The genes encoding the kininogenase, glandular tissue kallikrein, in rodents and man were first described in the mid-1980s. Remarkably, they appeared to be part of a much larger highly conserved family of genes (GK) in rodents, but only had two paralogs in man. This discrepancy was not rectified until the late 1990s/2000 with the identification of a cluster of 12 more kallikrein-related (KLK) genes in the human 19q13 locus and the subsequent identification of their rodent homologs. Interestingly, there are remarkable similarities in expression patterns, hormonal regulation and functional attributes of the old (GK) and new (KLK) families which underscore the evolutionary conservation across these loci and species. This historical perspective focuses on the lessons learned from earlier studies on the rodent GK gene families and the striking similarities of some attributes, yet uniqueness, of others. These earlier findings have all contributed to the current status of the KLK serine peptidase-encoding gene family as an exciting source of new biomarkers and therapeutic targets

Identification

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Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Human Molecular Genetics (2015)

Ali Amin Al Olama Tokhir Dadaev Dennis J. Hazelett Qiuyan Li Daniel Leongamornlert

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.

Genome-wide Association Study

Linkage Disequilibrium

Imputation (statistics)

Genetic Association

SNP

1000 Genomes Project

10.1093/hmg/ddv203

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Citations (76)

Nitrogen-Control of the nif Regulon in Klebsiella pneumoniae

Springer eBooks (1983)

M. J. Merrick Ariel Álvarez-Morales Judith A. Clements Ray Dixon Martin Drummond

Regulon

Molecular nitrogen

10.1007/978-1-4684-4538-1_24

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Citations (1)

KLK3 SNP–SNP interactions for prediction of prostate cancer aggressiveness

Scientific Reports (2021)

Hui‐Yi Lin Po‐Yu Huang Chia‐Ho Cheng Heng-Yuan Tung Zhide Fang

Abstract Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP–SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 ( P < 3.5 × 10 –9 ) and 3145 ( P < 1 × 10 –5 ) SNP–SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3 . The 3 most common gene–gene interactions were KLK3-COL4A1:COL4A2 , KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP–SNP interactions were supported by gene expression and protein–protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.

SNP

Tag SNP

10.1038/s41598-021-85169-7

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Citations (12)

Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility

Nature Communications (2017)

Amit Sud Hauke Thomsen Philip Law Asta Försti Miguel Inácio da Silva Filho

Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10

Nodular sclerosis

Genome-wide Association Study

Genetic Association

10.1038/s41467-017-00320-1

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Citations (46)

A comprehensive nomenclature for serine proteases with homology to tissue kallikreins

Biological Chemistry (2006)

Åke Lundwall Vimla Band Michael Blaber Judith A. Clements Yves Courty

The human kallikrein locus on chromosome 19q13.3–13.4 contains kallikrein 1 – the tissue kallikrein – and 14 related serine proteases. Recent investigations into their function and evolution have indicated that the present nomenclature for these proteins is inadequate or insufficient. Here we present a new nomenclature in which proteins without proven kininogenase activity are denoted kallikrein-related peptidase. Names are also given to the unique rodent proteins that are closely related to kallikrein 1.

Homology

10.1515/bc.2006.082

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Citations (143)

Ventilatory and cholinergic control of pulmonary surfactant in the rabbit

Journal of Applied Physiology (1977)

M Oyarzún Judith A. Clements

Four sets of experiments on surfactant secretion were performed using New Zealand rabbits under light pentobarbital anesthesia. Pa02, Paco2, and pHa remained normal during all experiments. In controls lung lavage yielded 1.62 +/- 0.26 (SD) mg of alveolar phospholipid (PL)/g lung; disaturated phosphatidylcholine comprised 55.5% of total PL. a) Acetylcholine infusion into the left pulmonary artery for 1-4 h caused a 13% increase in alveolar PL of left as compared to right lung. b) Efferent left vagus stimulation for 1 h increased alveolar PL of right and left lungs 31% as compared to controls (P = 0.012). c) Increasing minute ventilation by 100% by augmenting dead space for periods of 1, 2, and 4 h, increased alveolar PL 45% (P = 0.001), 54%, (P = 0.002), and 25% (P = 0.004), respectively, compared to controls. d) Administration of atropine prevented the increase in alveolar PL caused by increased ventilation. These findings show that increased ventilation can stimulate surfactant release through a cholinergically mediated mechanism but do not rule out the participation of other mechanisms.

10.1152/jappl.1977.43.1.39

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Citations (140)

Tracheal fluid in fetal lambs: spontaneous decrease prior to birth

Journal of Applied Physiology (1979)

Joseph A. Kitterman P. L. Ballard Judith A. Clements E. Joseph Mescher William H. Tooley

We studied tracheal fluid (TF) production in 14 fetal lambs: 6 controls, 6 receiving atropine on 1 or more of the last 7 days before birth, and 2 with bilateral section of the cervical vagosympathetic trunk. A cannula diverted all TF into an intrauterine bag; we collected TF intermittently and measured its volume. All ewes delivered spontaneously at 128-150 days' gestation. TF production decreased before birth in all fetuses except one control. TF production decreased before birth in all fetuses except one control. TF production did not correlate with fetal arterial blood gas tensions, hematocrit, or plasma proteins. In controls only, TF production correlated with fetal arterial pH (P less than 0.02); however, the pH range was small and the correlation has questionable physiological significance. For all fetuses, TF production during the 7 days before birth correlated inversely with the plasma cortisol concentration of 48 h previously (n = 36; r = -0.603; P less than 0.001). We conclude a) TF production in fetal lambs decreases before spontaneous term or preterm labor; b) this decrease is not affected by atropine or by section of the cervical vagosympathetic trunk; and c) the decrease in TF production may be related to increased secretion of cortisol.

10.1152/jappl.1979.47.5.985

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Citations (139)

8 Australian prostate cancer collaboration (APCC) bioresource

BJU International (2006)

Debbie Horsfall Judith A. Clements

The Mission Statement of the APCC is ‘To reduce mortality and morbidity and improve the quality of life of men with prostate cancer by facilitating translational research that will lead to improved prostate cancer management’. National enhancement of translational research endeavours requires establishment of an Australian Prostate Cancer BioResource and associated clinical database. Establishment funds were provided by Prostate Cancer Foundation of Australia (PCFA), Commonwealth Bank and Andrology Australia. Funding for the prospective tissue collection is from NHMRC via an Enabling Grant (July 2004 to June 2009). Tissue collections centre on four nodes, each with a network of affiliated public and private hospitals. The nodes are at Hanson Institute (Adelaide), QUT (Brisbane), Monash Institute (Melbourne), and Garvan Institute (Sydney). The nodes will be linked via a web-based database, which can be interrogated for assembly of specific research tissue cohorts. Access to the tissue and data collections will be equitably available to Australian prostate cancer researchers. An Access Policy has been developed. A business plan and a partial cost recovery program are under development to supplement funding. Fresh tissue procurement began October 2005. Expected annual accrual rate is 800–1000 patients. Between 2–6 × 5 mm punch biopsy cores per patient will be stored at –80°C. Current access to archived tissues for tissue microarray (TMA) construction is approximately 3000 patients. A TMA of 150 patients has been produced. Australian researchers will be able to access the collection in 2006. Tissue will be supplied to ethically approved, high quality research programs after peer review.

Translational Research

Tissue bank

10.1111/j.1464-410x.2006.06085_8.x

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Inhibitors of prostaglandin synthesis, tracheal fluid, and surfactant in fetal lambs

Journal of Applied Physiology (1981)

Joseph A. Kitterman G. C. Liggins Judith A. Clements Guilherme Campos C. H. Lee

To study their effects on tracheal fluid (TF) production and surfactant flux, we gave 12-h infusions of prostaglandin synthetase inhibitors (PGSI) on 16 occasions to 10 fetal lambs at gestational ages (GA) of 125--141 days. Results were similar with both sodium meclofenamate (13.9 +/- 3.4 mg.kg-1, 12 studies) and indomethacin (33.6 +/- 8.0 mg.kg-1, 4 studies). All studies were done at least 6 days after surgery and 4 days before spontaneous birth. During infusions of PGSI, there were no changes in fetal arterial blood pressure, pH, PaO2, PaCO2, TF production or its concentration of sodium, potassium, and chloride; calcium concentration in TF increased slightly. We expressed tracheal surfactant flux as micrograms.kg-1.h-1 of saturated phosphatidylcholine (SPC). If control SPC flux was less than 5 micrograms.kg-1.h-1 (10 studies at GA of 125--141 days), it did not change during infusion of PGSI; however, if control was greater than 5 micrograms.kg-1.h-1 (6 studies at GA 132--140 days), SPC flux decreased during the infusions in all studies. The results suggest that prostaglandins do not strongly influence TF production up to 4 days before birth and that prostaglandins are involved in the increased flux of surfactant which occurs in late gestation.

10.1152/jappl.1981.51.6.1562

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Citations (27)