Genetic Propensity to Obesity Shows up Early

June 4, 2012 — Infants with a genetic predisposition to obesity are no bigger at birth than other babies, but they quickly surge ahead. They gain more weight by age 3 years than their peers and regain adiposity, which is lost early in childhood, sooner and at a higher body mass index (BMI), according to a study published in the June 4 issue of the Archives of Pediatric & Adolescent Medicine.

Daniel W. Belsky, PhD, postdoctoral fellow at Duke University, Durham, North Carolina, and colleagues examined the association of genetic risk on obesity in a cohort of 1037 predominantly white children in New Zealand who have been followed from birth to age 38 years.

Cohort data included hospital birth weight records, and beginning at age 3 years, the children participated in 12 periodic weight and height measurements and interviews. At the time of the most recent interviews, participants were age 38 years, and the study had a retention rate of more 95%. The study participants, 52% of whom are men, were born in 1972 and 1973. When the children were aged 11 years, researchers obtained parental height and weight through self-report to determine parental BMI.

In the current study, Dr. Belsky and colleagues created a Genetic Risk Score (GRS) using previously identified single nucleotide polymorphisms (SNPs) associated with obesity. When tested in the New Zealand cohort, they found that a high GRS was associated with obesity through the fourth decade of life, independent of parental BMI.

"Children with higher GRSs had higher BMIs at every age assessed, from age 3 through 38 years," the authors write. "In the life-course growth model, higher GRSs predicted higher mean levels of BMI (intercept β = 0.38 [P < .001]), faster growth in childhood (β = 0.03 [P < .001]), and faster growth in adulthood (β = 0.02 [P = .02)."

"These findings have implications for clinical practice and for developmental and epidemiologic research," the authors note. "The results suggest promise for using genetic information in obesity risk assessments."

However, in an accompanying editorial, Jose R. Fernandez, PhD, associate professor, Department of Nutritional Sciences, University of Alabama at Birmingham, counseled caution. "Attempting to translate the findings from Belsky and colleagues to clinical practice would be naive at this point when more research is clearly needed to fully understand the genetic basis of many complex traits. We should keep in perspective that for obesity-related outcomes the environment plays a pivotal role."

Dr. Fernandez notes that BMI is roughly 50% heritable and that the genetic variants identified in genome-wide association studies explain less than 2% of the variation in BMI.

He further cautions against a "one-size-fits-all approach," noting that earlier studies have shown that ethnicity matters, such that results derived from research in 1 ethnic group may not apply to others.

GRS Associated With Obesity Risk

Dr. Belsky and colleagues derived the GRS using previously identified SNPs associated with obesity in genome-wide association studies and validated the measure against data from the Atherosclerosis Risk in Communities (ARIC) sample. They found that European-descent ARIC participants with higher weights and BMIs and larger waist circumferences also had higher GRSs. Those in the highest quintile of GRS distribution had a relative risk (RR) for obesity of 1.73 (95% confidence interval [CI], 1.51 - 1.97) compared with those in the lowest quintile.

This apparent association between GRS and weight starts early, but not during gestation. Using birth weight as their index, the researchers found that high GRS scores did not associate with fetal growth (r, 0.00; P > .90). However, by age 3 years, children with higher GRSs also had higher BMIs compared with their peers (r, 0.08; P = .04) and gained more weight than peers (r, 0.09; P = .01).

As seen in previous research, these children were more likely to become obese in later life. Weight gain from birth to age 3 years partially mediated the genetic risk for obesity in teenagers and for chronic obesity, but not for obesity at ages 21 to 38 years, the researchers found.

Adiposity rebound, the point where children gain body fat after losing it in early childhood, took place earlier in children with high GRSs (r, −0.13; P < .001) and at higher BMIs (r, 0.17; P < .001). Early adiposity rebound at higher BMI also increased the risk for later obesity.

GRS proved predictive of obesity regardless of parental BMI. "[T]he GRS contributed independent and additive information to the prediction of children's growth and their risk for obesity in adulthood beyond the family history information," the authors write.

In data adjusted for sex, children in the highest-risk GRS group were 2.41 times (95% CI, 1.31 - 4.41) more likely to be obese from age 11 to 20 years than children in the low-risk group, were 1.76 times (95% CI, 1.20 - 2.63) more likely to be obese at ages 21 to 30 years, and were 1.61 times (95% CI, 1.25 - 2.10) more likely to be obese at ages 31 to 38 years. Children with a high GRS were 1.90 times more likely to be obese than those with a low score (95% CI, 1.21 - 3.07).

The authors and editorialist have disclosed no relevant financial relationships.

Arch Pediatr Adolesc Med. 2012;166:515-521, 576-577. Article full text, Editorial full text