The COX-2 Gene and the Immune System

• ClinicalTrials.gov Identifier: NCT01678222
• Recruitment Status: Completed
• First Posted: September 3, 2012
• Last Update Posted: March 24, 2020
• Sponsor: National Institute of Environmental Health Sciences (NIEHS)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Environmental Health Sciences (NIEHS) )

Study Description

Brief Summary:

Background:

- The immune system contains several different types of cells in the blood and other parts of the body. The body can fight infections well with the right balance of these cell types. The wrong balance of cell types may cause diseases, such as allergies or asthma. The COX-2 gene may help decide the balance of cell types that the body makes as part of the immune system. It may also play a role in certain immune system diseases. Researchers want to see how COX-2 affects the cells in the immune system.

Objectives:

- To study how the COX-2 gene works in the body s immune system.

Eligibility:

- Individuals 18 years of age and above who are part of the Environmental Polymorphisms Registry.

Design:

• Participants will have one study visit at the National Institutes of Health. They will collect a urine sample at home on the morning of the study visit.
• Participants will have a physical exam and medical history. They will provide a blood sample. They will also give researchers the urine sample they collected that morning.
• No treatment will be provided as part of this study.

Condition or disease
Allergic Inflammation; Asthma

Detailed Description:

This is a cross-sectional, controlled study designed to investigate the association of single nucleotide polymorphisms (SNPs) in the cyclooxygenase-2 (COX2) gene, also called prostaglandin endoperoxidase synthase 2 (PTGS2), on T-cell differentiation and function. Specifically, the impact of the promoter-region SNP 765G>C (rs20417) and the 3 untranslated region (UTR) SNP 8473T>C (rs5275) on T helper cell (Th) 2, Th9, and Th17 differentiation and function will be examined. Non-Hispanic, White or Black/African American, non-pregnant adults, aged 18-65 years, who are wild type (WT), with respect to both the 765G>C and 8473T>C SNPs, WT with respect to 765G>C and homozygous for 8473T>C, and homozygous for both 765G>C and 8473T>C will be recruited into a total of three genotype groups. Potential participants will be identified from the Environmental Polymorphisms Registry, contacted by recruitment letter and pre-screened for eligibility. Pre-screened individuals will provide verbal consent to withhold certadata analysis, a urine collection cup, and pre-visit instructions. Participants will attend a single study visit that will take place at the National Institute of Environmental Health Sciences (NIEHS) Clinical Research Unit (CRU). During this visit, written informed consent will be obtained, and there will be a final screening and eligibility determination, medical history review, vital signs, physical examination and blood and urine samples will be collected. From peripheral blood, lymphocyte subsets, prostaglandin levels, and cytokine levels will be determined; stable prostaglandin metabolites, creatinine, total protein and albumin will be measured in urine. Lymphocytes will be isolated from peripheral blood for ex vivo analyses. Demographic characteristics (i.e., age) will be compared between the groups, and when possible, recruitment will be targeted to achieve an approximate match of race and gender across the groups. The primary objective of the study is to determine whether the 765G>C or 8473T>C SNPs exhibit altered Th2, Th9 and Th17 cell differentiation by examining lymphocyte subsets in vivo. The study will also examine the impact of these two SNPs on circulating Th2/Th9/Th17 cytokine levels and prostaglandins in vivo, on differentiation of naive CD4+T-cells to Th cell subsets in vitro, and on lymphocyte production of cytokines and prostaglandins in vitro.

Study Design

• Study Type: Observational
• Actual Enrollment: 117 participants
• Observational Model: Cohort
• Time Perspective: Cross-Sectional
• Official Title: The Role of Functionally Relevant Cyclooxygenase-2 (COX-2) Gene Single Nucleotide Polymorphisms -765G>C and 8473T>C in Lymphocyte Differentiation
• Actual Study Start Date: May 2, 2013

Groups and Cohorts

Group/Cohort
SNP; individuals who are homozygous for either the major or minor variant of both SNPs

Outcome Measures

Primary Outcome Measures :

1. To determine whether 765>C is associated with altered Th2, Th9, and Th17 differentiation in vivo [ Time Frame: Ongoing ]
   To determine whether 765>C is associated with altered Th2, Th9, and Th17 differentiation in vivo
2. To determine whether 8473T>C is associated with altered Th2, Th9, and Th17 differentiation in vivo [ Time Frame: Ongoing ]
   To determine whether 8473T>C is associated with altered Th2, Th9, and Th17 differentiation in vivo

Secondary Outcome Measures :

1. To determine whether 8473T>C is associated with altered Th2, Th9, and Th17 differentiation in vivo
2. To determine whether 765G>C is associated with altered prostaglandin and cytokine levels in vivo

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 150 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

individuals who are homozygous for either the major or minor variant of both SNPs@@@

Criteria

• INCLUSION CRITERIA:
• Participant of the Environmental Polymorphisms Registry and current contact information available

• Genotype information available for relevant 765G>C and 8473T>C COX2 polymorphisms, which indicates:

  • Individuals who are WT with respect to both 765G>C and 8473T>C (N=31)
  • Individuals who are WT with respect to 765G>C and homozygous for 8473T>C (N=31)
  • Individuals who are homozygous for both 765G>C and 8473T>C (N=31)
• Age 18- 65 years
• Race self-identified as White or Black and Non-Hispanic ethnicity
• Willing and able to provide informed consent
• Able to comply with all protocol procedures

EXCLUSION CRITERIA:

• History of infection within the preceding 1 week or an oral temperature >38 degrees C
• Current daily or chronic use of corticosteroids (systemic, inhaled and topical).
• Any current conditions known to impact peripheral white blood cell count (e.g., leukemia, lymphopenia, AIDS, other immunodeficiency disorders)
• Current daily or chronic use of systemic immunosuppressants.
• Current pregnancy or lactation

• Unwilling or unable to:

  • Fast (including alcohol and caffeine-containing products) and discontinue tobacco use for 12 hours prior to the study visit
  • Withhold all prescribed and over-the-counter medications and supplements the morning of the study visit, until after the visit is completed

  • Refrain from taking the following medications and supplements for 7 days prior to the study visit:

    • NSAIDs
    • Corticosteroids (nasal, inhaled, topical or systemic)
    • Fish oil and niacin supplements
• For blood draws that exceed 200ml, a hematocrit of <34% for women or <36% for men, or >56% for either gender.
• For blood draws exceeding 200ml, blood or plasma donation in the last 8 weeks

Contacts and Locations

Locations

United States, North Carolina

NIEHS Clinical Research Unit (CRU)

Research Triangle Park, North Carolina, United States

Sponsors and Collaborators

National Institute of Environmental Health Sciences (NIEHS)

Investigators

• Principal Investigator: Darryl C Zeldin, M.D.; National Institute of Environmental Health Sciences (NIEHS)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Li H, Bradbury JA, Dackor RT, Edin ML, Graves JP, DeGraff LM, Wang PM, Bortner CD, Maruoka S, Lih FB, Cook DN, Tomer KB, Jetten AM, Zeldin DC. Cyclooxygenase-2 regulates Th17 cell differentiation during allergic lung inflammation. Am J Respir Crit Care Med. 2011 Jul 1;184(1):37-49. doi: 10.1164/rccm.201010-1637OC. Epub 2011 Apr 7.

McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):272-7. Erratum in: Proc Natl Acad Sci U S A 1999 May 11;96(10):5890.

Mai J, Wang H, Yang XF. Th 17 cells interplay with Foxp3+ Tregs in regulation of inflammation and autoimmunity. Front Biosci (Landmark Ed). 2010 Jun 1;15:986-1006. Review.

• Responsible Party: National Institute of Environmental Health Sciences (NIEHS)
• ClinicalTrials.gov Identifier: NCT01678222
• Other Study ID Numbers: 120190; 12-E-0190
• First Posted: September 3, 2012
• Last Update Posted: March 24, 2020
• Last Verified: February 26, 2020

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Environmental Health Sciences (NIEHS) ):

Lymphocyte; Prostaglandin Endoperoxidase Synthase 2; COX-2

Additional relevant MeSH terms:

Inflammation; Pathologic Processes