Genetic architecture of lipid traits changes over time and differs by race: Princeton Lipid Follow-up Study.

Dyslipidemia is a major risk factor for CVD. Previous studies on lipid heritability have largely focused on white populations assessed after the obesity epidemic. Given secular trends and racial differences in lipid levels, this study explored whether lipid heritability is consistent across time and between races. African American and white nuclear families had fasting lipids measured in the 1970s and 22-30 years later. Heritability was estimated, and bivariate analyses between visits were conducted by race using variance components analysis. A total of 1,454 individuals (age 14.1/40.6 for offspring/parents at baseline; 39.6/66.5 at follow-up) in 373 families (286 white, 87 African American) were included. Lipid trait heritabilities were typically stronger during the 1970s than the 2000s. At baseline, additive genetic variation for LDL was significantly lower in African Americans than whites (P = 0.015). Shared genetic contribution to lipid variability over time was significant in both whites (all P < 0.0001) and African Americans (P ≤ 0.05 for total, LDL, and HDL cholesterol). African American families demonstrated shared environmental contributions to lipid variation over time (all P ≤ 0.05). Lower heritability, lower LDL genetic variance, and durable environmental effects across the obesity epidemic in African American families suggest race-specific approaches are needed to clarify the genetic etiology of lipids.

Paradoxically high adiponectin in obese 16-year-old girls protects against appearance of the metabolic syndrome and its components seven years later.

OBJECTIVE: To evaluate the relationships of adiponectin levels at age 16 years in obese schoolgirls to metabolic syndrome and its components at age 23 years. STUDY DESIGN: Seven-year prospective study of 381 females. RESULTS: In 144 white and 129 black non-obese 16-year old girls (body mass index < 24.6 kg/m(2)), race-specific median adiponectin levels (white 12 mg/L, black 11) was used to identify paradoxically high adiponectin levels in obese girls. Of 34 white and 74 black obese girls, 12 (35%) and 19 (26%) had paradoxically high adiponectin levels. In these 108 obese girls, adiponectin levels at age 16 years independently predicted high-density lipoprotein cholesterol (positive) and waist (negative), insulin (negative), and glucose (negative) at age 23 years; paradoxically high adiponectin levels at age 16 years was a negative independent predictor for waist, homeostatic model assessment-insulin resistance, and for the number of abnormal components of the metabolic syndrome at age 23 years. In 31 pairs of obese girls with and without paradoxically high adiponectin levels, matched by race and age 16 body mass index, adiponectin levels at age 16 years was a negative predictor for the number of abnormal metabolic syndrome components at age 23 years. CONCLUSION: Paradoxically high adiponectin levels in obese 16 year old girls protects against metabolic syndrome and its components at age 23 years.

Sex hormone-binding globulin, oligomenorrhea, polycystic ovary syndrome, and childhood insulin at age 14 years predict metabolic syndrome and class III obesity at age 24 years.

OBJECTIVE: We hypothesized that oligomenorrhea (menstrual cyclicity ≥42 days), hyperandrogenism, low levels of sex hormone-binding globulin (SHBG), childhood insulin, and metabolic syndrome (MetS) at age 14 years would predict MetS and class III obesity (body mass index ≥40 kg/m(2)) at age 24 years. STUDY DESIGN: In this prospective study of schoolgirls, at age 14 years, the girls were categorized as regularly cycling (n = 375), oligomenorrheic (n = 18), or oligomenorrhea plus biochemical hyperandrogenism (polycystic ovary syndrome [PCOS]; n = 12), together designated PCOS. RESULTS: Significant explanatory variables for MetS at age 24 years included childhood insulin, MetS, and PCOS category (all positive) and SHBG (negative) at age 14 years. Using categorical data, top decile of childhood insulin, MetS at age 14, bottom decile of SHBG, and PCOS category were significant positive predictors for MetS at age 24. SHBG (negative), black race (positive), and oligomenorrhea (positive) were significant explanatory variables for class III obesity at age 24. Using categorical data, black race, MetS at age 14, bottom decile of SHBG, PCOS category, and top decile of childhood insulin were positive explanatory variables for class III obesity at age 24 years. CONCLUSIONS: Oligomenorrhea, PCOS (a subcohort of oligomenorrhea), hyperandrogenism, low SHBG, MetS, and childhood insulin at age 14 years may represent a critical, reversible pathway for the development of MetS and class III obesity in young adulthood.

Obesity, free testosterone, and cardiovascular risk factors in adolescents with polycystic ovary syndrome and regularly cycling adolescents.

Adolescent girls with polycystic ovary syndrome (PCOS) have increased levels of factors constituting the metabolic syndrome: centripetal obesity, hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and hyperinsulinemia. Given the strong association reported between early, persistent obesity and development of metabolic syndrome 10 years later in girls, we speculated that if adolescent girls without PCOS had obesity measures similar to girls with PCOS, they would exhibit similar metabolic syndrome-cardiovascular disease risk factors. Within this context, we compared 37 adolescent girls with PCOS and 2 samples of normal, regularly cycling adolescent girls (controls) of similar ages, selected from the Cincinnati Clinic of the National Heart, Lung, and Blood Institute Growth and Health Study. The first sample included 157 controls selected using a stratified random sample based on age. As expected, girls with PCOS had higher body mass index (BMI), waist circumference, insulin, systolic blood pressure (SBP) and diastolic blood pressure, triglycerides (TGs), lower HDL-C, and higher low-density lipoprotein cholesterol (LDL-C) and free testosterone (FT) than controls. A second sample consisted of girls matched one to one with girls with PCOS for BMI and age. Comparisons of group differences were not significant for insulin, lipids, or blood pressure; girls with PCOS had a trend toward higher values for waist circumference (median, 92.7 vs 87.5 cm; P = .07) and much higher median FT (4.25 vs 1.42 ng/mL, P = .0001). After matching for BMI and age, by conditional regression analysis, we showed that the groups were not differentiated (P > .15) by insulin, HDL-C, LDL-C, TG, SBP, or diastolic blood pressure, but were differentiated by higher FT (P = .0024) and waist circumference (P = .0024) in PCOS than in controls. Prospective longitudinal analyses of NHGS controls showed that changes in BMI from ages 9 to 10 years to ages 15 to 16 years were positively associated with changes in waist circumference (P < .0001), LDL-C (P = .01), TG (P = .008), and SBP (P = .002). These findings suggest that if adolescent girls achieve adiposity equal to girls with PCOS, they then acquire major components of the metabolic syndrome, and excluding high FT and waist circumference, comparable increased cardiovascular disease risk.

Population-specific alleles: the polymorphism (K121Q) of the human glycoprotein PC-1 gene is strongly associated with race but not with insulin resistance in black and white children.

The K121Q polymorphism of the glycoprotein PC-1 gene was recently reported to associate with insulin resistance (IR) in an all-Caucasian, Sicilian population. Given black-white differences in plasma insulin and IR, we compared the prevalence of the KK, KQ, and QQ genotypes and their associations with insulin and IR in 2 large, biracial pediatric samples: 1 hospital-based (n = 301, 137 blacks and 164 whites) and 1 school-based (n = 639, 344 blacks and 295 whites). The Q allele frequencies in the hospital-based and school-based cohorts in black children were 0.80 and 0.77 and in the white children, 0.15 and 0.13. The K allele frequencies in the hospital-based and school-based cohorts in black children were 0.20 and 0.23 and in the white children, 0.85 and 0.87. Differences in allelic frequencies were highly significant (chi square test, P <.0001) for both the hospital-based cohort and the school-based cohort. Both cohorts were in Hardy-Weinberg equilibrium. Within race, after covariance adjusting for age and body mass index (BMI), there were no significant differences (P >/=.10) among the 3 PC-1 genotypes for insulin, glucose, or homeostasis model assessment (HOMA) IR. After covariance adjusting for age and BMI, black girls had higher insulin (P =.0007) and higher HOMA IR (P =.0002) than white girls. The K121Q polymorphism was not associated with insulin, glucose, or HOMA IR measures in black or white children. However, the QQ genotype was population-specific, encompassing most black children versus 1% to 3% of white children. As such, K121Q genotyping should be useful in epidemiology, population genetics, and forensic anthropology.

Lead-based paint health risk assessment in dependent children living in military housing.

OBJECTIVE: In children, lead can cause serious permanent damage as a neurotoxicant. The objectives of the study were to evaluate potential exposure to lead-based paint in family housing units at a typical U.S. military installation and determine blood lead (PbB) levels in children ages 6 years or younger residing in these housing units. METHODS: The authors conducted a risk assessment of 1,723 housing units and occupants at Fort Devens in Massachusetts. Data from the military dependent cohort was compared to estimates for the U.S. national population as reported from Phase 1 of the Third National Health and Nutrition Examination Survey (NHANES III). RESULTS: A total of 1992 individuals (1,009 males and 983 females) were screened for PbB, stratified into age groups, and separated into racial/ethnic categories. Four (0.3%) dust samples and 59 (11.6%) internal and 298 (77.8%) external paint chip samples contained hazardous levels of lead. The geometric mean PbB concentration for people ages 1 year and older reported by NHANES III was 2.8 micro g/dL, compared with 1.5 microg/dL for the military installation cohort (p<0.0001). PbB levels were higher for males than for females and higher for blacks than whites 6 years of age and older. Hispanics had lower PbB concentrations for all age groups except for those ages 1-2.9 years. Prevalence of PbB levels >10 microg/dL for all age groups was 1.6% in the military cohort, compared with 4.5% for the general population. For ages 1-2.9 years, no blacks or Hispanics and 0.6% of whites had PbB levels >10 micro g/dL, compared with 21.6% of blacks, 10.1% of Hispanics, and 8.5% of whites for the general population. For ages 3-5.99 years, 0.15% of blacks, 0% of Hispanics, and 0.3% of whites had PbB levels > or = 10 microg/dL, compared with 20.0% of blacks, 6.8% of Hispanics, and 3.7% of whites for the general population. CONCLUSION: Lead exposure for occupants of on-post military housing is much less than for those residing in the civilian sector.

Adolescent oligomenorrhea in a biracial schoolgirl cohort: a simple clinical parameter predicting impaired fasting glucose plus type 2 diabetes mellitus, insulin, glucose, insulin resistance, and centripetal obesity from age 19 to 25 years.

We hypothesized that adolescent oligomenorrhea (ages 14-19) would independently predict impaired fasting glucose (IFG; ≥110 to <126 mg/dL) plus type 2 diabetes mellitus (T2DM; ≥126 mg/dL), insulin and glucose levels, and insulin resistance (IR) in young adulthood (ages 19-25). A prospective 15-year follow-up of 370 schoolgirls starting at age 10 was performed. Age 14 waist circumference was the most important explanatory variable for IFG + T2DM during ages 19 to 24 (P = .002; odds ratio, 1.06; 95% confidence interval, 1.02-1.10), along with oligomenorrhea category from ages 14 to 19 (0, 1, 2, ≥3 reports over 6 years; P = .032; odds ratio, 1.82; 95% confidence interval, 1.05-3.14). Impaired fasting glucose + T2DM at ages 19 to 24 were more common in girls having 1 (6%), 2 (11%), and ≥3 (38%) oligomenorrhea reports from ages 14 to 19 than in girls without oligomenorrhea (3%; P = .0003). Positive explanatory variables (all Ps ≤ .05) for homeostasis model assessment of IR at ages 19 to 24 included age 14 waist (partial R(2) = 30.1%), oligomenorrhea with hyperandrogenism (polycystic ovary syndrome; partial R(2) = 4.1%), black race (3.8%), and oligomenorrhea frequency during ages 14 to 19 (0.8%); sex hormone binding globulin was a negative explanatory variable (0.7%). This is the first prospective study to report an independent association of adolescent oligomenorrhea with young adult IFG + T2DM, with insulin and glucose levels, and with IR. Age 14 waist circumference, oligomenorrhea with hyperandrogenism (polycystic ovary syndrome), black race, oligomenorrhea frequency at ages 14 to 19, and age 14 sex hormone binding globulin were independently associated with IR at ages 19 to 24, potentially facilitating primary prevention of IFG, T2DM, and hyperinsulinemia.

Ramifications of adolescent menstrual cycles ≥42 days in young adults.

OBJECTIVE: To determine to what degree annual reports from ages 14 to 19 years of menstrual cycles ≥42 days would be associated with increased body mass index (BMI), waist circumference, glucose, insulin, and homeostasis model assessment insulin resistance (HOMA-IR) at ages 14-25 years. DESIGN: Prospective 11-year follow-up from ages 14 to 25 years. SETTING: Urban-suburban schools, post-high school. PATIENT(S): A total of 370 schoolgirls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): BMI, waist, insulin, glucose, HOMA-IR. RESULT(S): From ages 14 to 19 years, 269 girls had 0/6 annual reports of menstrual cycles ≥42 days, 74 had 1, 19 had 2, and 8 had ≥3. Among these four categories, girls with ≥3 annual reports had highest free T and DHEAS at age 14, highest BMI and waist at ages 14, 19, and 25, highest insulin at age 25, and highest glucose and HOMA-IR at age 24 years. The number of annual reports of menstrual cycles ≥42 days was positively related to change in BMI and waist and inversely with change in high-density lipoprotein cholesterol from ages 14 to 25 years. CONCLUSION(S): Three or more annual reports of menstrual cycles ≥42 days during ages 14-19 are associated with high BMI, waist circumference, insulin, glucose, and HOMA-IR at ages 14-25 years.

High-sensitivity C reactive protein: associations with cardiovascular risk factors and tracking in female adolescents and young adults.

Objective. We assessed adolescent anthropometry, lipids, insulin, glucose, and blood pressures to identify factors associated with high-sensitivity C-reactive protein (hsCRP) and its tracking in young adults. Methods. Ten-year prospective study of 589 schoolgirls, 321 black, 268 white. Results. HsCRP did not differ (P > .08) by race or oral contraceptive use. HsCRP tracked from age 16 to 25 (r = 0.77), 16 to 26 (r = 0.50), 24 to 26 (r = 0.66), and 25 to 26 (r = 0.71), all P ≤ .02. By stepwise regression, at age 16, waist circumference accounted for 44.8% of hsCRP variance; BMI accounted for 33.1%, 34.4%, and 31.1% at ages 24, 25, and 26, P < .0001 for all. Changes in cholesterol and BMI were associated with change in hsCRP from age 24-26 (partial R(2) = 12.3% P < .0001, 6.6% P = .0012). Changes in BMI and triglyceride (partial R(2) = 8.5% P = .0001, 3.3%, P = .0045) were associated with change in hsCRP from age 25 to 26. Conclusions. HsCRP tracks from age 16 to 26, with BMI, waist circumference, and cholesterol as major determinants.

Paradoxically high adiponectin and the healthy obese phenotype in obese black and white 16-year-old girls.

Although adiponectin is correlated inversely with obesity, some obese adults without metabolic complications of obesity have paradoxically high adiponectin. Therefore, we assessed adiponectin risk factor relations in 133 obese 16-year-old school girls from a cohort of 448, focusing on paradoxically high adiponectin-risk in obesity and the healthy obese phenotype. Median adiponectin (11.9 mg/L) in nonobese girls (body mass index [BMI] < 24.6 kg/m²) was selected as a cutpoint to identify high adiponectin in obese girls. Of 90 black and 43 white obese girls (BMI ≥ 24.6), 25 black (28%) and 13 white (30%) girls had paradoxically high adiponectin (>11.9). The 38 obese girls with adiponectin >11.9 versus the 95 obese girls with adiponectin ≤11.9 had higher median high-density lipoprotein (HDL) cholesterol (54 vs 46 mg/dL, P = 0.0007) and apolipoprotein A1 (ApoA1) (181 vs 164 mg/dL, P = 0.011) and had lower insulin (14 vs 20 uU/mL, P = 0.0006). In the 133 obese girls, through stepwise regression, the adiponectin category (>11.9, ≤ 11.9 mg/L) was a significant independent positive determinant of HDL cholesterol (partial r² = 8.4%, P = 0.001), ApoA1 (partial r² = 4.1%, P = 0.025), and it was associated inversely with fasting serum insulin (partial r² = 5.4%, P = 0.0074). By stepwise logistic regression in the 133 obese girls, the adiponectin category (high vs low) was a significant inverse explanatory variable for metabolic syndrome (odds ratio 0.20, 95% confidence intervals 0.04-0.95, P = 0.043). We conclude that paradoxically high adiponectin is associated with the healthy obese phenotype in obese adolescent black and white girls.

Hyperhomocysteinemia is associated with low plasma pyridoxine levels in children with sickle cell disease.

Elevated plasma homocysteine levels have been shown to be a risk factor for endothelial cell damage and thrombosis, which are implicated in sickle cell disease (SCD)-related vaso-occlusion. The aim of this study was to determine the prevalence of hyperhomocysteinemia in SCD. Fasting and postmethionine load (PML) homocysteine, red cell folate, and the MTHFR C677T mutation were determined in 77 patients with SCD and 110 African-American controls. Plasma methylmalonic acid and pyridoxine levels were determined in 54 patients and all controls. For analysis, the subjects were divided into two age groups (2-10 years and 10.1-21 years). In both age groups, median PML homocysteine levels were significantly elevated in patients with SCD compared with controls. Fasting homocysteine levels were elevated in patients with SCD versus controls only in those older than 10 years. Hyperhomocysteinemia was noted in 38% of patients versus 7% in controls. Folate levels were higher among patients than controls and showed a significant negative correlation with PML homocysteine levels in patients with SCD. Pyridoxine levels in patients with SCD were significantly lower than in controls and showed a negative correlation with PML homocysteine levels. Among patients with SCD, pyridoxine deficiency was more common (62%) among those with hyperhomocysteinemia compared with those with normal homocysteine levels (30%). Homozygosity for the MTHFR C677T mutation was rare. These data suggest that children with SCD have significant hyperhomocysteinemia, associated with pyridoxine and relative folate deficiencies.