biological mechanisms and genetic pathways through which variants in FTO can increase susceptibility to decline in verbal memory detectable in middle-aged, community-dwelling adults

Role of BMI in the Association of the TCF7L2 rs7903146 Variant with Coronary Heart Disease: The Atherosclerosis Risk in Communities (ARIC) Study

We examined the association of variation in the type 2 diabetes risk-conferring TCF7L2 gene with the risk of incident coronary heart disease (CHD) among the lean, overweight, and obese members of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Cox proportional hazard regression analyses were performed using a general model, with the major homozygote as the reference category. For 9,865 whites, a significant increase in the risk of CHD was seen only among lean (BMI &lt; 25 kg/m 2 ) individuals homozygous for the T allele of the TCF7L2 rs7903146 gene risk variant (hazard ratio 1.42; 95% CI 1.03,1.97; P = .01). No association was found among 3,631 blacks, regardless of BMI status. An attenuated hazard ratio was observed among the nondiabetic ARIC cohort members. This study suggests that body mass modifies the association of the TCF7L2 rs7903146 T allele with CHD risk