In addition, rs61752561 in KLK3 showed an association with hK2 amount and concentration in seminal plasma, but has a low minor allele frequency (MAF) of only 0.03.
The genotypes of all 3 KLK3 SNPs (rs2271094, rs61752561, and rs1058205) were associated with PSA amount or concentration in seminal plasma (Table 3).
Our hypothesis is that very low serum PSA concentrations may reflect inactivating gene mutations or gross genetic rearrangements involving KLK3. To test this hypothesis, we conducted a detailed genetic analysis of 30 individuals with the lowest observed PSA concentrations ([less than or equal to] 0.1 [micro]g/L) in a cohort of approximately 85 000 men from the Prostate Testing for Cancer and Treatment (ProtecT) study (14).
We sequenced all exons and the regulatory region of KLK3 to search for genetic defects in KLK3 that would lead to abnormal PSA concentrations.
Interestingly, the KLK3
variant (rs2735839) was associated only with increased prostate cancer risk during the PSA era, but no era effect was observed for the other variants.
 Human genes: KLK8, kallikrein-related peptidase 8; KLK3
, kallikrein-related peptidase 3; KLK5, kallikrein-related peptidase 5; KLK6, kallikrein-related peptidase 6; KLK7, kallikrein-related peptidase 7; KLK10, kallikrein-related peptidase 10; KLK11, kallikrein-related peptidase 11; KLK13, kallikrein-related peptidase 13; KLK14, kallikrein-related peptidase 14; ERBB4, v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian); LOX, lysyl oxidase.
For that purpose, we measured miR-155, miR-200c, and CDH16, PPIA, and TBP expression in samples of nonmalignant renal tissue after radical nephrectomy and measured miR-130b, miR205, and HIF1A, KLK3
, and HPRT1 expression in nonmalignant samples of prostate tissue after radical prostatectomy (Fig.
Very restricted (tissue) Tissue abundance restricted (tissue) Wide KLK2 (prostate) KLK5 (skin, salivary, breast, esophagus) KLK1 KLK3
(prostate) KLK6 (brain/central nervous system) KLK4 KLK7 (esophagus, heart, liver, skin) KLK9 KLK8 (breast, esophagus, skin, tonsil) KLK10 KLK13 (esophagus, tonsil) KLK11 KLK12 KLK14 KLK15
Given that two splice variants with intron retention were already identified, i.e., Psa-rp2 for KLK3
(GenBank accession no.
Both genes, KLK2 and KLK3
, belong to the human tissue kallikrein gene family, which was recently found to consist of at least 15 members (8).
It was previously reported that the KLK3
(PSA) gene is regulated by steroid hormones (27) and that serum hK3 (PSA) gradually increases with increasing age in healthy males (28).
The human kallikrein gene family was, until recently, thought to include only three members: KLK1, which encodes for pancreatic/renal kallikrein (hK1);  KLK2, which encodes for human glandular kallikrein 2 (hK2); and KLK3
, which encodes for prostate-specific antigen (PSA; hK3) (3).