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. 2019 Apr;28(4):715-723.
doi: 10.1158/1055-9965.EPI-18-0935. Epub 2019 Mar 20.

Cross-Cancer Pleiotropic Associations with Lung Cancer Risk in African Americans

Carissa C Jones  1   2 , Yuki Bradford  3 , Christopher I Amos  4 , William J Blot  5 , Stephen J Chanock  6 , Curtis C Harris  7 , Ann G Schwartz  8 , Margaret R Spitz  4 , John K Wiencke  9 , Margaret R Wrensch  9   10   11 , Xifeng Wu  12 , Melinda C Aldrich  13   2   5   14
Affiliations

Cross-Cancer Pleiotropic Associations with Lung Cancer Risk in African Americans

Carissa C Jones et al. Cancer Epidemiol Biomarkers Prev. 2019 Apr.

Abstract

Background: Identifying genetic variants with pleiotropic associations across multiple cancers can reveal shared biologic pathways. Prior pleiotropic studies have primarily focused on European-descent individuals. Yet population-specific genetic variation can occur, and potential pleiotropic associations among diverse racial/ethnic populations could be missed. We examined cross-cancer pleiotropic associations with lung cancer risk in African Americans.

Methods: We conducted a pleiotropic analysis among 1,410 African American lung cancer cases and 2,843 controls. We examined 36,958 variants previously associated (or in linkage disequilibrium) with cancer in prior genome-wide association studies. Logistic regression analyses were conducted, adjusting for age, sex, global ancestry, study site, and smoking status.

Results: We identified three novel genomic regions significantly associated (FDR-corrected P <0.10) with lung cancer risk (rs336958 on 5q14.3, rs7186207 on 16q22.2, and rs11658063 on 17q12). On chromosome16q22.2, rs7186207 was significantly associated with reduced risk [OR = 0.43; 95% confidence interval (CI), 0.73-0.89], and functional annotation using GTEx showed rs7186207 modifies DHODH gene expression. The minor allele at rs336958 on 5q14.3 was associated with increased lung cancer risk (OR = 1.47; 95% CI, 1.22-1.78), whereas the minor allele at rs11658063 on 17q12 was associated with reduced risk (OR = 0.80; 95% CI, 0.72-0.90).

Conclusions: We identified novel associations on chromosomes 5q14.3, 16q22.2, and 17q12, which contain HNF1B, DHODH, and HAPLN1 genes, respectively. SNPs within these regions have been previously associated with multiple cancers. This is the first study to examine cross-cancer pleiotropic associations for lung cancer in African Americans.

Impact: Our findings demonstrate novel cross-cancer pleiotropic associations with lung cancer risk in African Americans.

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Conflict of interest statement

The authors declare no potential conflicts of interest.

Figures

Figure 1.
Figure 1.
Manhattan plot of genetic association p-values. Logistic regression models for lung cancer risk show several novel and known genetic associations among African Americans. Red line represents 10% false discovery rate.
Figure 2.
Figure 2.
Rank normalized gene expression. Single nucleotide polymorphism rs7186207 in DHODH is an expression quantitative trait loci (eQTL) (p-value=2.1×10−7) in lung tissue. The data and figure is from the GTEx Portal (48). Homozygous reference (Homo Ref) represents TT genotype, Heterozygous (Het) represents TC genotype and Homozygous Alternative (Homo Alt) represents CC genotype.
See this image and copyright information in PMC

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