Ashley Tehranchi

Ashley Tehranchi

rs6445975 is located on chromosome 3p14.3and corresponds to intron 4 in the PXK gene (Phox homology domain containing serine/threonine kinase) and is associated with systemic lupus erythematosus (SLE). It is expressed in a variety of tissues including brain, heart, skeletal muscle, and peripheral blood lymphocytes.This SNP has also been implicated as being an important modulator of cancer cell growth. [PMID 21568903]For the rs6445975 SNP, the ancestral allele is a T and the disease associated SNP is a G.

rs6445975 was first identified in 2008 and was found to be associated with SLE in women of European ancestry. The study was conducted using 720 women with SLE and 2,337 controlsand showed strong evidence for association (P=7.1x10–9; OR=1.25) [PMID 18204446]. Additionally, a study in 2010 found that in a pool of 9 SLE SNPs including rs6445975, an increase in genetic susceptibility to SLE was associated with early disease onset. [PMID 20881011].

Other studies have shown no association of rs6445975 to SLE. A study using 804 patients with SLE and 667 healthy controls, mainly of Mexican ancestry, found no association (Odds ratio=1.077; 95% CI=0.8–1.45; P=0.622). Another study using 910 SLE patients and 1440 healthy controls from Chinese living in Hong Kong and 278 SLE patients and 383 controls in Thailand, also found no association of rs6445975 to SLE (P=0.36, OR=1.06, 95% CI: 0.93–1.21). [PMID 19225526].

A study from 2009 investigated if rs6445975 was associated with Rheumatoid Arthritis (RA) because SLE and RA share a complex etiology. They found no association of several SLE SNPs with RA, including rs6445975 (OD=1.11; 95% CI=1.0–1.2).[PMID 19714582]

A study of SLE in the Chinese mainland population used 288 cases and 357 controls and showed that rs6445975 is not associated with SLE (P=0.969; OR=0.99, 95% CI=0.75–1.32). [PMID 20829310]. Another study performed in a Korean population used 527 Korean patients with SLE and 517 healthy Korean control subjects. They found no association of rs6445975 with SLE(OR= 1.06; P=0.57). [PMID 21243490]

A study investigating the link between SLE and a decreased breast cancer risk used a breast cancer GWAS dataset involving 3,659 breast cancer cases and 4,897controls of primarily European descent. They found a slight, positive, association with breast cancerfor rs6445975-G (OR=1.0911; P=0.0097) but concluded an overall weak association of breast cancer with SLE. [PMID 22495874]

A recent study performed a meta-analysis of 13 separate studies and identified anassociation between SLE and the G allele of rs6445975 in the overall population (OR=1.151, 95 % CI=1.086–1.291, P=1.8E-06). They also found a significant association between rs6445975 and SLE in Europeans (OR=1.198, 95 % CI=1.118–1.285, P=3.4E-07), but not in Asians as expected from other studies. [PMID 22592861]

Currently there is no cure for SLE, but symptoms can be managed by immunosuppressant drug treatments such as cyclophosphamide and corticosteroids. Generally, SLE is more common in women than in men and include SNPs in the following genes:ITGAM, KIAA1542, PXK, FCGR2A,PTPN22andSTAT4. Additionally, SNPs in the HLA-DQA1and IRF5 genes have been shown to have a protective phenotype in women of European ancestry but not Asian ancestry. Most of the GWA studies performed for SLE that have been duplicated, found their results to be reproducible after accounting for differences in populations such as Europeans and Asians. rs6445975 particularly, has been shown to affect Europeans but not Asians or Mexicans. Some other studies such as those performed on Mexican or African American populations have yet to be repeated and so reliable data is not currently available.

PMID 22592861Associations between PXK and TYK2 polymorphisms and systemic lupus erythematosus: a meta-analysis.

PMID 22495874Decreased breast cancer risk in systemic lupus erythematosus: the search for a genetic basis continues.

PMID 21243490 Different genetic effect of PXK on systemic lupus erythematosus in the Korean population.

PMID 20829310Polymorphisms of PXK are associated with autoantibody production, but not disease risk, of systemic lupus erythematosus in Chinese mainland population.

PMID 19714582Rheumatoid arthritis does not share most of the newly identified systemic lupus erythematosus genetic factors.

PMID 19225526Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese.