Genetic predisposition to higher body fat yet lower cardiometabolic risk in children and adolescents

Most obese children show cardiometabolic impairments, such as insulin resistance, dyslipidemia, and hypertension. Yet some obese children retain a normal cardiometabolic profile. The mechanisms underlying this variability remain largely unknown. We examined whether genetic loci associated with increased insulin sensitivity and relatively higher fat storage on the hip than on the waist in adults are associated with a normal cardiometabolic profile despite higher adiposity in children. We constructed a genetic score using variants previously linked to increased insulin sensitivity and/or decreased waist–hip ratio adjusted for body mass index (BMI), and examined the associations of this genetic score with adiposity and cardiometabolic impairments in a meta-analysis of six cohorts, including 7391 European children aged 3–18 years. The genetic score was significantly associated with increased degree of obesity (higher BMI-SDS beta = 0.009 SD/allele, SE = 0.003, P = 0.003; higher body fat mass beta = 0.009, SE = 0.004, P = 0.031), yet improved body fat distribution (lower WHRadjBMI beta = −0.014 SD/allele, SE = 0.006, P = 0.016), and favorable concentrations of blood lipids (higher HDL cholesterol: beta = 0.010 SD/allele, SE = 0.003, P = 0.002; lower triglycerides: beta = −0.011 SD/allele, SE = 0.003, P = 0.001) adjusted for age, sex, and puberty. No differences were detected between prepubertal and pubertal/postpubertal children. The genetic score predicted a normal cardiometabolic profile, defined by the presence of normal glucose and lipid concentrations, among obese children (OR = 1.07 CI 95% 1.01–1.13, P = 0.012, n = 536). Genetic predisposition to higher body fat yet lower cardiometabolic risk exerts its influence before puberty.


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The prevalence of pediatric overweight and obesity has increased worldwide during the past 82 decades (1). Most overweight or obese children exhibit cardiometabolic risk factors, such as 83 insulin resistance, impaired glucose tolerance, dyslipidemia, and elevated blood pressure (2). 84 However, depending on the criteria used, 3-68% of obese children and adolescents have been 85 found to have a cardiometabolic risk profile within normal range, a controversial condition 86 sometimes called "metabolically healthy obesity" (3). While the clinical usefulness and 87 stability of this condition have been questioned, these observations suggest that the effect of 88 body adiposity on cardiometabolic health may vary among children and adolescents (3). The 89 mechanisms underlying such differences remain largely unknown. 90 In adult populations, many genetic variants associated with increased insulin 91 sensitivity (4) and relatively higher fat storage on the hip than on the waist (5), are related to 92 increased body fatness, yet improved cardiometabolic risk profile. These findings may reflect 93 an enhanced ability to store fat subcutaneously, which may lead to a decreased accumulation 94 of ectopic fat and prevention of lipotoxic effects (6, 7). While it remains unclear whether such 95 effects are already apparent in childhood, longitudinal studies suggest that some obese children 96 with a favorable metabolic profile may preserve the phenotype into adulthood (8). This 97 indicates that the underlying mechanisms may be partly shared between children and adults. 98 Identification of genetic variation contributing to the link between adiposity and its 99 complications in children and adolescents is important, as it could shed light on the underlying 100 mechanisms and help distinguishing between the children who are most and least prone to 101 developing cardiometabolic impairments upon weight gain. 102 Here, we report the results of a meta-analysis of 7 391 children and adolescents from 103 Finland, Denmark, and the United Kingdom, showing that genetic predisposition to increased 104 body fat yet improved metabolic profile is observed in both pre-pubertal and post-pubertal  Nutrition in Children (PANIC) study (13); and 326 Danish children 3 years of age from the 119 Småbørns Kost Og Trivsel I and II (SKOT) studies (14). We excluded children without genetic 120 data or BMI, and children with known history of type 1 diabetes (31 children), type 2 diabetes 121 (2 children), mental or developmental disorders (29 children) or known monogenic forms of 122 obesity (21 children). We also excluded children with non-European ancestry or with known 123 medication for hypercholesterolemia or hypertension. For twin-pairs, one twin was excluded.

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All studies were conducted in accordance with the principles of the Declaration of Helsinki

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To construct genetic scores, we used 53 single nucleotide polymorphisms (SNPs) 169 previously reported to associate with an insulin resistance-related phenotype (defined as higher    Table 4). 255 Recently, an analysis comparing the obese and population-based samples of the  5-6, Figure 3), whereas no significant differences 263 between the groups were detected for other cardiometabolic traits.

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When stratifying the analyses according to pubertal status, we found that the 265 associations of the combined score with adiposity and cardiometabolic traits were consistent 266 between pre-pubertal (Supplemental Table 7) and pubertal/post-pubertal (Supplemental 267   Table 8) children and adolescents (Supplemental Figure 2), suggesting that genetic 268 predisposition to increased body fat yet improved cardiometabolic profile exerts its influence 269 already before puberty.

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When comparing the effect of the combined score between girls (Supplemental 271   Table 9) and boys (Supplemental Table 10), no significant differences between the groups 272 were detected (Supplemental Figure 3). 273    Our findings may reflect a beneficial impact of the genetic score on the ability to store 320 fat subcutaneously rather than viscerally or otherwise ectopically, which has been suggested to 321 be an underlying mechanism for both insulin resistance and WHRadjBMI loci (4, 5).

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Subcutaneous fat tissue is the naturally preferred place to store lipids, and when its capacity 323 becomes saturated, the excess fat may "over spill" to non-adipose tissues (34). The excess of 324 14 lipids may then accumulate in metabolically relevant organs such as pancreatic beta cells, liver, 325 heart, and skeletal muscle, where they may lead to lipotoxic effects.

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Given that increased muscle mass has a favorable effect on cardiometabolic health, we 327 also studied whether the association of the genetic score with increased BMI could be due to 328 increased muscle mass. However, the genetic score showed strong association with increased 329 body fat mass but no association with body lean mass, which suggests that the underlying 330 genetic mechanisms are mainly related to adipose tissue (4, 5). Aerobic fitness has a beneficial 331 impact on cardiometabolic health, independent of body adiposity. While it remains to be 332 examined whether the genetic score is associated with aerobic fitness, such association seems 333 unlikely considering the adipose-related effect of this score.

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Our results underline that some children and adolescents may be genetically more  In contrast to other cardiometabolic variables, we found that the adiposity-increasing 350 genetic score we examined was not associated with beneficial effects on blood pressure. In 351 contrast, we found an association with increased blood pressure, suggesting that biological 352 mechanisms regulating the link between increased body fatness and elevated blood pressure 353 may be distinct from those regulating the relationship between body fatness and other 354 cardiometabolic risk factors. Indeed, body fatness is suggested to impact blood pressure largely 355 through mechanical stress and chronic over activation of the sympathetic nervous system, 356 acting independently from the pathways regulating insulin resistance and dyslipidemia (37). 357 We also found that the adiposity increasing genetic score predicted the absence of  Puberty is a time of considerable metabolic and hormonal changes and is associated 362 with a marked decrease in insulin sensitivity (38). It has been reported that obese adolescents 363 do not sustain insulin sensitivity at the end of puberty (39). Therefore, the stability of 364 cardiometabolically normal profile among obese children in puberty has been questioned and 365 entering puberty has been considered as a predictor for switching from "metabolically healthy" 366 to unhealthy obese state (39). In the present study, we found that the adiposity-increasing yet 367 metabolically beneficial effects of the genetic score were found independent of pubertal status, 368 suggesting that the underlying biological mechanisms may be functioning already before  The limitations of our study include the heterogeneity between the six study 393 cohorts in age composition, sample size, and measurement methods for blood pressure, body 394 composition, puberty assessment, and fasting insulin. Considering that the observed 395 differences in adiposity and cardiometabolic characteristics were rather small, even when    Linear regression analysis to test the association of the combined insulin sensitivity-increasing and 545 WHRadjBMI-decreasing genetic score with adiposity and cardiometabolic variables in all children and 546 adolescents as beta values (standard errors) of the inverse-normally transformed traits. The results are 547 aligned according to the insulin sensitivity-increasing/ WHRadjBM-decreasing allele of the genetic score. 548 All analyses are adjusted for age, sex, puberty and first three genome-wide principal components. The 549 effects were pooled using fixed effects models meta-analysis. *P-values <0.05. The numerical values 550 for betas, standard errors, p-values and the number of subjects are presented in Supplemental Table 3. 551