Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty.

Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9 × 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6 × 10(-5)) and short adult stature (p = 7.5 × 10(-6)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.

High birth weight is associated with obesity and increased carotid wall thickness in young adults: the cardiovascular risk in young Finns study.

OBJECTIVE: There is some evidence that people born with high birth weight may be at increased risk of cardiovascular disease in adulthood. Details of the underlying mechanisms remain unknown. We sought to determine whether people born large for gestational age have poor arterial health, increased adiposity, and a poor cardiovascular risk factor profile. APPROACH AND RESULTS: Carotid intima-media thickness, brachial flow-mediated dilatation, and cardiovascular risk factors were compared between young adults (24-45 years) born at term who were large for gestational age (birth weight >90th percentile; n=171), and a control group with normal birth weight (50-75th percentile; n=525), in the Cardiovascular Risk in Young Finns Study. Those born large for gestational age had higher body mass index throughout childhood, adolescence, and as young adults (26.4 kg/m(2) [SD 4.9], versus normal birth weight 25.1 kg/m(2) [SD 4.6]; P=0.002), and 2-fold greater risk of obesity. Other cardiovascular risk factors and arterial function did not differ; however, carotid intima-media thickness was increased in people born large for gestational age (0.60 mm [SD 0.09], versus normal birth weight 0.57 mm [SD 0.09]; P=0.003), independent of cardiovascular risk factors (P=0.001 after adjustment). Both obesity and high birth weight were independently associated with carotid intima-media thickness in a graded and additive fashion. CONCLUSIONS: Young adults born large for gestational age are more likely to be obese, yet have an otherwise healthy cardiovascular risk profile. Nonetheless, they have increased carotid intima-media thickness, a marker of subclinical atherosclerosis, consistent with an increased risk of cardiovascular disease.

Tissue inhibitor of matrix metalloproteinases 4 (TIMP4) in a population of young adults: relations to cardiovascular risk markers and carotid artery intima-media thickness. The Cardiovascular Risk in Young Finns Study.

OBJECTIVES: The tissue inhibitor of metalloproteinases 4 (TIMP4) is present in significant amounts in human atherosclerotic coronary artery lesions, but its relations with the early pathogenesis of atherosclerotic changes have not been clarified. We studied the associations of circulating TIMP4 with pre-clinical markers of atherosclerosis and traditional cardiovascular risk factors by using longitudinal data on carotid artery intima-media (cIMT) thickness in a population-based cohort of asymptomatic young adult Finns. METHODS: Data on cIMT, plasma TIMP4, lipids, CRP, blood pressure, BMI, smoking status and daily alcohol intake were obtained from 980 24-39 year-old participants in 2001. The 6-year follow-up in cIMT measurements were performed in 2007 for 769 participants. RESULTS: Plasma TIMP4 concentrations (mean ± SD) were 2.3 ± 1.7 ng/mL in men and 2.5 ± 1.8 ng/mL in women. Age, LDL-cholesterol, BMI and systolic blood pressure were directly associated with TIMP4 concentration. In a multivariable model, the independent determinants of TIMP4 included systolic blood pressure (p = 0.008) and daily smoking (p = 0.009), both being inversely associated with TIMP4. These two baseline variables explained 1.5% of the variation in TIMP4. TIMP4 was significantly and inversely associated with cIMT measured 6 years later (beta =- 0.0135, p = 0.01) explaining 0.7% of the variability of cIMT. CONCLUSION: In young apparently healthy adults, circulating TIMP4 concentration was independently and inversely associated with cIMT, a marker of vascular structure and function.

Plasminogen activator inhitor-1 associates with cardiovascular risk factors in healthy young adults in the Cardiovascular Risk in Young Finns Study.

AIMS: Hypofibrinolysis displayed by elevated serum plasminogen activator inhibitor 1 (PAI-1) level has been associated with cardiovascular disease (CVD) and its risk factors such as obesity and insulin resistance. However, no studies have examined associations between PAI-1 and CVD risk factors in healthy subjects. We examined associations between serum PAI-1, ultrasound markers of atherosclerosis and CVD risk factors and whether PAI-1 improves prediction of atherosclerosis over known risk factors in a cohort of asymptomatic adults. METHODS: We analyzed PAI-1 and CVD risk factors and assessed carotid intima-media thickness (cIMT), distensibility (CDist) and the presence of a carotid atherosclerotic plaque and flow-mediated dilation (FMD) ultrasonographically for 2202 adults (993 men and 1,209 women, aged 30-45 years) participating in the ongoing longitudinal cohort study, The Cardiovascular Risk in Young Finns Study. High cIMT was defined as >90th percentile and/or carotid plaque and low CDist and low FMD as <20th percentile. RESULTS: In bivariate analyses, PAI-1 correlated directly with cIMT and the risk factors: blood pressure, BMI, waist and hip circumference, alcohol use, total and LDL-cholesterol, triglycerides, glomerular filtration rate, high-sensitivity CRP and glucose (all P<0.005). PAI-1 was higher in men and increased with age. Inverse correlation was observed with CDist, HDL-cholesterol and adiponectin in both sexes, with testosterone and sex hormone binding globulin in men and with creatinine and oral contraceptive use in women (P<0.005). Independent direct associations were observed between PAI-1 and waist circumference, serum triglycerides, insulin, alcohol use and age and inverse with serum creatinine, HDL-cholesterol and adiponectin. PAI-1 did not improve estimation of high cIMT, low CDist and low FMD over conventional risk factors (P for difference in area under curve ≥ 0.37). CONCLUSION: PAI-1 was independently associated with several known CVD risk factors, especially obesity markers, in both men and women. However, addition of PAI-1 to known risk factors did not improve cross-sectional prediction of high cIMT, low CDist and low FMD suggesting that PAI-1 is not a clinically important biomarker in early atherosclerosis.

Associations between serum uric acid and markers of subclinical atherosclerosis in young adults. The cardiovascular risk in Young Finns study.

BACKGROUND AND METHODS: Serum uric acid (SUA) is a suggested biomarker for established coronary artery disease, but the role of SUA in early phases of atherosclerosis is controversial. The relations of SUA with vascular markers of subclinical atherosclerosis, including carotid artery intima-media thickness (cIMT), carotid plaque, carotid distensibility (Cdist) and brachial flow-mediated dilatation (FMD) were examined in 1985 young adults aged 30-45 years. In addition to ordinary regression, we used Mendelian randomization techniques to infer causal associations. RESULTS: In women, the independent multivariate correlates of SUA included BMI, creatinine, alcohol use, triglycerides, glucose and adiponectin (inverse association) (Model R(2) = 0.30). In men, the correlates were BMI, creatinine, triglycerides, C-reactive protein, alcohol use, total cholesterol and adiponectin (inverse) (Model R(2) = 0.33). BMI alone explained most of the variation of SUA levels both in women and men (Partial R(2) âˆ¼ 0.2). When SUA was modeled as an explanatory variable for vascular markers, it directly associated with cIMT and inversely with Cdist in age- and sex-adjusted analysis. After further adjustments for BMI or glomerular filtration rate, these relations were reduced to non-significance. No associations were found between SUA and FMD or the presence of a carotid plaque. Mendelian randomization analyses using known genetic variants for BMI and SUA confirmed that BMI is causally linked to SUA and that BMI is a significant confounder in the association between SUA and cIMT. CONCLUSION: SUA is associated with cardiovascular risk markers in young adults, especially BMI, but we found no evidence that SUA would have an independent role in the pathophysiology of early atherosclerosis.

Childhood physical, environmental, and genetic predictors of adult hypertension: the cardiovascular risk in young Finns study.

BACKGROUND: Hypertension is a major modifiable cardiovascular risk factor. The present longitudinal study aimed to examine the best combination of childhood physical and environmental factors to predict adult hypertension and furthermore whether newly identified genetic variants for blood pressure increase the prediction of adult hypertension. METHODS AND RESULTS: The study cohort included 2625 individuals from the Cardiovascular Risk in Young Finns Study who were followed up for 21 to 27 years since baseline (1980; age, 3-18 years). In addition to dietary factors and biomarkers related to blood pressure, we examined whether a genetic risk score based on 29 newly identified single-nucleotide polymorphisms enhances the prediction of adult hypertension. Hypertension in adulthood was defined as systolic blood pressure ≥ 130 mm Hg and/or diastolic blood pressure ≥ 85 mm Hg or medication for the condition. Independent childhood risk factors for adult hypertension included the individual's own blood pressure (P<0.0001), parental hypertension (P<0.0001), childhood overweight/obesity (P=0.005), low parental occupational status (P=0.003), and high genetic risk score (P<0.0001). Risk assessment based on childhood overweight/obesity status, parental hypertension, and parental occupational status was superior in predicting hypertension compared with the approach using only data on childhood blood pressure levels (C statistics, 0.718 versus 0.733; P=0.0007). Inclusion of both parental hypertension history and data on novel genetic variants for hypertension further improved the C statistics (0.742; P=0.015). CONCLUSIONS: Prediction of adult hypertension was enhanced by taking into account known physical and environmental childhood risk factors, family history of hypertension, and novel genetic variants. A multifactorial approach may be useful in identifying children at high risk for adult hypertension.

Association of ADIPOR2 gene variants with cardiovascular disease and type 2 diabetes risk in individuals with impaired glucose tolerance: the Finnish Diabetes Prevention Study.

BACKGROUND: Adiponectin is an adipokine with insulin-sensitising and anti-atherogenic effects. Two receptors for adiponectin, ADIPOR1 and ADIPOR2, have been characterized that mediate effects of adiponectin in various tissues. We examined whether genetic variation in ADIPOR2 predicts the development of cardiovascular disease (CVD) and/or Type 2 Diabetes (T2DM) in individuals with impaired glucose tolerance (IGT) participating the Finnish Diabetes Prevention Study (DPS). METHODS: CVD morbidity and mortality data were collected during a median follow-up of 10.2 years (range 1-13 years) and conversion from IGT to T2DM was assessed during a median follow-up of 7 years (range 1-11 years). Altogether eight SNPs in the ADIPOR2 locus were genotyped in 484 participants of the DPS. Moreover, the same SNPs were genotyped and the mRNA expression levels of ADIPOR2 were determined in peripheral blood mononuclear cells and subcutaneous adipose tissue samples derived from 56 individuals participating in the Genobin study. RESULTS: In the DPS population, four SNPs (rs10848554, rs11061937, rs1058322, rs16928751) were associated with CVD risk, and two remained significant (p = 0.014 for rs11061937 and p = 0.020 for rs1058322) when all four were included in the same multi-SNP model. Furthermore, the individuals homozygous for the rare minor alleles of rs11061946 and rs11061973 had increased risk of converting from IGT to T2DM. Allele-specific differences in the mRNA expression levels for the rs1058322 variant were seen in peripheral blood mononuclear cells derived from participants of the Genobin study. CONCLUSIONS: Our results suggest that SNPs in the ADIPOR2 may modify the risk of CVD in individuals with IGT, possibly through alterations in the mRNA expression levels. In addition an independent genetic signal in ADIPOR2 locus may have an impact on the risk of developing T2DM in individuals with IGT. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00518167.

Association of ADIPOQ gene variants with body weight, type 2 diabetes and serum adiponectin concentrations: the Finnish Diabetes Prevention Study.

BACKGROUND: Adiponectin, secreted mainly by mature adipocytes, is a protein with insulin-sensitising and anti-atherogenic effects. Human adiponectin is encoded by the ADIPOQ gene on the chromosomal locus 3q27. Variations in ADIPOQ are associated with obesity, type 2 diabetes (T2DM) and related phenotypes in several populations. Our aim was to study the association of the ADIPOQ variations with body weight, serum adiponectin concentrations and conversion to T2DM in overweight subjects with impaired glucose tolerance. Moreover, we investigated whether ADIPOQ gene variants modify the effect of lifestyle changes on these traits. METHODS: Participants in the Finnish Diabetes Prevention Study were randomly assigned to a lifestyle intervention group or a control group. Those whose DNA was available (n = 507) were genotyped for ten ADIPOQ single nucleotide polymorphisms (SNPs). Associations between SNPs and baseline body weight and serum adiponectin concentrations were analysed using the univariate analysis of variance. The 4-year longitudinal weight data were analysed using linear mixed models analysis and the change in serum adiponectin from baseline to year four was analysed using Kruskal-Wallis test. In addition, the association of SNPs with the risk of developing T2DM during the follow-up of 0-11 (mean 6.34) years was analysed by Cox regression analysis. RESULTS: rs266729, rs16861205, rs1501299, rs3821799 and rs6773957 associated significantly (p < 0.05) with body weight at baseline and in the longitudinal analyses. The rs266729 C allele and the rare minor alleles of rs2241766 and rs2082940 were associated with an increased adjusted hazard ratio of developing T2DM. The differences in baseline serum adiponectin concentrations were seen according to rs16861210, rs17366568, rs2241766, rs6773957 and rs2082940 and differences in the change of serum adiponectin levels from baseline to the four year examination were seen according to rs16861205, especially in subjects who were able to lose weight during the first year of intervention. CONCLUSIONS: These results from the Finnish Diabetes Prevention Study support the concept that genetic variation in ADIPOQ locus contributes to variation in body size and serum adiponectin concentrations and may also modify the risk of developing T2DM. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00518167.

Physical activity, diet, and incident diabetes in relation to an ADRA2B polymorphism.

PURPOSE: The 12Glu9 polymorphism of the alpha2B-adrenergic receptor gene may impair insulin secretion and modify the effects of a lifestyle intervention on the risk of type 2 diabetes, but the interaction with specific lifestyle components is unknown. We assessed the associations of leisure-time physical activity (LTPA), dietary changes, and weight loss on the risk of type 2 diabetes according to the 12Glu9 polymorphism in 481 participants of the Finnish Diabetes Prevention Study. METHODS AND RESULTS: The lifestyle intervention decreased the risk of diabetes in 9Glu carriers (9Glu9, intervention vs control, relative risk (RR) = 0.23, 95% confidence interval (CI) 0.09-0.62), but not in 12Glu12 homozygotes. In the combined intervention and control groups, increased total LTPA as estimated with a questionnaire decreased the risk of diabetes in 12Glu carriers (12Glu12, upper vs lower third, RR = 0.12, 95% CI 0.03-0.53) but not in 9Glu9 homozygotes (P for the interaction 0.033). In contrast, favorable dietary changes, estimated using a dietary score, reduced the risk of diabetes in those with the 9Glu9 genotype (upper vs lower third, RR = 0.21, 95% CI 0.06-0.75) but not in those with the 12Glu allele. Weight loss significantly decreased the risk of diabetes only in 12Glu carriers. CONCLUSION: Increased LTPA decreased the risk of type 2 diabetes more in those with the 12Glu allele of the ADRA2B gene, whereas dietary changes may have mediated the greater risk reduction of the lifestyle intervention in 9Glu homozygotes.