More About Eating Than Genetics

“While a healthy lifestyle is always to strive for, findings from the current study and previous work indicate that obesity influenced by environmental factors may be more deleterious than obesity influenced by genetic factors,” the group concluded.

By examining only identical twins within the cohort, researchers were able to eliminate the difference in the link between obesity and polygenic risk score across the categories.

Influence of Obesity on Health Might Be More Dependent on Environmental Factors Than Genetics

“Importantly, this indicates that the negative health effects of obesity may be influenced by other factors, rather than by the obesity in itself, as we would otherwise expect similar effects of obesity, regardless of if it is predicted by genetic predisposition or environmental factors,” Karlsson and colleagues suggested.

They also noted that this is not an isolated finding, pointing to heterogeneity in genetically versus environmentally driven obesity seen in U.S. data for important outcomes such as dementia and mortality.

The study included data from sub-studies of the Swedish Twin Registry, a population-based register of nearly all twins born in the country. The study included 15,786 Swedish twins born before 1959 with BMIs measured at ages 40-64 and 5,488 with BMIs measured at age 65 or later (3,286 were in both groups). CVD was determined using prospective data from linked nationwide healthcare and cause of death registries through 2016, with an average follow-up of 18 years.

Genotyping was available in all of the included registry sub-studies (conducted between 1984 and 2010) to generate individuals’ polygenic scores for BMI. The risk score was derived from the most recent genome-wide association study for BMI, which identified 941 genetic variants that were significantly associated with BMI and explained 6-14% of the trait variance.

When adjusted for gender and age when BMI was measured, each standard deviation higher polygenic risk score was associated with a 1.23 (95% CI 1.07-1.18) unit higher BMI in midlife and a 1.16 (95% CI 1.07-1.26) unit higher BMI in late life. The estimates were unaffected by adjustments for smoking and education. When the polygenic risk score was elevated by one standard deviation compared to the average, people with obesity had a 14% lower CVD risk.

Obesity’s Link to Mortality in Late Life: A Complex Relationship

“Results were similar when obesity was measured in late life, but suffered from low power,” Karlsson and team noted, although they acknowledged that “the causes and consequences of overweight or obesity in late life are more complicated, with evidence of an inverse association with mortality.”

The researchers also looked at pairs of twins: 3,124 fraternal and 2,020 identical twins with BMI assessed in midlife to determine genetic factors not captured by those variants in the polygenic risk score. 769 and 443 pairs were discordant for CVD status, respectively.

“As twins share both DNA (to a varying extent), in utero environment, and early life environment, the co-twin control design elegantly controls for such confounding,” the researchers wrote. Prior twin studies have estimated the heritability of BMI at 45-85%.

The associations were masked in these analyses. The hazard ratios for the impact of obesity on CVD risk in identical twin pairs were 1.14 (95% CI 0.64-2.02) and 1.64 (95% CI 1.11-2.42) in fraternal twin pairs.

Role of Genetics in the Link between Obesity and Cardiovascular Disease

The difference in the CVD-obesity link between those genetically predicted to have a low versus high BMI disappeared when identical twin pairs were sorted into polygenic risk score groups (HR 1.21 and 1.29, respectively).

“If effect estimates remain stable within twin pairs (especially within monozygotic twin pairs, sharing identical DNA) it indicates, but is not proof of, a causal association,” Karlsson and team noted. “In contrast, if the effect estimate is close to zero within twin pairs, it is strong evidence against a causal association, as it indicates that the association is driven by genetic or another familial confounding.”

The study’s limitations included the use of self-measured height and weight data in the analyses for calculating BMI, which could have resulted in some misclassification, biassing the findings towards the null if non-differential about the outcome. Furthermore, the registries lacked primary care data, which would have made finding associations with milder CVD impossible.

“Even though we all know that it takes more than exercise and diet to combat obesity, there’s still a large stigma attached to it,” Karlsson said in a statement. “I think much could be gained by focusing on what has caused the obesity and what we can do to reduce the risk of comorbidities in each individual instead of mainly focusing on BMI.”

Source: Medindia