Comprehensive assessment of variation at the transforming growth factor beta type 1 receptor locus and colorectal cancer predisposition

Abstract

The role of transforming growth factor beta receptor type 1 (TGFBR1) polymorphisms, particularly a coding CGC insertion (rs11466445, TGFBR1*6A/9A) in exon 1, has been extensively investigated in regard to colorectal cancer (CRC) risk. These investigations have generated conflicting results. More recently, allele-specific expression (ASE) of TGFBR1 mRNA has been suggested as predisposing to CRC, with a relative risk of nearly 10-fold and a population attributable risk of approximately 10%. Owing to the potential importance of TGFBR1 variants in CRC, we performed a comprehensive examination of tagging SNPs at and around the gene in 3,101 CRC cases and 3,334 controls of northern European ancestry. To test whether rare or subpolymorphic TGFBR1 variants were associated with CRC risk, we sequenced the gene's exons in a subset of patients. We also evaluated TGFBR1 ASE in a panel of CRC cases and controls. Overall, we found no association between TGFBR1 polymorphisms and CRC risk. The rare variant screen did not identify any changes of potentially pathogenic effects. No evidence of greater ASE in cases than controls was detected, and no haplotype around TGFBR1 could account for the ASE reported in other studies. We conclude that neither genetic variation nor ASE at TGFBR1 is likely to be a major CRC risk factor.

Fig. 1.

Association between SNPs in the TGFBR1 locus haplotypes and CRC risk. Approximate location of TGFBR1 (Top), linkage disequilibrium patterns (r²) in the CEPH 1000genome data (Middle), and −log₁₀ (P values) for the allelic test across the region (Bottom) are shown.

Fig. 2.

Box-and-whiskers plots showing log (allelic dosage) at rs11466445 and rs1590 relative to the geometrical mean for that polymorphism in all samples. Dosage is shown for cases and controls at TGFBR1*6A/9A in cDNA (A), rs1590 in cDNA (B), TGFBR1*6A/9A in gDNA (C), and rs1590 in gDNA (D). Note the outlying samples shown by diamonds.