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1.  Genetic variation in KLK2 and KLK3 is associated with levels of hK2 and PSA in seminal plasma and in serum in young men 
Clinical chemistry  2013;60(3):490-499.
Genetic variants in KLK2 and KLK3 have been associated with increased serum levels of their encoded proteins human kallikrein-related peptidase 2 (hK2) and prostate-specific antigen (PSA), and with prostate cancer in older men. Catalytic PSA, possibly activated by hK2, cleaves semenogelin I and II in semen to release motile sperm; low PSA levels in seminal plasma are associated with low sperm motility. To evaluate whether common genetic variants in KLK2 and KLK3 affect physiological prostatic secretion, we studied the association of SNPs with hK2 and PSA levels in seminal plasma and serum of young healthy men.
Leukocyte DNA was extracted from 303 male military conscripts (median age 18.1 years). Nine SNPs across KLK2-KLK3 were genotyped. PSA and hK2 were measured in seminal plasma and serum with immunofluorometric assays. The association of genotype frequencies with hK2 and PSA levels was tested using the Kruskal-Wallis test.
Four KLK2 SNPs (rs198972, rs198977, rs198978, and rs80050017) were strongly associated with hK2 levels in seminal plasma and serum, with individuals homozygous for the major alleles having 3- to 7-fold higher levels than the other homozygote and heterozygotes having intermediate levels (all P<0.001). Three of these SNPs were significantly associated with %fPSA in serum (all P<0.007). Three KLK3 SNPs showed associations with PSA in seminal plasma and the rs1058205 SNP was associated with total PSA in serum (P=0.001), and with lower %free PSA (P=0.015).
In young men without prostate disease, both the seminal plasma and serum levels of hK2 and PSA are associated with several genetic variants in KLK2 and KLK3 that could be used to refine models of PSA cut-off values in prostate cancer testing.
PMCID: PMC3943614  PMID: 24270797
prostate cancer; prostate-specific antigen; tumor markers; seminal fluid
2.  Susceptibility Loci Associated with Prostate Cancer Progression and Mortality 
Prostate cancer is a heterogenous disease with a variable natural history that is not accurately predicted by currently used prognostic tools.
Experimental Design
We genotyped 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to clinical data. The survival analysis was adjusted for Gleason score and PSA. We investigated associations between 29 single nucleotide polymorphisms (SNPs) and biochemical recurrence, castration-resistant metastasis, and prostate cancer-specific survival. Subsequently, we performed an independent analysis using a high resolution panel of 13 SNPs.
On univariate analysis, 2 SNPs were associated (p<0.05) with biochemical recurrence; 3 SNPs were associated with clinical metastases; and 1 SNP was associated with prostate cancer-specific mortality. Applying a Bonferroni correction (p<0.0017), one association with biochemical recurrence (p=0.0007) was significant. Three SNPs showed associations on multivariable analysis, although not after correcting for multiple testing. The secondary analysis identified an additional association with prostate cancer-specific mortality in KLK3 (p<0.0005 by both univariate and multivariable analysis).
We identified associations between prostate cancer susceptibility SNPs and clinical endpoints. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region associated strongly with prostate cancer-specific survival, and rs10486567 in 7JAZF1 gene associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models.
PMCID: PMC3732009  PMID: 20460480
Single nucleotide polymorphisms; Prostate cancer; Prognosis
3.  Copy Number Variants in the Kallikrein Gene Cluster 
PLoS ONE  2013;8(7):e69097.
The kallikrein gene family (KLK1-KLK15) is the largest contiguous group of protease genes within the human genome and is associated with both risk and outcome of cancer and other diseases. We searched for copy number variants in all KLK genes using quantitative PCR analysis and analysis of inheritance patterns of single nucleotide polymorphisms. Two deletions were identified: one 2235-bp deletion in KLK9 present in 1.2% of alleles, and one 3394-bp deletion in KLK15 present in 4.0% of alleles. Each deletion eliminated one complete exon and created out-of-frame coding that eliminated the catalytic triad of the resulting truncated gene product, which therefore likely is a non-functional protein. Deletion breakpoints identified by DNA sequencing located the KLK9 deletion breakpoint to a long interspersed element (LINE) repeated sequence, while the deletion in KLK15 is located in a single copy sequence. To search for an association between each deletion and risk of prostate cancer (PC), we analyzed a cohort of 667 biopsied men (266 PC cases and 401 men with no evidence of PC at biopsy) using short deletion-specific PCR assays. There was no association between evidence of PC in this cohort and the presence of either gene deletion. Haplotyping revealed a single origin of each deletion, with most recent common ancestor estimates of 3000-8000 and 6000-14 000 years for the deletions in KLK9 and KLK15, respectively. The presence of the deletions on the same haplotypes in 1000 Genomes data of both European and African populations indicate an early origin of both deletions. The old age in combination with homozygous presence of loss-of-function variants suggests that some kallikrein-related peptidases have non-essential functions.
PMCID: PMC3718828  PMID: 23894413
4.  Investigating highly replicated asthma genes as candidate genes for allergic rhinitis 
BMC Medical Genetics  2013;14:51.
Asthma genetics has been extensively studied and many genes have been associated with the development or severity of this disease. In contrast, the genetic basis of allergic rhinitis (AR) has not been evaluated as extensively. It is well known that asthma is closely related with AR since a large proportion of individuals with asthma also present symptoms of AR, and patients with AR have a 5–6 fold increased risk of developing asthma. Thus, the relevance of asthma candidate genes as predisposing factors for AR is worth investigating. The present study was designed to investigate if SNPs in highly replicated asthma genes are associated with the occurrence of AR.
A total of 192 SNPs from 21 asthma candidate genes reported to be associated with asthma in 6 or more unrelated studies were genotyped in a Swedish population with 246 AR patients and 431 controls. Genotypes for 429 SNPs from the same set of genes were also extracted from a Singapore Chinese genome-wide dataset which consisted of 456 AR cases and 486 controls. All SNPs were subsequently analyzed for association with AR and their influence on allergic sensitization to common allergens.
A limited number of potential associations were observed and the overall pattern of P-values corresponds well to the expectations in the absence of an effect. However, in the tests of allele effects in the Chinese population the number of significant P-values exceeds the expectations. The strongest signals were found for SNPs in NPSR1 and CTLA4. In these genes, a total of nine SNPs showed P-values <0.001 with corresponding Q-values <0.05. In the NPSR1 gene some P-values were lower than the Bonferroni correction level. Reanalysis after elimination of all patients with asthmatic symptoms excluded asthma as a confounding factor in our results. Weaker indications were found for IL13 and GSTP1 with respect to sensitization to birch pollen in the Swedish population.
Genetic variation in the majority of the highly replicated asthma genes were not associated to AR in our populations which suggest that asthma and AR could have less in common than previously anticipated. However, NPSR1 and CTLA4 can be genetic links between AR and asthma and associations of polymorphisms in NPSR1 with AR have not been reported previously.
PMCID: PMC3653682  PMID: 23663310
Allergic rhinitis; Association; Asthma; Case–control; Replication
5.  Poor Reproducibility of Allergic Rhinitis SNP Associations 
PLoS ONE  2013;8(1):e53975.
Replication of reported associations is crucial to the investigation of complex disease. More than 100 SNPs have previously been reported as associated with allergic rhinitis (AR), but few of these have been replicated successfully. To investigate the general reproducibility of reported AR-associations in candidate gene studies, one Swedish (352 AR-cases, 709 controls) and one Singapore Chinese population (948 AR-cases, 580 controls) were analyzed using 49 AR-associated SNPs. The overall pattern of P-values indicated that very few of the investigated SNPs were associated with AR. Given published odds ratios (ORs) most SNPs showed high power to detect an association, but no correlations were found between the ORs of the two study populations or with published ORs. None of the association signals were in common to the two genome-wide association studies published in AR, indicating that the associations represent false positives or have much lower effect-sizes than reported.
PMCID: PMC3559641  PMID: 23382861
6.  Toll-like receptor gene polymorphisms are associated with allergic rhinitis: a case control study 
BMC Medical Genetics  2012;13:66.
The Toll-like receptor proteins are important in host defense and initiation of the innate and adaptive immune responses. A number of studies have identified associations between genetic variation in the Toll-like receptor genes and allergic disorders such as asthma and allergic rhinitis. The present study aim to search for genetic variation associated with allergic rhinitis in the Toll-like receptor genes.
A first association analysis genotyped 73 SNPs in 182 cases and 378 controls from a Swedish population. Based on these results an additional 24 SNPs were analyzed in one Swedish population with 352 cases and 709 controls and one Chinese population with 948 cases and 580 controls.
The first association analysis identified 4 allergic rhinitis-associated SNPs in the TLR7-TLR8 gene region. Subsequent analysis of 24 SNPs from this region identified 7 and 5 significant SNPs from the Swedish and Chinese populations, respectively. The corresponding risk-associated haplotypes are significant after Bonferroni correction and are the most common haplotypes in both populations. The associations are primarily detected in females in the Swedish population, whereas it is seen in males in the Chinese population. Further independent support for the involvement of this region in allergic rhinitis was obtained from quantitative skin prick test data generated in both populations.
Haplotypes in the TLR7-TLR8 gene region were associated with allergic rhinitis in one Swedish and one Chinese population. Since this region has earlier been associated with asthma and allergic rhinitis in a Danish linkage study this speaks strongly in favour of this region being truly involved in the development of this disease.
PMCID: PMC3459792  PMID: 22857391
Allergic rhinitis; Toll-like receptor; Polymorphism; Genetics; Haplotype; Case–control
7.  Polymorphisms at the Microseminoprotein-beta (MSMB) Locus Associated With Physiological Variation in Beta-Microseminoprotein (β-MSP) and Prostate Specific Antigen (PSA) Levels 
rs10993994, a single nucleotide polymorphism (SNP) at the genetic locus encoding ß-microseminoprotein (β-MSP), is associated with both prostate cancer risk and levels of blood prostate-specific antigen (PSA), a biomarker used in prostate cancer screening. Therefore, we wished to determine the association between SNPs at MSMB, the gene encoding β-MSP, and levels of the prostate-produced biomarkers β-MSP, PSA, and human kallikrein 2 (hK2) in blood and semen.
Blood and semen from 304 healthy young Swedish men (aged 18-21) were assayed for β-MSP, PSA and hK2. SNPs around MSMB were genotyped from matched DNA and analyzed for quantitative association with biomarker levels. Empirical p-values were multiple test corrected and independence of each SNP’s effect was determined.
rs10993994 is significantly associated with blood and semen levels of β-MSP (both p<1.0×10−7) and PSA (p=0.00014 and p=0.0019), and semen levels of hK2 (p=0.00027). Additional copies of the prostate cancer risk allele resulted in lower β-MSP but higher PSA levels, and singly explained 23% and 5% of the variation seen in semen β-MSP and PSA. Additional SNPs at MSMB are associated with β-MSP and PSA independently of rs10993994.
SNPs at MSMB correlate with physiological variation in β-MSP and PSA levels in the blood and semen of healthy young Swedish men. In particular, rs10993994 has a strong effect on β-MSP levels.
Our results suggest a mechanism by which rs10993994 may predispose to prostate cancer and raise the possibility that genetic variation may need to be considered in interpreting levels of these biomarkers.
PMCID: PMC2946372  PMID: 20696662
PSA; beta-MSP; prostate biomarker; rs10993994; microseminoprotein beta; PSP94; hK2
8.  Blood biomarker levels to aid discovery of cancer-related single nucleotide polymorphisms: kallikreins and prostate cancer 
Polymorphisms associated with prostate cancer include those in three genes encoding major secretory products of the prostate: KLK2 (encoding kallikrein-related peptidase 2; hK2), KLK3 (encoding prostate-specific antigen; PSA), and MSMB (encoding beta-microseminoprotein). PSA and hK2, members of the kallikrein family, are elevated in serum of men with prostate cancer. In a comprehensive analysis which included sequencing of all coding, flanking, and 2kb of putative promoter regions of all 15 kallikrein (KLK) genes spanning ≈280 Kb on chromosome 19q, we identified novel SNPs and genotyped 104 SNPs in 1419 cancer cases and 736 controls in CAPS1, with independent replication in 1267 cases and 901 controls in CAPS2. This verified prior associations of SNPs in KLK2 and in MSMB (but not in KLK3) with prostate cancer. Twelve SNPs in KLK2 and KLK3 were associated with levels of PSA forms or hK2 in plasma of control subjects. Based on our comprehensive approach, this is likely to represent all common KLK variants associated with these phenotypes. A T allele at rs198977 in KLK2 associated with increased cancer risk and a striking decrease of hK2 levels in blood. We also found a strong interaction between rs198977 genotype and hK2 levels in blood in predicting cancer risk. Based on this strong association, we developed a model for predicting prostate cancer risk from standard biomarkers, rs198977 genotype, and rs198977 x hK2 interaction; this model had greater accuracy than did biomarkers alone (AUC 0.874 vs 0.866), providing proof in principle to clinical application for our findings.
PMCID: PMC2865570  PMID: 20424135
prostate cancer; prostate-specific antigen; human kallikrein-related peptidase 2; genetic variation; case-control study
9.  A Systematic Study of Gene Mutations in Urothelial Carcinoma; Inactivating Mutations in TSC2 and PIK3R1 
PLoS ONE  2011;6(4):e18583.
Urothelial carcinoma (UC) is characterized by frequent gene mutations of which activating mutations in FGFR3 are the most frequent. Several downstream targets of FGFR3 are also mutated in UC, e.g., PIK3CA, AKT1, and RAS. Most mutation studies of UCs have been focused on single or a few genes at the time or been performed on small sample series. This has limited the possibility to investigate co-occurrence of mutations.
Methodology/Principal Findings
We performed mutation analyses of 16 genes, FGFR3, PIK3CA, PIK3R1 PTEN, AKT1, KRAS, HRAS, NRAS, BRAF, ARAF, RAF1, TSC1, TSC2, APC, CTNNB1, and TP53, in 145 cases of UC. We show that FGFR3 and PIK3CA mutations are positively associated. In addition, we identified PIK3R1 as a target for mutations. We demonstrate a negative association at borderline significance between FGFR3 and RAS mutations, and show that these mutations are not strictly mutually exclusive. We show that mutations in BRAF, ARAF, RAF1 rarely occurs in UC. Our data emphasize the possible importance of APC signaling as 6% of the investigated tumors either showed inactivating APC or activating CTNNB1 mutations. TSC1, as well as TSC2, that constitute the mTOR regulatory tuberous sclerosis complex were found to be mutated at a combined frequency of 15%.
Our data demonstrate a significant association between FGFR3 and PIK3CA mutations in UC. Moreover, the identification of mutations in PIK3R1 further emphasizes the importance of the PI3-kinase pathway in UC. The presence of TSC2 mutations, in addition to TSC1 mutations, underlines the involvement of mTOR signaling in UC.
PMCID: PMC3077383  PMID: 21533174
10.  Comprehensive evaluation of genetic variation in S100A7 suggests an association with the occurrence of allergic rhinitis 
Respiratory Research  2008;9(1):29.
S100A7 is a calcium-binding protein with chemotactic and antimicrobial properties. S100A7 protein levels are decreased in nasal lavage fluid from individuals with ongoing allergic rhinitis, suggesting a role for S100A7 in allergic airway inflammation. The aims of this study were to describe genetic variation in S100A7 and search for associations between this variation and allergic rhinitis.
Peripheral blood was collected from 184 atopic patients with a history of pollen-induced allergic rhinitis and 378 non-atopic individuals, all of Swedish origin. DNA was extracted and the S100A7 gene was resequenced in a subset of 47 randomly selected atopic individuals. Nine polymorphisms were genotyped in 184 atopic and 378 non-atopic individuals and subsequently investigated for associations with allergic rhinitis as well as skin prick test results. Haplotypes were estimated and compared in the two groups.
Thirteen polymorphisms were identified in S100A7, of which 7 were previously undescribed. rs3014837 (G/C), which gives rise to an Asp → Glu amino acid shift, had significantly increased minor allele frequency in atopic individuals. The major haplotype, containing the major allele at all sites, was more common in non-atopic individuals, while the haplotype containing the minor allele at rs3014837 was equally more common among the atopic individuals. Additionally, heterozygotes at this site had significantly higher scores in skin prick tests for 9 out of 11 tested allergens, compared to homozygotes.
This is the first study describing genetic variation, associated with allergy, in S100A7. The results indicate that rs3014837 is linked to allergic rhinitis in our Swedish population and render S100A7 a strong candidate for further investigations regarding its role in allergic inflammation.
PMCID: PMC2335106  PMID: 18373864
11.  The Moraxella catarrhalis Immunoglobulin D-Binding Protein MID Has Conserved Sequences and Is Regulated by a Mechanism Corresponding to Phase Variation 
Journal of Bacteriology  2003;185(7):2285-2295.
The prevalence of the Moraxella catarrhalis immunoglobulin D (IgD)-binding outer membrane protein MID and its gene was determined in 91 clinical isolates and in 7 culture collection strains. Eighty-four percent of the clinical Moraxella strains expressed MID-dependent IgD binding. The mid gene was detected in all strains as revealed by homology of the signal peptide sequence and a conserved area in the 3′ end of the gene. When MID proteins from five different strains were compared, an identity of 65.3 to 85.0% and a similarity of 71.2 to 89.1% were detected. Gene analyses showed several amino acid repeat motifs in the open reading frames, and MID could be called a putative autotransport protein. Interestingly, homopolymeric {polyguanine [poly(G)]} tracts were detected at the 5′ ends within the open reading frames. By flow cytometry, using human IgD and fluorescein isothiocyanate-conjugated anti-IgD polyclonal antibodies, most strains showed two peaks: one high- and one low-intensity peak. All isolates expressing high levels of MID had 1, 2, or 3 triplets of G's in their poly(G) tracts, while strains not expressing MID had 4, 7, 8, or 10 G’s in their poly(G) tracts or point mutations causing a putative preterminated translation. Northern blot analysis revealed that the mid gene was regulated at the transcriptional level. Experiments with nonclumping variants of M. catarrhalis proved that bacteria lost their MID expression by removing a G in their poly(G) tracts. Moraxella strains isolated from the nasopharynx or from blood and sputum specimens expressed MID at approximately the same frequency. In addition, no variation was observed between strains of different geographical origins (Australia, Europe, Japan, or the United States). MID and the mid gene were found solely in M. catarrhalis, whereas related Neisseria and Moraxella species did not express MID. Taken together, MID appears to be a conserved protein that can be found in essentially all M. catarrhalis strains. Furthermore, MID is governed by poly(G) tracts when bacteria undergo phase variation.
PMCID: PMC151486  PMID: 12644500

Results 1-11 (11)