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A common variant on chromosome 14 confers a 19% lower risk of bladder cancer, in part because of the variant's association with increased length of telomeres.

Houston-A common variant on chromosome 14 confers a 19% lower risk of bladder cancer, in part because of the variant's association with increased length of telomeres, the end caps that help maintain chromosomal integrity and stability.

The findings came from a genome-wide association study to identify genetic determinants of telomere length. Starting with 300,000 single-nucleotide polymorphisms (SNPs), researchers from the University of Texas MD Anderson Cancer Center in Houston honed the list of candidates down to four SNPs, one of which proved to be an independent predictor of telomere length and bladder cancer risk.

"A common human SNP on 14q21 was associated with both telomere length and bladder cancer risk," first author Jian Gu, PhD, said at the 2011 American Association for Cancer Research annual meeting in Orlando, FL.

Telomere length has emerged as a focus of numerous studies examining genetic components of cancer risk. Telomere length decreases as a consequence of aging, and telomere shortening has been implicated in multiple age-related conditions, such as stroke, Alzheimer's disease, diabetes, cardiovascular disease, and cancer. Various forms of chronic stress also can shorten telomeres, increasing chromosomes' susceptibility to mutations.

Dr. Gu and colleagues examined the 300,000 SNPs in 459 healthy individuals and identified 15,120 SNPs that were significantly associated with telomere length (p<.05). Next, they validated the SNPs in two additional independent populations of healthy individuals. The analyses revealed four SNPs that were significantly associated with longer telomere length in all three populations (combined p<10-5 ). The four SNPs included rs398652 on 14q21.

The authors then analyzed the four SNPs with respect to cancer risk in a case-control study involving 969 patients with bladder cancer and 946 healthy controls. They found that carriers of the variant allele of rs398652 had a statistically significant 19% lower risk of bladder cancer (OR 0.81, p=.025), which was consistent with the variant's association with longer telomeres. The other three SNPs were not associated with bladder cancer risk.

Dr. Gu and colleagues conducted a mediation analysis to determine whether the association between rs398652 and reduced bladder cancer risk was mediated entirely by the effect of rs398652 on telomere length. They found that telomere length was a significant mediator of the association between the variant and bladder cancer risk (p=.013), but explained only 14% of the effect.

The rs398652 variant's location on chromosome 14 is near a gene known as PELI2, which is involved in immune and inflammatory responses.

More basic research needed

"We think the remaining portion of the SNP effect on bladder cancer may be caused by inflammation or immune response," Dr. Gu said in a prepared statement. "Understanding the remainder of the risk will require more basic research."

Other research groups had reported associations between telomere length and either cancer risk or genetic variation. The study by Dr. Gu and colleagues is the first to make both connections.

In addition to the presentation at the AACR meeting, findings from the study were published in Cancer Prevention Research (2011; 4:514-21).