Metabolome-wide association study identified the association between a circulating polyunsaturated fatty acids variant rs174548 and lung cancer

Abstract

Quantitative trait loci (QTLs) are widely used as instruments to infer causal risk factors of diseases based on the idea of mendelian randomization. Plasma metabolites can serve as risk factors of cancer, and the heritability of many circulating metabolites was high. We conducted a metabolome-wide association study (MWAS) to systematically investigate the effects of genetic variants on metabolites and lung cancer based on published genome-wide association study (GWASs) and metabolic-QTL (mQTL) study. Then we confirmed the results by subsequent genetic and metabolic validations and inferred the causal relationship between identified metabolites and lung cancer through genetic variant(s). We firstly identified six polyunsaturated fatty acids (PUFAs) represented by rs174548-linked haplotype were significantly associated with lung cancer risk in a Chinese GWAS (2311 cases and 3077 controls). Rs174548 was further confirmed to be associated with lung cancer in 13 821 Europeans and 18 471 Asians (ORmeta = 0.87, Pmeta = 1.76 × 10-15) and the effect was much stronger in females (Pinteraction = 6.00 × 10-4). We next validated rs174548-plasma PUFA association in 253 Chinese subjects (β = -0.57, P = 1.68 × 10-3). Rs174548 was also found associated with FADS1 (the major fatty acid desaturase of identified PUFAs) expression in liver tissues. Taken together, we found that rs174548 was associated with both PUFAs and lung cancer. Because rs174548 was the only mQTL variant of PUFAs reported by previous GWASs and explained a large proportion of heritability, we proposed that plasma PUFAs could be causally associated with lung cancer based on the idea of mendelian randomization. These findings provide a diet-related risk factor and may have important implications for prevention on lung cancer.

Independent and joint associations of blood lipids and lipoproteins with lung cancer risk in Chinese males: A prospective cohort study

“…11 A recent metaanalysis that pooled all the individual studies above found a significant association between low levels of TC and increased lung cancer risk (RR highest vs. lowest = 0.89, 95%CI: 0.83-0.94), which was consistent with the results of the present study. 25 Additionally, a metabolome-wide association study (MWAS) proposed that higher levels of plasma polyunsaturated fatty acids (PUFAs), which can lower TC levels, might be a causal risk factor for lung cancer 26 and could further explain the inverse association between TC and lung cancer. The differences in sample size, races, grouping of blood lipid levels and integrity of potential confounders that were adjusted for might explain the variation in the results to some extent.…”

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region

“…Very rarely, individuals can carry inherited mutations in TP53 increasing lung cancer risk. 49 The availability of results from our GWAS will allow additional exposures to be studied using Mendelian Randomization approaches (as exemplified in Wang et al 50 ). Developing models that can identify never-smokers at highest risk for lung cancer development could improve early detection.…”

Cross-Cancer Pleiotropic Analysis Reveals Novel Susceptibility Loci for Lung Cancer

“…While the protective allele of rs2516448 and rs7193541 were related to decreased expression of MICA (β = −0.34, P = 1.50 × 10 −14 , Supplementary Figure 2D) and RFWD3 (β = −0.23, P = 2.20 × 10 −7 , Supplementary Figure 2E). The rs174549 was in high LD with rs174548 (r 2 = 0.98), which was proven to be correlated with lung cancer risk by regulating FADS1 gene expression in liver tissues (β = −0.23, P = 2.20 × 10 −7 , Supplementary Figure 2F) and plasma levels of polyunsaturated fatty acids (PUFAs) according to our recent study (22).…”

“…Rs3869062 showed significant association with increased expression of HLA-G, which has been reported to be involved in immune recognition and might manipulate tumor specific immune responses through cytokine production (40). For rs174549, a recent metabolome-wide association study identified its high LD (r 2 = 0.98) variant, rs174548, associated with both plasma levels of polyunsaturated fatty acids (PUFAs) and lung cancer risk, proposing that plasma PUFAs might function as risk indicator of lung cancer (22). However, challenge remains to unravel the molecular mechanisms underlying observations and further investigations are needed.…”