The Genetics of Obesity in Transition

Recent advances in human genetics have revealed a number of genes influencing the susceptibility to obesity and related conditions, but it is likely that their contribution to disease is contingent on numerous environmental factors. As the obesity epidemic has occurred over a relatively short period of recent history, use of gene-by-year of birth analysis may be a useful approach for quantifying, in aggregate, the interaction between genetic susceptibility to obesity and the numerous known and unknown environmental factors that have changed during nutrition and health transitions globally during this recent increase in obesity rates. Evidence from one family-based longitudinal study set in the United States is showcased, which points to significant increases in the effect of common genetic variants on childhood and adulthood BMI over an 80 year period spanning from 1929 to the present. First, common genetic variants previously known to be associated with age at menarche through genome-wide association analysis were examined in aggregate using a genetic risk score approach. The menarche genetic risk score, composed of 42 single-nucleotide polymorphisms (SNPs) was significantly associated with peri-pubertal BMI in both boys and girls, but themagnitude of the association was strongly dependent on year of birth, with greater effect as birth year increased. Second, a similar approach was taken using instead a BMI genetic risk score composed of 32 common variants previously found to be associated with BMI. This score was strongly associated with adulthood BMI, waist circumference, and skinfold thickness, as expected, but the magnitude of the association increased with later year of birth. Such gene environment interactions call for greater focus on the mechanisms by which environmental factors impact the functional output of the human genome, including how epigenetic mechanisms may be altered during social, technological, nutritional, and ecological transitions

The Genetics of Obesity in Transition

Recent advances in human genetics have revealed a number of genes influencing the susceptibility to obesity and related conditions, but it is likely that their contribution to disease is contingent on numerous environmental factors. As the obesity epidemic has occurred over a relatively short period of recent history, use of gene-by-year of birth analysis may be a useful approach for quantifying, in aggregate, the interaction between genetic susceptibility to obesity and the numerous known and unknown environmental factors that have changed during nutrition and health transitions globally during this recent increase in obesity rates. Evidence from one family-based longitudinal study set in the United States is showcased, which points to significant increases in the effect of common genetic variants on childhood and adulthood BMI over an 80 year period spanning from 1929 to the present. First, common genetic variants previously known to be associated with age at menarche through genome-wide association analysis were examined in aggregate using a genetic risk score approach. The menarche genetic risk score, composed of 42 single-nucleotide polymorphisms (SNPs) was significantly associated with peri-pubertal BMI in both boys and girls, but themagnitude of the association was strongly dependent on year of birth, with greater effect as birth year increased. Second, a similar approach was taken using instead a BMI genetic risk score composed of 32 common variants previously found to be associated with BMI. This score was strongly associated with adulthood BMI, waist circumference, and skinfold thickness, as expected, but the magnitude of the association increased with later year of birth. Such gene environment interactions call for greater focus on the mechanisms by which environmental factors impact the functional output of the human genome, including how epigenetic mechanisms may be altered during social, technological, nutritional, and ecological transitions

High-fructose corn-syrup-sweetened beverage intake increases 5-hour breast milk fructose concentrations in lactating women

This study determined the effects of consuming a high-fructose corn syrup (HFCS)-sweetened beverage on breast milk fructose, glucose, and lactose concentrations in lactating women. At six weeks postpartum, lactating mothers (n = 41) were randomized to a crossover study to consume a commercially available HFCS-sweetened beverage or artificially sweetened control beverage. At each session, mothers pumped a complete breast milk expression every hour for six consecutive hours. The baseline fasting concentrations of breast milk fructose, glucose, and lactose were 5.0 ± 1.3 µg/mL, 0.6 ± 0.3 mg/mL, and 6.8 ± 1.6 g/dL, respectively. The changes over time in breast milk sugars were significant only for fructose (treatment × time, p < 0.01). Post hoc comparisons showed the HFCS-sweetened beverage vs. control beverage increased breast milk fructose at 120 min (8.8 ± 2.1 vs. 5.3 ± 1.9 µg/mL), 180 min (9.4 ± 1.9 vs. 5.2 ± 2.2 µg/mL), 240 min (7.8 ± 1.7 vs. 5.1 ± 1.9 µg/mL), and 300 min (6.9 ± 1.4 vs. 4.9 ± 1.9 µg/mL) (all p < 0.05). The mean incremental area under the curve for breast milk fructose was also different between treatments (14.7 ± 1.2 vs. −2.60 ± 1.2 µg/mL × 360 min, p < 0.01). There was no treatment × time interaction for breast milk glucose or lactose. Our data suggest that the consumption of an HFCS-sweetened beverage increased breast milk fructose concentrations, which remained elevated up to five hours post-consumption

Association of Age at Menopause With Incident Heart Failure: A Prospective Cohort Study and Meta‐Analysis

BACKGROUND: Early age (<45 years) at menopause has been postulated to be associated with increased cardiovascular disease risk; however, evidence of its relation with heart failure (HF) incidence is limited. We examined whether age at menopause is associated inversely with HF incidence in the Atherosclerosis Risk In Communities (ARIC) study and summarized all existing data in a meta-analysis. METHODS AND RESULTS: In ARIC, data were obtained from 5629 postmenopausal women (mean age 56 years, 26% with bilateral oophorectomy) without HF. During a median follow-up of 21.4 years, 965 incident HF events occurred. In a Cox regression model adjusted for reproductive health and HF risk factors, the hazard ratios for incident HF across categories of age at menopause (<45, 45-49, 50-54, and ≥55 years) were 1.32, 1.17, 1.00 (referent), and 1.12, respectively. Compared with women with later onset of menopause (aged ≥45 years), those with early menopause had elevated HF risk (hazard ratio 1.20, 95% CI 1.01-1.43). For the meta-analysis, we searched Medline and Embase for articles published through December 2015 that prospectively evaluated age at menopause and HF risk. Summarized estimates from the 3 included studies (3568 events) showed higher HF risk among women with early menopause compared with those with later menopause (hazard ratio 1.33, 95% CI 1.15-1.53). CONCLUSIONS: These results provided evidence that early age at menopause is associated with a modestly greater risk of HF. Identification of women with early menopause offers a window of opportunity to implement interventions that will improve overall cardiovascular health during the postmenopausal years

Sequence variation in telomerase reverse transcriptase (TERT) as a determinant of risk of cardiovascular disease: the Atherosclerosis Risk in Communities (ARIC) study

Abstract Background Telomerase reverse transcriptase (TERT) maintains telomere ends during DNA replication by catalyzing the addition of short telomere repeats. The expression of telomerase is normally repressed in somatic cells leading to a gradual shortening of telomeres and cellular senescence with aging. Interindividual variation in leukocyte telomere length has been previously associated with susceptibility to cardiovascular disease. The aim of the present study was to determine whether six variants in the TERT gene are associated with risk of incident coronary heart disease, incident ischemic stroke, and mortality in participants in the biracial population-based Atherosclerosis Risk in Communities (ARIC) study, including rs2736100 that was found to influence mean telomere length in a genome-wide analysis. Methods ARIC is a prospective study of the etiology and natural history of atherosclerosis in 15,792 individuals aged 45 to 64 years at baseline in 1987–1989. Haplotype tagging SNPs in TERT were genotyped using a custom array containing nearly 49,000 SNPs in 2,100 genes associated with cardiovascular and metabolic phenotypes. Cox proportional hazards models were used to assess the association between the TERT polymorphisms and incident cardiovascular disease and mortality over a 20-year follow-up period in 8,907 whites and 3,022 African-Americans with no history of disease at the baseline examination, while individuals with prevalent cardiovascular disease were not excluded from the analyses of mortality. Results After adjustment for age and gender, and assuming an additive genetic model, rs2736122 and rs2853668 were nominally associated with incident coronary heart disease (hazards rate ratio = 1.20, p = 0.02, 95 % confidence interval = 1.03– 1.40) and stroke (hazards rate ratio = 1.17, p = 0.05, 95 % confidence interval = 1.00 - 1.38), respectively, in African-Americans. None of the variants was significantly associated with cardiovascular disease in white study participants or with mortality in either racial group. Conclusions Replication in additional population-based samples combined with genotyping of polymorphisms in other genes involved in maintenance of telomere length may help to determine whether genetic variants associated with telomere homeostasis influence the risk of cardiovascular disease in middle-aged adults

The positive association of infant weight gain with adulthood body mass index has strengthened over time in the Fels Longitudinal Study

Background Infant weight gain is positively related to adulthood body mass index (BMI), but it is unknown whether or not this association is stronger for individuals born during (compared to before) the obesity epidemic. Objectives To examine how the infant weight gain–adulthood BMI association might have changed across successive birth year cohorts spanning most of the 20th century. Methods The sample comprised 346 participants in the Fels Longitudinal Study. Confounder-adjusted regression models were used to test the associations of conditional weight-for-length Z-score (WLZ), capturing weight change between ages 0-2 years, with young adulthood BMI and blood pressure, including cohort (1933-1949 (N=137), 1950-1969 (N=108), 1970-1997 (N=101)) as an effect modifier. Results Conditional WLZ was positively related to adulthood BMI, but there was significant effect modification by birth year cohort such that the association was over two times stronger in the 1970-1997 cohort (β 2.31; 95% confidence interval 1.59, 3.03) compared to the 1933-1949 (0.98; 0.31, 1.65) and 1950-1969 (0.87; 0.21, 1.54) cohorts. A similar pattern was found for systolic blood pressure. Conclusions The infant weight gain–adulthood BMI association was over two times stronger among a cohort born during the obesity epidemic era compared to cohorts born earlier in the 20th century

The Importance of Mid-to-Late-Life Body Mass Index Trajectories on Late-Life Gait Speed

Background: Prior studies suggest being overweight may be protective against poor functional outcomes in older adults. Methods: Body mass index (BMI, kg/m2) was measured over 25 years across five visits (1987-2011) among Atherosclerosis Risk in Communities Study participants (baseline Visit 1 n = 15,720, aged 45-64 years). Gait speed was measured at Visit 5 ("late-life", aged ≥65 years, n = 6,229). BMI trajectories were examined using clinical cutpoints and continuous mixed models to estimate effects of patterns of BMI change on gait speed, adjusting for demographics and comorbidities. Results: Mid-life BMI (baseline visit; 55% women; 27% black) was associated with late-life gait speed 25 years later; gait speeds were 94.3, 89.6, and 82.1 cm/s for participants with baseline normal BMI (<25), overweight (25 ≤ BMI < 30), and obese (BMI ≥ 30) (p < .001). In longitudinal analyses, late-life gait speeds were 96.9, 88.8, and 81.3 cm/s for participants who maintained normal, overweight, and obese weight status, respectively, across 25 years (p < .01). Increasing BMI over 25 years was associated with poorer late-life gait speeds; a 1%/year BMI increase for a participant with a baseline BMI of 22.5 (final BMI 28.5) was associated with a 4.6-cm/s (95% confidence interval: -7.0, -1.8) slower late-life gait speed than a participant who maintained a baseline BMI of 22.5. Conclusion: Being overweight in older age was not protective of mobility function. Maintaining a normal BMI in mid- and late-life may help preserve late-life mobility

Mediterranean Diet in Pregnancy and its Association with Newborns` Body Size in Dalmatia, Croatia – The Preliminary Results of the Croatian Islands Birth Cohort Study

A pregnant woman’s nutrition has an impact on her offspring’s birth size. Although health benefits of Mediterranean diet are widely confirmed, the poor compliance with its recommendations has been detected in the population of Dalmatia, coastal region of Croatia. Data from 122 mother–newborn pairs, participants in the ongoing Croatian Islands` Birth Cohort Study (CRIBS), were analyzed: (1) to test whether pregnant women in the study consume Mediterranean diet that is traditional in this area, and (2) to examine the association of maternal diet in pregnancy with newborns` birth weight, length and head circumference. The preliminary results of the factor analysis of 20 items from Food Frequency Questionnaire (FFQ) resulted in two significant factors, both having positive loading with the components of Mediterranean diet. Factor 1 had highest positive loadings for blue fish, white fish, olive oil and fatty cheese consumption consistent with the Mediterranean diet and Factor 2 had highest loading coefficients for fermented milk products (yogurt), sea food, cereals and legumes. Linear regression analyses resulted in model for weight at birth (R2=0.071, p<0.05) which included as predictors living location (island or mainland) and FFQ Factor 2, which was also, in combination with moderate physical activity, predictive for newborns with z-scored weight at birth values above 15% of the lowest values in the logistic regression model. Pregnant women from the CRIBS study mostly follow Mediterranean diet but its association with weight at birth, although found in this research, has to be confirmed on a bigger sample

Evaluation of microarray-based DNA methylation measurement using technical replicates: the Atherosclerosis Risk In Communities (ARIC) Study

Background: DNA methylation is a widely studied epigenetic phenomenon; alterations in methylation patterns influence human phenotypes and risk of disease. As part of the Atherosclerosis Risk in Communities (ARIC) study, the Illumina Infinium HumanMethylation450 (HM450) BeadChip was used to measure DNA methylation in peripheral blood obtained from ~3000 African American study participants. Over 480,000 cytosine-guanine (CpG) dinucleotide sites were surveyed on the HM450 BeadChip. To evaluate the impact of technical variation, 265 technical replicates from 130 participants were included in the study. Results: For each CpG site, we calculated the intraclass correlation coefficient (ICC) to compare variation of methylation levels within- and between-replicate pairs, ranging between 0 and 1. We modeled the distribution of ICC as a mixture of censored or truncated normal and normal distributions using an EM algorithm. The CpG sites were clustered into low- and high-reliability groups, according to the calculated posterior probabilities. We also demonstrated the performance of this clustering when applied to a study of association between methylation levels and smoking status of individuals. For the CpG sites showing genome-wide significant association with smoking status, most (~96%) were seen from sites in the high reliability cluster. Conclusions: We suggest that CpG sites with low ICC may be excluded from subsequent association analyses, or extra caution needs to be taken for associations at such sites

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