Shengxu Li

Genetic variation in LIN28B is associated with the timing of puberty

The timing of puberty is highly variable. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 × 10−8). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08–0.16; P = 2.8 × 10−10; combined P = 3.6 × 10−16). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 × 10−7; N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing, as the first genetic determinant regulating the timing of human pubertal growth and development.

Childhood Blood Pressure as a Predictor of Arterial Stiffness in Young Adults: The Bogalusa Heart Study

Abstract—Increased arterial stiffness is an independent predictor of cardiovascular disease and mortality in middle-aged and older adults. However, limited data are available regarding the relationship of arterial stiffness in young adults with risk factors measured in childhood, adulthood, or as a cumulative burden from childhood to adulthood. This aspect was examined in a sample of 835 black and white young adults (72% whites, 44% men) aged 24 to 44 years who had at least 4 measurements of traditional risk factors over an average follow-up period of 26.5 years since childhood. Brachial-ankle pulse wave velocity (baPWV) measured by a simple automatic oscillometric technique was used as an index of arterial stiffness. The cumulative burden of risk factors since childhood was measured as area under the curve divided by follow-up years. In young adults, the baPWV was higher in males versus females (P <0.001) and blacks versus whites (P <0.001). In multiple regression analyses, independent predictors of baPWV in young adults were systolic blood pressure in childhood; systolic blood pressure, high-density lipoprotein cholesterol, triglycerides, and smoking in adulthood; and cumulative burden of systolic blood pressure and triglycerides and duration of smoking years from childhood. Thus, systolic blood pressure beginning in childhood is a consistent predictor of arterial stiffness in free-living, asymptomatic young adults. These findings underscore the importance of childhood blood pressure in the evolution of arterial stiffness and the need for beginning preventive cardiology early in life.

Physical activity attenuates the genetic predisposition to obesity in 20,000 men and women from EPIC-Norfolk prospective population study.

Shengxu Li and colleagues use data from a large prospective observational cohort to examine the extent to which a genetic predisposition toward obesity may be modified by living a physically active lifestyle.

Childhood Adiposity as a Predictor of Cardiac Mass in Adulthood The Bogalusa Heart Study

Background—The association between left ventricular hypertrophy, an independent predictor of cardiovascular (CV) morbidity and mortality, and CV risk factors has been well documented in childhood and in adulthood. However, information on the relationship between left ventricular mass (LVM) in adults and longitudinal measurements of CV risk factors from childhood to adulthood is limited. Methods and Results—LVM was obtained with 2D M-mode echocardiography in a community-based sample of 467 young adults (71% white and 29% black) aged 20 to 38 years who were examined an average of 6 times for CV risk factors from childhood to adulthood. The average follow-up period was 21.5 years. The cumulative burden of each risk factor was calculated as the area under the curve for each individual. Compared with whites, blacks had greater LVM (indexed to height2.7; P<0.05). In multiple regression analyses, adiposity (measured as body mass index) in childhood, adiposity and systolic blood pressure in adulthood, and the cumulative burden of adiposity and systolic blood pressure from childhood to adulthood were significant predictors of LVM index in young adults. Conclusions—These observations, by showing that adiposity beginning in childhood is a consistent predictor of LVM in young adults, underscore the importance of obesity in the development of left ventricular hypertrophy and the need for early prevention.

Cumulative effects and predictive value of common obesity-susceptibility variants identified by genome-wide association studies

BACKGROUND Large-scale genome-wide association studies have identified 12 genetic loci that are robustly associated with body mass index (BMI). OBJECTIVES We examined associations and compared effect sizes of these newly identified obesity susceptibility loci with various anthropometric traits and assessed their cumulative effects and predictive value for obesity risk. DESIGN We genotyped 12 single nucleotide polymorphisms (SNPs) from each locus in 20,431 individuals (age: 39-79 y) from the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort. General linear model and logistic regression were used to examine associations, and the area under the receiver operating characteristic curve (AUC) was used to assess the predictive value of these variants for obesity risk. RESULTS Effect sizes of the risk alleles ranged between 0.058 and 0.329 for BMI (in kg/m(2)), between 0.094 and 0.866 kg for weight, and between 0.085 and 0.819 cm for waist circumference, with rs1121980 (FTO locus) showing the largest effect. Risk alleles of rs7132908 (FAIM2 locus) and rs17782313 (MC4R locus) were also associated with taller height. On average, each additional risk allele was associated with increases of 0.149 in BMI (P = 1.54 x 10(-22)), 0.444 kg in body weight (P = 9.88 x 10(-22)), and 0.357 cm in waist circumference (P = 1.10 x 10(-18)) and 10.8% (P = 9.83 x 10(-16)) and 5.5% (P = 3.38 x 10(-10)) increased risks of obesity and overweight, respectively. All SNPs combined explained 0.9% of BMI variation, with an AUC of 0.574 (95% CI: 0.559, 0.590) for prediction of obesity. CONCLUSIONS Common variants for BMI have small effects on obesity measures and show different association patterns with anthropometric traits, with the largest effect shown for the FTO locus. These variants have cumulative effects, yet their predictive value for obesity risk is limited.

Physical activity attenuates the body mass index–increasing influence of genetic variation in the FTO gene

BACKGROUND Intronic variation in the FTO (fat mass and obesity-associated) gene has been unequivocally associated with increased body mass index (BMI; in kg/m(2)) and the risk of obesity in populations of different ethnicity. OBJECTIVE We examined whether this robust genetic predisposition to obesity can be attenuated by being more physically active. DESIGN The FTO variant rs1121980 was genotyped in 20,374 participants (39-79 y of age) from the European Prospective Investigation into Cancer and Nutrition-Norfolk Study, an ethnically homogeneous population-based cohort. Physical activity (PA) was assessed with a validated self-reported questionnaire. The interaction between rs1121980 and PA on BMI and waist circumference (WC) was examined by including the interaction term in mixed-effect models. RESULTS We confirmed that the risk (T) allele of rs1121980 was significantly associated with BMI (0.31-unit increase per allele; P < 0.001) and WC (0.77-cm increase per allele; P < 0.001). The PA level attenuated the effect of rs1121980 on BMI and WC; ie, whereas in active individuals the risk allele increased BMI by 0.25 per allele, the increase in BMI was significantly (P for interaction = 0.004) more pronounced (76%) in inactive individuals (0.44 per risk allele). We observed similar effects for WC (P for interaction = 0.02): the risk allele increased WC by 1.04 cm per allele in inactive individuals but by only 0.64 cm in active individuals. CONCLUSIONS Our results showed that PA attenuates the effect of the FTO rs1121980 genotype on BMI and WC. This observation has important public health implications because we showed that a genetic susceptibility to obesity induced by FTO variation can be overcome, at least in part, by adopting a physically active lifestyle.

Predictors of Carotid Intima-Media Thickness Progression in Young Adults The Bogalusa Heart Study

Background and Purpose— We sought to evaluate the predictors of carotid intima-media thickness (CIMT) progression in young adults and to determine whether they differed between the sexes. Although risk factors for the progression of atherosclerosis in middle-aged and elderly adults are well known, they are less well understood in young adults. CIMT is a validated measure of subclinical atherosclerosis. Methods— B-mode ultrasound images of the far walls of both carotid arteries were obtained in 336 young adults in the Bogalusa Heart Study, whose mean±SD age was 32.3±3.0 years. CIMT and risk factors were measured at baseline (1995–1996) and after 5.8±0.6 years. Multivariable regression was used to determine the predictors of CIMT progression. Results— CIMT progression rates in women (0.015±0.024 mm/y) and men (0.020±0.027 mm/y) were not statistically different after controlling for body mass index (P=0.155). Smoking was a statistically significant predictor of common and composite CIMT progression in both sexes. In men, systolic blood pressure was an independent predictor of internal carotid and composite CIMT progression, fasting glucose predicted common CIMT progression, and family history predicted composite CIMT progression. Conclusions— In young adults, smoking was a consistent predictor of short-term CIMT progression in men and women. Traditional risk factors also predicted CIMT progression in men.

An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease.

BackgroundEpigenetic biomarkers of aging (the “epigenetic clock”) have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors.ResultsWe analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue.ConclusionsEpigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women.

Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design?

The INSIG2 rs7566605 polymorphism was identified for obesity (BMI≥30 kg/m2) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status (‘healthy population’, HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I2 measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I2 measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI≥32.5, 35.0, 37.5, 40.0 kg/m2 versus BMI<25 kg/m2) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.

Distribution and cross-sectional age-related increases of carotid artery intima-media thickness in young adults: the Bogalusa Heart Study.

Background and Purpose— Reference values and age-related changes of carotid intima-media thickness (CIMT) have not been described in a community-based sample of young asymptomatic adults. CIMT measurements from the Bogalusa Heart Study, a study of the natural history of atherosclerosis in young adults and children, were used to characterize age-, race-, and sex-specific CIMT distributions and yearly rates of change. Methods— Age-, sex-, and race-specific CIMT percentile values and cross-sectional changes with age were estimated using B-mode carotid ultrasound images from 519 young adults (mean age 32 years, 61% female, 29% black). Nomograms of CIMT percentiles between the ages of 25 and 40 years are provided in 5-year increments. Results— CIMT was thickest in the carotid bulb and increased linearly with age, most rapidly in the bulb. With age, composite CIMT increased most slowly in white females and most rapidly in white males. Sample size estimates projected that 268 to 462 subjects are needed to detect CIMT changes ≥0.010 mm/year. Conclusions— These estimated CIMT distributions and percentiles can serve as reference values for assessment of subclinical atherosclerosis in young adults. The observed age-related differences in CIMT can be used to plan epidemiological and clinical trials investigating atherosclerosis and anti-atherosclerotic interventions.