|(G;G)||2||disease risk associated|
|Condition||Systemic lupus erythematosus in women|
rs6445975 is located on chromosome 3p14.3 and corresponds to intron 4 in the PXK gene (Phox homology domain containing serine/threonine kinase) and is associated with systemic lupus erythematosus (SLE). PXK 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 risk allele is a G.
rs6445975 was first found to be associated with SLE in 2008 in women of European ancestry. The study included 720 women with SLE and 2,337 controls and showed strong evidence for association (P=7.1x10–9; OR=1.25) [PMID 18204446] . Additionally, a study in 2010 found that many SLE SNPs including rs6445975 showed that an increase in genetic susceptibility to SLE was associated with early disease onset. [PMID 20881011] .
Other studies have shown no association of rs6445975 with SLE. A study of patients mainly of Mexican ancestry included 804 patients with SLE and 667 healthy controls and found no association (Odds ratio=1.077; 95% CI=0.8–1.45; P=0.622). Another study of 910 SLE patients and 1440 healthy controls from Chinese living in Hong Kong and 278 SLE patients and 383 controls from 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 examined the association of rs6445975with SLE in 527 Korean patients with SLE and 517 healthy Korean control subjects. They found no association of the rs6445975 risk allele with SLE (OR= 1.06; P=0.57). [PMID 21243490]
A study investigated the link between SLE and a decreased breast cancer risk in a cohort of 3,659 breast cancer cases and 4,897controls of primarily European descent. They found a slight positive association with breast cancer for the G risk allele of rs6445975 (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 an association 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). There was 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 SLE is associated with disease risk alleles of SNPs in the following genes: ITGAM, KIAA1542, PXK, FCGR2A, PTPN22 and STAT4. Additionally, SNPs in the HLA-DQA1 and 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 22592861] Associations between PXK and TYK2 polymorphisms and systemic lupus erythematosus: a meta-analysis
[PMID 22495874] Decreased breast cancer risk in systemic lupus erythematosus: the search for a genetic basis continues
[PMID 19225526] Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese
[PMID 19714582] Rheumatoid arthritis does not share most of the newly identified systemic lupus erythematosus genetic factors
[PMID 20829310] Polymorphisms of PXK are associated with autoantibody production, but not disease risk, of systemic lupus erythematosus in Chinese mainland population
[PMID 21243490] Different genetic effect of PXK on systemic lupus erythematosus in the Korean population
[PMID 18853133] Gene variants influencing measures of inflammation or predisposing to autoimmune and inflammatory diseases are not associated with the risk of type 2 diabetes.
[PMID 19442287] Replication of recently identified systemic lupus erythematosus genetic associations: a case-control study.
[PMID 21379322] Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes.
[PMID 21408207] Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production.
|qualified_impact||Insufficiently evaluated pathogenic|
[PMID 25862617] Genome-wide search followed by replication reveals genetic interaction of CD80 and ALOX5AP associated with systemic lupus erythematosus in Asian populations