Body mass index and incidence of lung cancer in the HUNT study: using observational and Mendelian randomization approaches

Abstract

Background Traditional observational studies have shown an inverse association between body mass index (BMI) and lung cancer risk. Mendelian randomization (MR) analysis using genetic variants as instruments for BMI may clarify the nature of the association. Aims We studied the causal association between BMI and lung cancer incidence using observational and MR approaches. Methods We followed up 62,453 cancer-free Norwegian adults from 1995–97 (HUNT2) until 2017. BMI at baseline in HUNT2 was classified as < 25.0, 25.0–29.9 and ≥ 30.0 kg/m2. BMI change over ten years between HUNT1 (1984–86) and HUNT2 was calculated and classified into quartiles. Seventy-five genetic variants were included as instruments for BMI (among which 14 also associated with smoking behavior). Incident lung cancer cases were ascertained from the Cancer Registry of Norway. Cox regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Multivariable MR was used to examine the effect of BMI after genetically controlling for smoking. Results During a median follow-up of 21.1 years, 1009 participants developed lung cancer including 327 with lung adenocarcinoma. The HRs and 95% CIs for incidence of adenocarcinoma were 0.73 (0.58–0.92) for BMI 25.0–29.9 kg/m2 and 0.53 (0.37–0.76) for BMI ≥ 30 kg/m2 compared with BMI < 25.0 kg/m2 in HUNT2 (P for trend < 0.001). However, there was little evidence of a dose–response relationship between the BMI change from HUNT1 to HUNT2 in quartiles and the incidence of adenocarcinoma (P for trend = 0.08). Furthermore, multivariable MR approach suggested a positive association between genetically determined 1 kg/m2 increase in BMI and the incidence of adenocarcinoma (HR 1.25, 95% CI 1.02–1.53). No associations were found with other lung cancer histologic types. Conclusions Our study suggests that the inverse association between baseline BMI and lung adenocarcinoma in observational analysis may not be causal. More MR studies are needed to confirm our finding of a positive association between BMI and lung adenocarcinoma.

Mendelian randomization to explore the direct or mediating associations between socioeconomic status and lung cancer

“…Decreased BMI was also found to be associated with poorer overall survival of lung cancer, while weight gain increased the risk of death but was not statistically significant ( 50 ). Other studies have found a positive correlation between BMI and the incidence of lung cancer or lung adenocarcinoma ( 51 , 52 ). Additionally, an observational study showed that higher BMI was associated with a lower risk of lung cancer ( 53 ).…”

Body mass index and lung cancer risk: Pooled analysis of 10 prospective cohort studies in Japan

“…The emergence of MR—an approach using genetic variants as instrumental variables to approximate environmental exposure—has offered a solution to circumvent the limitations (confounding and reverse causation) that are inherent in observational studies 33 . Several MR studies revealed that genetically predicted BMI was associated with an increased risk of lung cancer of all types, 34–38 a finding that contrasts with the inverse association seen in observational studies. One interpretation is that MR studies evaluated the association of lung cancer with static, genetically determined BMI throughout one's lifetime, while observational studies often examined associations with one single baseline BMI measurement in adulthood.…”

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“…A separate study used data from the HUNT study to examine the causal association between BMI and lung cancer incidence using observational and Mendelian randomization approaches and found that BMI was inversely associated with lung adenocarcinoma but not with other lung cancer types [14].…”