A comprehensive resequence analysis of the KLK15-KLK3-KLK2 locus on chromosome 19q13.33.
Single nucleotide polymorphisms (SNPs) in the KLK3 gene on chromosome 19q13.33 are associated with serum prostate-specific antigen (PSA) levels. Recent genome wide association studies of prostate cancer have yielded conflicting results for association of the same SNPs with prostate cancer risk. Since the KLK3 gene encodes the PSA protein that forms the basis for a widely used screening test for prostate cancer, it is critical to fully characterize genetic variation in this region and assess its relationship with the risk of prostate cancer. We have conducted a next-generation sequence analysis in 78 individuals of European ancestry to characterize common (minor allele frequency, MAF >1%) genetic variation in a 56 kb region on chromosome 19q13.33 centered on the KLK3 gene (chr19:56,019,829-56,076,043 bps). We identified 555 polymorphic loci in the process including 116 novel SNPs and 182 novel insertion/deletion polymorphisms (indels). Based on tagging analysis, 144 loci are necessary to tag the region at an r (2) threshold of 0.8 and MAF of 1% or higher, while 86 loci are required to tag the region at an r (2) threshold of 0.8 and MAF >5%. Our sequence data augments coverage by 35 and 78% as compared to variants in dbSNP and HapMap, respectively. We observed six non-synonymous amino acid or frame shift changes in the KLK3 gene and three changes in each of the neighboring genes, KLK15 and KLK2. Our study has generated a detailed map of common genetic variation in the genomic region surrounding the KLK3 gene, which should be useful for fine-mapping the association signal as well as determining the contribution of this locus to prostate cancer risk and/or regulation of PSA expression.
Parikh
Hemang
H
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Gaithersburg, MD 20877, USA.
Deng
Zuoming
Z
Yeager
Meredith
M
Boland
Joseph
J
Matthews
Casey
C
Jia
Jinping
J
Collins
Irene
I
White
Ariel
A
Burdett
Laura
L
Hutchinson
Amy
A
Qi
Liqun
L
Bacior
Jennifer A
JA
Lonsberry
Victor
V
Rodesch
Matthew J
MJ
Jeddeloh
Jeffrey A
JA
Albert
Thomas J
TJ
Halvensleben
Heather A
HA
Harkins
Timothy T
TT
Ahn
Jiyoung
J
Berndt
Sonja I
SI
Chatterjee
Nilanjan
N
Hoover
Robert
R
Thomas
Gilles
G
Hunter
David J
DJ
Hayes
Richard B
RB
Chanock
Stephen J
SJ
Amundadottir
Laufey
L
D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D054643:INDEL Mutation; D007610:Kallikreins / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017430:Prostate-Specific Antigen / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000208:ethnology / Q000235:genetics; D017422:Sequence Analysis, DNA; D020840:Tissue Kallikreins / Q000235:genetics*; D044465:White People / Q000235:genetics
C501608:KLK15 protein, human; D007610:Kallikreins; D020840:Tissue Kallikreins; D017430:Prostate-Specific Antigen