Common variants in human CRC genes as low-risk alleles.
The genetic susceptibility to colorectal cancer (CRC) has been estimated to be around 35% and yet high-penetrance germline mutations found so far explain less than 5% of all cases. Much of the remaining variations could be due to the co-inheritance of multiple low penetrant variants. The identification of all the susceptibility alleles could have public health relevance in the near future. To test the hypothesis that what are considered polymorphisms in human CRC genes could constitute low-risk alleles, we selected eight common SNPs for a pilot association study in 1785 cases and 1722 controls. One SNP, rs3219489:G>C (MUTYH Q324H) seemed to confer an increased risk of rectal cancer in homozygous status (OR=1.52; CI=1.06-2.17). When the analysis was restricted to our 'super-controls', healthy individuals with no family history for cancer, also rs1799977:A>G (MLH1 I219V) was associated with an increased risk in both colon and rectum patients with an odds ratio of 1.28 (CI=1.02-1.60) and 1.34 (CI=1.05-1.72), respectively (under the dominant model); while 2 SNPs, rs1800932:A>G (MSH6 P92P) and rs459552:T>A (APC D1822V) seemed to confer a protective effect. The latter, in particular showed an odds ratio of 0.76 (CI=0.60-0.97) among colon patients and 0.73 (CI=0.56-0.95) among rectal patients. In conclusion, our study suggests that common variants in human CRC genes could constitute low-risk alleles.
Picelli
Simone
S
Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
Zajac
Pawel
P
Zhou
Xiao-Lei
XL
Edler
David
D
Lenander
Claes
C
Dalén
Johan
J
Hjern
Fredrik
F
Lundqvist
Nils
N
Lindforss
Ulrik
U
Påhlman
Lars
L
Smedh
Kennet
K
Törnqvist
Anders
A
Holm
Jörn
J
Janson
Martin
M
Andersson
Magnus
M
Ekelund
Susanne
S
Olsson
Louise
L
Lundeberg
Joakim
J
Lindblom
Annika
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019683:Penetrance; D011110:Polymorphism, Genetic; D012307:Risk Factors; D013548:Sweden / Q000453:epidemiology; D055815:Young Adult