The Influence of Dietary Counseling Over 20 Years on Tracking of Non-High-Density Lipoprotein Cholesterol from Infancy to Young Adulthood.

This 26-year study found that non-high-density lipoprotein cholesterol (non-HDL-C) levels tracked from infancy to young adulthood suggesting early-life non-HDL-C could predict future levels. However, infancy-onset dietary counseling reduced the odds of maintaining at-risk non-HDL-C, highlighting the potential importance of early interventions in preventing cardiovascular risk associated with high pediatric non-HDL-C.

Dietary Intervention in Infancy and Cognitive Function in Young Adulthood: The Special Turku Coronary Risk Factor Intervention Project.

OBJECTIVE: Consumption of saturated fatty acids (SAFAs), polyunsaturated fatty acids (PUFAs), cholesterol, and fiber have been linked with cognitive function in adults. We evaluated these associations from childhood by leveraging data from the Special Turku Coronary Risk Factor Intervention Project (STRIP). STUDY DESIGN: STRIP recruited children aged 5 months and randomly assigned them into intervention/control groups. The intervention introduced a heart-healthy diet, characterized mainly by low consumption of SAFAs and cholesterol, through counseling at least biannually between age 7 months and 20 years. Diet was assessed repeatedly using food diaries. Six years after the end of the intervention phase, at age 26 years, the participants were invited to the first postintervention follow-up, which included cognitive testing that covered learning and memory, verbal memory, short-term working memory, reaction time, information processing, and cognitive flexibility and inhibitory control. We studied the associations of the STRIP intervention and the consumptions of SAFAs, PUFAs, cholesterol, and fiber within these cognitive domains. RESULTS: Participants in the STRIP intervention group had better cognitive flexibility and inhibitory control and were better able to manage conflicting information and ignore task-irrelevant information (0.18 SD higher in the intervention group, adjusted for sex and socioeconomic status). No associations were observed with the dietary components studied. CONCLUSIONS: The infancy-onset STRIP intervention, which promoted a heart-healthy diet, was favorably associated with cognitive flexibility and inhibitory control at age 26 years. No associations were found for the intervention targets studied, indicating that these specific dietary components did not underlie the observed effect of the intervention.

Prevalence Implications of the 2017 American Academy of Pediatrics Hypertension Guideline and Associations with Adult Hypertension.

OBJECTIVE: To evaluate the impact of the 2017 American Academy of Pediatrics hypertension Clinical Practice Guideline (CPG), compared with the previous guideline ("Fourth Report"), on the frequency of hypertensive blood pressure (BP) measurements in childhood and associations with hypertension in adulthood using data from the International Childhood Cardiovascular Cohort Consortium. STUDY DESIGN: Childhood BPs were categorized in normal, prehypertensive/elevated, and hypertensive (stage 1 and 2) ranges using the Fourth Report and the CPG. Participants were contacted in adulthood to assess self-reported hypertension. The associations between childhood hypertensive range BPs and self-reported adult hypertension were evaluated. RESULTS: Data were available for 34 014 youth (10.4 ± 3.1 years, 50.6% female) with 92 751 BP assessments. Compared with the Fourth Report, the CPG increased hypertensive readings from 7.6% to 13.5% and from 1.3% to 2.5% for stage 1 and 2 hypertensive range, respectively (P < .0001). Of 12 761 adults (48.8 ± 7.9 years, 43% male), 3839 (30.1%) had self-reported hypertension. The sensitivity for predicting adult hypertension among those with hypertensive range BPs at any point in childhood, as defined by the Fourth Report and the CPG, respectively, was 13.4% and 22.4% (specificity 92.3% and 85.9%, P < .001), with no significant impact on positive and negative predictive values. Associations with self-reported adult hypertension were similar and weak (c-statistic range 0.61-0.68) for hypertensive range BPs as defined by the Fourth Report and CPG. CONCLUSIONS: The CPG significantly increased the prevalence of childhood BPs in hypertensive ranges and improved the sensitivity, without an overall strengthened association, of predicting self-reported adult hypertension.

Association between Number of Siblings and Cardiovascular Risk Factors in Childhood and in Adulthood: The Cardiovascular Risk in Young Finns Study.

OBJECTIVE: To determine the association of number of siblings on cardiovascular risk factors in childhood and in adulthood. STUDY DESIGN: In total, 3554 participants (51% female) from the Cardiovascular Risk in Young Finns Study with cardiovascular disease risk factor data at baseline 1980 (age 3-18 years) and 2491 participants with longitudinal risk factor data at the 2011 follow-up. Participants were categorized by number of siblings at baseline (0, 1, or more than 1). Risk factors (body mass index, physical activity, hypertension, dyslipidemia, and overweight, and metabolic syndrome) in childhood and in adulthood were used as outcomes. Analyses were adjusted for age and sex. RESULTS: In childhood, participants without siblings had higher body mass index (18.2 kg/m2, 95% CI 18.0-18.3) than those with 1 sibling (17.9 kg/m2, 95% CI 17.8-18.0) or more than 1 sibling (17.8 kg/m2, 95% CI 17.7-17.9). Childhood physical activity index was lower among participants without siblings (SD -0.08, 95% CI -0.16-0.00) compared with participants with 1 sibling (SD 0.06, 95%CI 0.01-0.11) or more than 1 sibling (SD -0.02, 95% CI -0.07-0.03). OR for adulthood hypertension was lower among participants with 1 sibling (OR 0.73, 95% CI 0.54-0.98) and more than 1 sibling (OR 0.71, 95% CI 0.52-0.97) compared with participants with no siblings. OR for obesity was lower among participants with 1 sibling (OR 0.72, 95% CI 0.54-0.95) and more than 1 sibling (OR 0.75, 95% CI 0.56-1.01) compared with those with no siblings. CONCLUSIONS: Children without siblings had poorer cardiovascular risk factor levels in childhood and in adulthood. The number of siblings could help identify individuals at increased risk that might benefit from early intervention.

Age-Specific Estimates and Comparisons of Youth Tri-Ponderal Mass Index and Body Mass Index in Predicting Adult Obesity-Related Outcomes.

OBJECTIVES: To estimate and compare tri-ponderal mass index (TMI) and body mass index (BMI) at each age from childhood to young adulthood in the prediction of adulthood obesity-related outcomes. STUDY DESIGN: Participants of this observational study (n = 432) were from a 20-year infancy-onset randomized atherosclerosis prevention trial. BMI and TMI were calculated using weight and height measured annually from participants between ages 2 and 20 years. Outcomes were aortic intima-media thickness (at the age of 15, 17, or 19 years), impaired fasting glucose and elevated insulin levels, homeostasis model assessment of insulin resistance index, serum lipids, and hypertension at the age of 20 years. Poisson regressions, Pearson correlation, logistic regression, and area under the curve (AUC) were used to estimate and/or compare associations and predictive utilities between BMI and TMI with all outcomes. RESULTS: The associations and predictive utilities of BMI and TMI with all outcomes were stronger at older ages. BMI had significantly stronger correlations than TMI with insulin (at age 16 years), systolic blood pressure (age 5-20 years), and triglycerides (age 18 years). BMI had significantly greater predictive utilities than TMI for insulin resistance (at age 14-16 years; difference in AUC = 0.018-0.024), elevated insulin levels (age 14-16 years; difference in AUC = 0.018 and 0.025), and hypertension (age 16 to 20 years; difference in AUC = 0.017-0.022) but they were similar for other outcomes. CONCLUSIONS: TMI is not superior to BMI at any ages from childhood to young adulthood in the prediction of obesity-related outcomes in young adulthood.

Tracking of secretory phospholipase A2 enzyme activity levels from childhood to adulthood: a 21-year cohort / Monitoramento dos níveis de atividade da enzima fosfolipase A2 secretória da infância à vida adulta: uma coorte de 21 anos

Abstract Objective: Secretory phospholipase A2 (sPLA2) enzyme activity is a potential inflammatory biomarker for cardiovascular disease. We examined the tracking, or persistence, of sPLA2 enzyme activity levels from childhood to adulthood, and identify potentially modifiable factors affecting tracking. Method: Prospective cohort of 1735 children (45% females) who had serum sPLA2 enzyme activity levels and other cardiovascular disease risk factors measured in 1980 that were followed-up in 2001. Results: sPLA2 activity tracked from childhood to adulthood for males (r = 0.39) and females (r = 0.45). Those who decreased body mass index relative to their peers were more likely to resolve elevated childhood sPLA2 levels than have persistent elevated sPLA2 levels in childhood and adulthood. Those who consumed less fruit, and gained more body mass index relative to their peers, began smoking or were a persistent smoker between childhood and adulthood were more likely to develop incident elevated sPLA2 levels than those with persistent not elevated sPLA2 levels. Conclusions: Childhood sPLA2 enzyme activity levels associate with adult sPLA2 levels 21 years later. Healthful changes in modifiable risk factors that occur between childhood and adulthood might prevent children from developing elevated sPLA2 levels in adulthood.

Resumo Objetivo: A atividade da enzima fosfolipase A2 secretória (sPLA2) é um possível biomarcador inflamatório de doença cardiovascular. Examinamos o monitoramento, ou a persistência, dos níveis de atividade da enzima sPLA2 da infância à vida adulta e identificamos fatores possivelmente modificáveis que afetam o monitoramento. Método: Coorte prospectiva de 1.735 crianças (45% do sexo feminino) cujos níveis de atividade da enzima sPLA2 no soro e outros fatores de risco para doença cardiovascular foram medidos em 1980 e acompanhados até 2011. Resultados: Atividade da enzima sPLA2 monitorada da infância à vida adulta para indivíduos do sexo masculino (r = 0,39) e sexo feminino (r = 0,45). Aqueles que diminuíram seus índices de massa corporal com relação a seus pares foram mais propensos à redução dos níveis elevados de sPLA2 na infância do que a manter níveis persistentemente elevados de sPLA2 na infância e vida adulta. Aqueles que consumiram menos frutas e ganharam mais índice de massa corporal com relação a seus pares, que começaram a fumar ou foram fumantes persistentes entre a infância e vida adulta foram mais propensos a desenvolver níveis de sPLA2 elevados do que aqueles com níveis de sPLA2 não elevados persistentes. Conclusões: Os níveis de atividade da enzima sPLA2 na infância estão associados aos níveis de sPLA2 na vida adulta, 21 anos mais tarde. As mudanças saudáveis nos fatores de risco modificáveis que ocorrem entre a infância e a vida adulta podem evitar que as crianças desenvolvam níveis elevados de sPLA2 na vida adulta.

Tracking of secretory phospholipase A2 enzyme activity levels from childhood to adulthood: a 21-year cohort.

OBJECTIVE: Secretory phospholipase A2 (sPLA2) enzyme activity is a potential inflammatory biomarker for cardiovascular disease. We examined the tracking, or persistence, of sPLA2 enzyme activity levels from childhood to adulthood, and identify potentially modifiable factors affecting tracking. METHOD: Prospective cohort of 1735 children (45% females) who had serum sPLA2 enzyme activity levels and other cardiovascular disease risk factors measured in 1980 that were followed-up in 2001. RESULTS: sPLA2 activity tracked from childhood to adulthood for males (r=0.39) and females (r=0.45). Those who decreased body mass index relative to their peers were more likely to resolve elevated childhood sPLA2 levels than have persistent elevated sPLA2 levels in childhood and adulthood. Those who consumed less fruit, and gained more body mass index relative to their peers, began smoking or were a persistent smoker between childhood and adulthood were more likely to develop incident elevated sPLA2 levels than those with persistent not elevated sPLA2 levels. CONCLUSIONS: Childhood sPLA2 enzyme activity levels associate with adult sPLA2 levels 21 years later. Healthful changes in modifiable risk factors that occur between childhood and adulthood might prevent children from developing elevated sPLA2 levels in adulthood.

Effect of Dietary Counseling on a Comprehensive Metabolic Profile from Childhood to Adulthood.

OBJECTIVES: To study the effects of repeated, infancy-onset dietary counseling on a detailed metabolic profile. Effects of dietary saturated fat replacement on circulating concentrations of metabolic biomarkers still remain unknown. STUDY DESIGN: The Special Turku Coronary Risk Factor Intervention Project (STRIP) study is a longitudinal, randomized atherosclerosis prevention trial in which repeated dietary counseling aimed at reducing the proportion of saturated fat intake. Nuclear magnetic resonance metabolomics quantified circulating metabolites from serum samples assessed at age 9 (n = 554), 11 (n = 553), 13 (n = 508), 15 (n = 517), 17 (n = 457), and 19 (n = 417) years. RESULTS: The intervention reduced dietary intake of saturated fat (mean difference in daily percentage of total energy intake: -2.1 [95% CI -1.9 to -2.3]) and increased intake of polyunsaturated fat (0.6 [0.5-0.7]). The dietary counseling intervention led to greater serum proportions of polyunsaturated fatty acids (P < .001), with greater proportions of both circulating omega-3 (P = .02) and omega-6 (P < .001) fatty acids. The proportion of saturated fatty acids in serum was lower for both boys and girls in the intervention group (P < .001), whereas the serum proportion of monounsaturated fat was lower for boys in the intervention group only (P < .001). The intervention also reduced circulating intermediate-density lipoprotein and low-density lipoprotein lipid concentrations (P < .01). Dietary intervention effects on nonlipid biomarkers were minor except from greater concentrations of glutamine in the intervention group. CONCLUSIONS: Repeated dietary counseling from infancy to early adulthood yielded favorable effects on multiple circulating fatty acids and lipoprotein subclass lipids, particularly in boys. These molecular effects substantiate the beneficial role of saturated fat replacement on the metabolic risk profile. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00223600.

Continuous and Dichotomous Metabolic Syndrome Definitions in Youth Predict Adult Type 2 Diabetes and Carotid Artery Intima Media Thickness: The Cardiovascular Risk in Young Finns Study.

OBJECTIVES: To examine the utility of continuous metabolic syndrome (cMetS) scores vs a dichotomous metabolic syndrome (MetS) definition in youth to predict adult type 2 diabetes mellitus (T2DM) and carotid intima-media thickness (IMT). STUDY DESIGN: Participants (n = 1453) from the population-based, prospective, observational Cardiovascular Risk in Young Finns Study who were examined in youth (when aged 9-18 years) and re-examined 15-25 years later. Four cMetS scores were constructed according to procedures most often used in the literature that comprised the youth risk factor inputs of body mass index, blood pressure, glucose, insulin, high-density lipoprotein-cholesterol, and triglycerides. Adult outcomes included T2DM and high carotid IMT (≥ 90 th percentile). RESULTS: For a 1 SD increase in cMetS scores in youth, participants had a 30%-78% increased risk of T2DM and 12%-61% increased risk of high carotid IMT. Prediction of adult T2DM and high carotid IMT using cMetS scores in youth was essentially no different to a dichotomous MetS definition with area under the receiver-operating characteristic curve ranging from 0.54-0.60 (continuous definitions) and 0.55-0.59 (dichotomous) with 95% CIs often including 0.5, and integrated discrimination improvement from -0.2% to -0.6%. CONCLUSIONS: cMetS scores in youth are predictive of cardiometabolic outcomes in adulthood. However, they do not have increased predictive utility over a dichotomous definition of MetS.

Association of Adiponectin with Adolescent Cardiovascular Health in a Dietary Intervention Study.

OBJECTIVE: To investigate whether an infancy-onset, low saturated fat-oriented dietary intervention influences serum adiponectin concentration in adolescents, and to study the association of adiponectin with subclinical markers of vascular health, and cardio-metabolic risk factors. STUDY DESIGN: The longitudinal, randomized Special Turku Coronary Risk Factor Intervention Project aimed to modify child's dietary fat quality replacing saturated fat with unsaturated fat. Serum adiponectin (n = 521) along with weight, height, high-density lipoprotein cholesterol, C-reactive protein (CRP), triglycerides, and insulin were measured at age 15 years. Adiposity was assessed using body mass index, waist circumference, and abdominal fat thickness measured with ultrasound. Metabolic syndrome was defined according to International Diabetes Foundation criteria. Vascular ultrasound measures including carotid intima-media thickness (IMT) were assessed. RESULTS: Adiponectin concentrations were similar in the intervention and control groups (P = .16). Adiponectin associated with carotid IMT (r = -0.13, P = .005), high-density lipoprotein cholesterol (r = 0.18, P < .0001), triglycerides (r = -0.16, P = .0004), CRP (r = -0.10, P = .02), insulin (r = -0.14, P = .002), and adiposity (r = -0.18-0.24, P ≤ .0001). When adjusted for adiposity indices, the association with carotid IMT was only marginally diluted (P = .03-.06), but the associations with insulin and CRP became nonsignificant. Adolescents with adiponectin ≤median had 4-fold risk of metabolic syndrome than peers with adiponectin >median (CI 1.8-10.2, P = .0001). CONCLUSIONS: In healthy adolescents, low serum adiponectin is related with carotid IMT and metabolic syndrome. We found no evidence that repeated low saturated fat-oriented dietary counseling would influence serum adiponectin in adolescence. TRIAL REGISTRATION: Registered with ClinicalTrials.gov: NCT00223600.

The association of dietary alpha-linolenic acid with blood pressure and subclinical atherosclerosis in people born small for gestational age: the Special Turku Coronary Risk Factor Intervention Project study.

OBJECTIVE: To determine whether dietary alpha-linolenic (omega-3) fatty acid intake is associated with lower blood pressure and aortic intima-media thickness (IMT) in people born small for gestational age (SGA). STUDY DESIGN: Participants were recruited at age 6 months and followed up every 6-12 months until age 19 years. Blood pressure and food records were assessed at each visit. A total of 1009 participants had at least one blood pressure measure and complete birth weight and gestational age data, including 115 (11%) born SGA (birth weight≤10th percentile). Aortic IMT was assessed by ultrasound at 19 years (n=413). Analysis was by linear mixed models and multivariable linear regression. RESULTS: Children born SGA had greater systolic and pulse pressure from age 14 years onwards. In those born SGA, systolic blood pressure was 2.1 mm Hg lower ([95% CI 0.8-3.3]; P=.001) and pulse pressure 1.4 mm Hg lower ([95% CI 0.3-2.4]; P=.01), per exponential increase in alpha-linolenic acid (ALA) intake; weakened by adjustment for anthropometric measures. Long-term ALA intake was inversely associated with aortic IMT at 19 years in those born SGA (-0.30 mm [95% CI -0.52, -0.08] per exponential greater ALA intake; P=.008), independent of other dietary and anthropometric factors. CONCLUSION: Long-term dietary ALA intake during childhood is associated with improved vascular health in people born SGA.

High lipoprotein(a) concentrations are associated with impaired endothelial function in children.

OBJECTIVE: To examine the association between familial high lipoprotein(a), or Lp(a), concentrations and endothelial function in children participating in the Special Turku Coronary Risk Factor Intervention Project study. STUDY DESIGN: Seven-month-old children (n = 1062) with their families were randomized to a risk intervention group or to a control group. The intervention group received individualized dietary counseling to reduce the total cholesterol concentration. Children's Lp(a) and lipid values were measured repeatedly. At age 11 years, children were recruited to an ultrasound study of the flow-mediated dilation (FMD) of the brachial artery. The association between relative peak FMD and Lp(a) concentration was examined in 198 control and 193 intervention group children by linear regression analyses adjusted for sex, total cholesterol concentration, and basal artery diameter. The analyses were made in both the control and intervention groups and in the familial risk children who had a parent with Lp(a) concentration greater than 250 mg/l. RESULTS: Lp(a) concentrations were similar at age 11 years in the intervention and control groups. In all control children, FMD (%) associated inversely with Lp(a) concentration: (ß [%/1000 mg/L] = -3.74, 95% CI [-6.43, -1.45]; P = .007) and in 68 familial risk children (ß = -4.92, 95% CI [-8.18, -1.66]; P = .0037). In the intervention group the associations were lacking (P > .5), and FMD in the children with high Lp(a) concentrations (>500 mg/L, n = 12) had no attenuation (P = .027). CONCLUSIONS: Familial high Lp(a) concentration is associated with attenuated endothelial function. This association may be mitigated by an early lifestyle intervention. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00223600.

Does initial breastfeeding lead to lower blood cholesterol in adult life? A quantitative review of the evidence

Objective: We aimed to examine whether breastfeeding is associated with lower blood cholesterol concentrations in adulthood...

Amerindian-specific regions under positive selection harbour new lipid variants in Latinos.

Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican-Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans.

Higher maternal body mass index is associated with an increased risk for later type 2 diabetes in offspring.

OBJECTIVES: To investigate whether the body mass index (BMI) of a child's mother is associated with an increased future risk of type 2 diabetes, independent of genetic risk or childhood metabolic, behavioral, and environmental factors. STUDY DESIGN: The analyses were based on the Cardiovascular Risk in Young Finns Study including 1835 individuals aged 3-18 years at baseline with data on maternal BMI, childhood metabolic factors, as well as 34 newly identified type 2 diabetes susceptibility alleles. These subjects were then followed-up over 21-27 years. RESULTS: Maternal BMI (OR for 1-SD increase 1.54 [95% CI 1.12-2.11], P = .008) and child's systolic blood pressure (1.54 [1.01-2.35], P = .04) were significantly associated with increased odds for later type 2 diabetes, in a multivariable analysis adjusted for age, sex, type 2 diabetes genetic risk score, childhood BMI, insulin, lipids, dietary factors, socioeconomic status, and mother's age, and history of type 2 diabetes. A risk prediction model, which included maternal BMI status outperformed one which utilized only child's BMI data (area under the receiver operating characteristic curve 0.720 vs 0.623, P = .02). The inclusion of genetic risk score and other baseline risk variables did not additionally improve prediction (area under the receiver operating characteristic curve 0.720 vs 0.745, P = .40). CONCLUSIONS: Maternal BMI is a useful variable in determining offspring risk of developing type 2 diabetes.

Tracking of serum lipid levels, blood pressure, and body mass index from childhood to adulthood: the Cardiovascular Risk in Young Finns Study.

OBJECTIVES: To examine tracking and predictiveness of childhood lipid levels, blood pressure, and body mass index for risk profile in adulthood and the best age to measure the childhood risk factor levels. STUDY DESIGN: Study subjects were participants of the longitudinal Cardiovascular Risk in Young Finns Study, started in 1980 (age 3, 6, 9, 12, 15, and 18 years). A total of 2204 subjects participated to the 27-year follow-up in 2007 (age, 30 to 45 years). RESULTS: In both sex groups and in all age groups, childhood risk factors were significantly correlated with levels in adulthood. The correlation coefficients for cholesterol levels and body mass index were 0.43 to 0.56 (P < .0001), and for blood pressure and triglyceride levels, they were 0.21 to 0.32 (P < .0001). To recognize children with abnormal adult levels, the National Cholesterol Education Program and the National High Blood Pressure Education Program cutoff points for lipid and blood pressure values and international cutoff points for overweight and obesity were used. Age seemed to affect associations. The best sensitivity and specificity rates were observed in 12- to 18-year-old subjects. CONCLUSIONS: Childhood blood pressure, serum lipid levels, and body mass index correlate strongly with values measured in middle age. These associations seemed to be stronger with increased age at measurements.

WW-domain-containing oxidoreductase is associated with low plasma HDL-C levels.

Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 x 10(-7)). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 x 10(-4) to 2 x 10(-5). Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function.