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CPPS and Genes

Several recent studies have linked chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and IC to specific genetic profiles

Latest research:

Biochim Biophys Acta 2002 Jan 2;1586(1):99-107

X Chromosomal short tandem repeat polymorphisms near the phosphoglycerate kinase gene in men with chronic prostatitis.

Riley DE, Krieger JN.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) causes substantial morbidity afflicting approximately 10% of adult males. Treatment is often empirical and ineffective since the etiology is unknown. Other prostate and genitourinary diseases have genetic components suggesting that CP/CPPS may also be influenced by genetic predisposition. We recently reported a highly polymorphic short tandem repeat (STR) locus near the phosphoglycerate kinase gene within Xq11-13. Because this STR is in a region known to predispose towards other prostate diseases, we compared STR polymorphisms in 120 CP/CPPS patients and 300 control blood donors. Nine distinct allele sizes were detected, ranging from 8 to 15 repeats of the tetrameric STR plus a mutant allele (9.5) with a six base deletion in the flanking DNA sequence. The overall allele size distribution in the CP/CPPS patients differed from controls (Chi-square=19.252, df=8, P=0.0231). Frequencies of two specific alleles, 9.5 and 15, differed significantly in CP/CPPS vs. control subjects and allele 10 differed with marginal significance. Alleles 9.5 and 10 were both more common in CP/CPPS patients than controls while allele 15 was less common. These observations suggest that Xq11-13 may contain one or more genetic loci that predispose toward CP/CPPS. Further investigations involving family studies, larger patient populations, and other control groups may help elucidate this potential genetic predisposition in CP/CPPS.

Renowned CP/CPPS researcher Dr Daniel Shoskes stated in October 2001:

The results of my genetic polymorphism study are now complete.

The genes that produce cytokines in humans are polymorphic; there are differences between individuals that control how much is produced for a given stimulus. For instance, different people may produce different amounts of IL-6 in response to identical types of bacterial infections. High or low levels of pro- and anti-inflammatory cytokines can confer high or low susceptibility to infectious and autoimmune diseases. More information is available at a current comprehensive database of polymorphisms and their association with human disease (or lack thereof).

We looked at genetic polymorphisms in men with CPPS and compared them to a control population of 252 people without CPPS and to published expected frequencies. In each case, the interesting numbers came from the gene type associated with the "low expression" for the given cytokine.

As a whole, CPPS patients had a significantly higher proportion expressing the "low IL-10" gene. IL-10 is protective against autoimmune disease, therefore having low IL-10 expression would predispose to autoimmune disease. Interestingly, none of the patients with positive cultures had the low IL-6 gene but the numbers in this subgroup was too small for statistical significance.

Groups were analyzed according to many pretreatment and posttreatment factors. The most interesting finding was that all patients who failed therapy with Prosta-Q had the low TNF-alpha gene and a significantly lower proportion had the low IL-10 gene. One would expect an inflammatory/autoimmune condition to be associated with high TNF-alpha and low IL-10 expression so the Prosta-Q appears to not be effective in those patients with the opposite condition (low TNF and high IL-10). There were no differences seen for any of the cytokines based on treatment response to antibiotics, other anti-inflammatories, alpha-blockers or neuromuscular agents.

Daniel Shoskes MD
Cleveland Clinic Florida

In females we have a precendent:

Gene linked to painful intercourse

February 18, 2000
By Penny Stern, MD

NEW YORK, Feb 18 -- Vulvar vestibulitis, inflammation of small glands in the vagina, is the most common cause of painful intercourse in young women. Because a physical examination does not usually find anything abnormal, the problem is difficult to diagnose. A new study from New York researchers suggests that a rare gene plays a role in this syndrome, a finding that may lead to new treatments -- and reassure patients that their problem is physical, not psychological.

A study by Dr. Steven Witkin and colleagues at Weill Medical College of Cornell University may have solved the riddle of vulvar vestibulitis syndrome, a condition that has long puzzled both doctors and patients. Their report is published in the American Journal of Obstetrics and Gynecology.

"Vulvar vestibulitis, characterized by chronic vulvar pain and painful sexual intercourse, has been shown (by our team) to be associated in about half the cases with a rare form of a gene that regulates inflammation," Witkin explained to Reuters Health.

The gene implicated, called the interleukin-1 receptor antagonist gene, is involved in regulating inflammation, the body's normal response to any type of irritation. The study suggests that women with vulvar vestibulitis have inherited a rare form of the gene.

"When an inflammatory response is triggered by any means, women with this form of the gene have difficulty ending the response even after the initial stimulus is gone... (with) the result (being) chronic prolonged inflammation and pain," Witkin said.

Witkin had previously been studying a possible association between a viral infection and the interleukin-1 receptor antagonist gene using samples obtained from several gynecologists. Those received from study co-author Dr. William Ledger yielded strikingly different results than the others, prompting a closer look.

After analyzing the curious finding, Witkin and Ledger "discovered that many of the samples Ledger sent us were from women with vulvar vestibulitis," Witkin said. Of the nearly 70 women with vulvar vestibulitis evaluated in their study, the researchers determined that the particular variant of the interleukin-1 receptor antagonist gene was present in over half of them.

Based on their understanding of the gene, the investigators think effective treatment options can be developed to control the problem. Witkin also points out, "women were often told that the problem was in their heads, that they had a sexual problem and that they needed psychiatric care."

These study findings "will be reassuring and comforting to many women that there is nothing psychologically wrong with them," he said. For women who have the problem, or suspect they might, Witkin suggests they "need to (be examined) to rule out an infectious cause for their symptoms. In the absence of infection, a genetic analysis... may provide an explanation for the problem."

SOURCE: American Journal of Obstetrics and Gynecology 2000;192.

And here is a study linking a genetic treatment to pain resolution in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS):

GENE THERAPY FOR UROGENITAL PAIN; PROOF OF CONCEPT WITH HERPES SIMPLEX VIRUS VECTORS EXPRESSING PREPROENKEPHALIN (HSV-PPE).

Michael E. Franks, Naoki Yoshimura, Teruhiko Yokoyama, William F. Goins, Matthew O. Fraser, William C. de Groat, Joseph C. Glorioso, Michael B. Chancellor Pittsburgh, PA

INTRODUCTION AND OBJECTIVES: Chronic urogenital pain syndromes such as bladder pain syndrome/interstitial cystitis (BPS/IC) and chronic prostatitis have been major challenges to all urologists to understand and treat. We propose a revolutionary concept in the treatment of chronic urogenital pain that would be independent of pathophysiology. We hypothesize that the use of gene transfer to produce targeted and localized expression of enkephalin, an endogeneous opioid protein with analgesic properties, can treat urogenital pain.

METHODS: Herpes simplex virus (HSV) vectors (1x106-8 pfu) containing LacZ or an opioid precursor protein, human preproenkephalin (PPE) gene were injected into the bladder wall, testis, and prostate of adult Sprague Dawley rats. One to two weeks after HSV-LacZ injection, LacZ staining was performed in bladder tissue and and L6-S1 dorsal root ganglia (DRG). Immunohistochemistry using anti-met-enkephalin polyclonal antibody to determine enkephalin expression was also performed in HSV-PPE injected animals. Cystometric studies using saline and saline containing the C-fiber afferent neurotoxin capsaicin (15-30 mM) were then conducted to compare the bladder intercontraction interval (ICI) of sham (n=9) and HSV-PPE injected animals (n=9) under urethane anesthesia.

RESULTS: Following HSV-LacZ vector injection into the bladder wall, positive LacZ staining was observed in the bladder and L6-S1 DRG. Positive staining for enkephalin was also seen in neuronal and nonneuronal tissues at the injection site following HSV-PPE injection into the bladder, testis and prostate. In cystometry, mean ICI was significantly reduced in sham rats by instillation of capsaicin, which stimulates nociceptive afferents, by 45% (3.8 to 2.1 min, p=0.007), while no significant change was noted in ICI of HSV-PPE treated rats after capsaicin (21%, 2.9 to 2.3 min).

CONCLUSIONS: Neogenes carried by HSV vectors injected into the urogenital organs can express the genes locally in target organs and also transfer the genes to afferent nerves. The technique of HSV-PPE gene therapy may be applicable to the treatments of various types of urogenital pain syndromes, including bladder pain syndrome/interstitial cystitis (BPS/IC), chronic prostatitis, prostadynia, and chronic orchialgia.