Gene That Cause Premature Death in Rheumatoid Patients Identified

UK researchers have revealed that HLA-DRB1 gene, which is linked to increased risk of developing inflammatory arthritis, might also increase patients' risk of dying from cardiovascular disease.

The study, led by Dr. Tracey M. Farragher at the University of Manchester, investigated whether genetic variants linked to the likelihood of developing rheumatoid arthritis (RA) might also make patients more likely to die from cardiovascular disease (CVD).

In the study, the researchers focused on two genes, HLA-DRB1and PTPN22, and their interactions with known RA risk factors.

The evidence implicates HLA-DRB1 genotypes, already associated with RA susceptibility and severity, as a predictor of premature death from CVD for inflammatory arthritis patients.

For particularly RA patients, having the shared epitope (SE), a group of HLA-DRB1 alleles with kindred amino acid traits, plus anti-cyclic citrullinated peptide (anti-CCP) antibodies and current smoking is an especially deadly combination.

For the study, the researchers focused on 1,022 patients with inflammatory polyarthritis (IP) recruited from a primary-care-based register of adults.

The data for each participant included the results of blood tests for rheumatoid factor (RF), elevation of the C-reactive protein (CRP), and anti-CCP antibodies; evaluations of joint pain and functional disability; smoking habits; and, when applicable, the cause and date of death. DNA samples were also available. 751 of the total patients met the American College of Rheumatology criteria for RA.

HLA-DRB1 and PTPN22 genotyping was performed on every participant's DNA. The researchers assessed the association of each gene family with the risk of death from all causes and from cardiovascular disease using Cox proportional hazards regression models.

They also studied the interactions between SE presence, anti-CCP status, and smoking history, adjusted by patient sex and age at symptom onset.

242 (24 percent) of the patients died in the years between the register's inception and the study's completion. CVD was the cause of death for 76 (31.4 percent) of the deceased.

According to the analysis, having two copies of the SE alleles increased the risk of death from all causes and from CVD. For individuals with the HLA-DRB1 combination, the risk of death from CVD was increased more than 3-fold. The fatal impact was independent of RF and CRP levels. However, it was aggravated by the interaction of SE, anti-CCP antibodies, and smoking.

Current smokers who carried 2 SE alleles and had anti-CCP antibodies had the highest risk of dying from all causes, as well as a substantially higher risk of dying early from CVD. In calculations focusing on RA patients only, this finding remained consistent. There was no evidence of any link between the PTPN22 gene and the risk of death.

This study is the first one to associate the HLA-DRB1 genotype with premature death, particularly from CVD, for those afflicted with any form of inflammatory arthritis, including RA.

The study is published in the February 2008 issue of Arthritis & Rheumatism.

Source-ANI
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