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Jurnal Sle

This study identifies two new genetic loci associated with systemic lupus erythematosus (SLE). Genetic variants near the BLK and C8orf13 genes on chromosome 8 and in the ITGAM-ITGAX region on chromosome 16 were associated with increased risk of SLE. Variants near BLK were also associated with changes in mRNA expression levels in B cell lines. The study confirms the role of genetics in SLE susceptibility and pathogenesis.

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Pratidina Dwinda HE
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236 views2 pages

Jurnal Sle

This study identifies two new genetic loci associated with systemic lupus erythematosus (SLE). Genetic variants near the BLK and C8orf13 genes on chromosome 8 and in the ITGAM-ITGAX region on chromosome 16 were associated with increased risk of SLE. Variants near BLK were also associated with changes in mRNA expression levels in B cell lines. The study confirms the role of genetics in SLE susceptibility and pathogenesis.

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Pratidina Dwinda HE
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JURNAL SLE

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with strong


genetic and environmental components. Autoantibodies play an important role in
the pathogenesis of SLE, and the diverse clinical manifestations of the disease are
caused by the deposition of antibody-containing immune complexes in blood
vessels, leading to inflammation in the kidney, brain, and skin. Direct pathogenic
effects of the autoantibodies contribute to hemolytic anemia and thrombocytopenia.
During the past 20 years, many linkage and candidate-gene studies have been
performed to identify genetic factors contributing to a susceptibility to SLE. For
example, haplotypes carrying the HLA class II alleles DRB1*0301 and DRB1*1501
are clearly associated with SLE and the presence of antibodies to nuclear
autoantigens. More recently, variants of the genes encoding interferon regulatory
factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) have
been discovered to be risk factors for SLE. The identification of IRF5 and STAT4 as
SLE risk genes supports the hypothesis that the type I interferon pathway is central
to disease pathogenesis.
Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which
the risk of disease is influenced by complex genetic and environmental
contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility
genes; there is strong evidence for the existence of additional risk loci.
We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA
samples from 1311 case subjects with SLE and 1783 control subjects; all subjects
were North Americans of European descent. Genotypes from 1557 additional control
subjects were obtained from public data repositories. We measured the association
between the SNPs and SLE after applying strict quality-control filters to reduce
technical artifacts and to correct for the presence of population stratification.
Replication of the top loci was performed in 793 case subjects and 857 control
subjects from Sweden.
Genetic variation in the region upstream from the transcription initiation site of the
gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1)
was associated with disease risk in both the U.S. and Swedish casecontrol series
(rs13277113; odds ratio, 1.39; P=11010) and also with altered levels of
messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near
the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X
(ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio,
1.33; P=31011).
We identified and then confirmed through replication two new genetic loci for SLE: a
promoter-region allele associated with reduced expression of BLK and increased
expression of C8orf13 and variants in the ITGAMITGAX region.

Lupus eritematosus sistemik (SLE) adalah penyakit autoimun kronis dengan


komponen genetik dan lingkungan yang kuat. Autoantibodi memainkan peran
penting dalam patogenesis SLE, dan manifestasi klinis beragam penyakit yang
disebabkan oleh pengendapan antibodi yang mengandung kompleks imun dalam
pembuluh darah, menyebabkan peradangan pada ginjal, otak, dan kulit. Efek
patogen langsung dari autoantibodi berkontribusi terhadap anemia hemolitik dan
trombositopenia.
Selama 20 tahun terakhir, banyak keterkaitan dan calon-gen penelitian telah
dilakukan untuk mengidentifikasi faktor genetik berkontribusi pada kerentanan
terhadap SLE. Misalnya, haplotipe membawa HLA kelas II alel DRB1 * 0301 dan
DRB1 * 1.501 jelas terkait dengan SLE dan adanya antibodi terhadap autoantigens
nuklir. Baru-baru ini, varian dari gen penyandi faktor interferon peraturan 5 (IRF5)
dan transduser sinyal dan aktivator transkripsi 4 (STAT4) telah ditemukan menjadi
faktor risiko untuk SLE. Identifikasi IRF5 dan STAT4 sebagai gen resiko SLE
mendukung hipotesis bahwa tipe I interferon jalur merupakan pusat patogenesis
penyakit.Lupus eritematosus sistemik (SLE) adalah penyakit klinis heterogen di
mana risiko penyakit dipengaruhi oleh kontribusi genetik dan lingkungan yang
kompleks. Alel, HLA-DRB1 IRF5, dan STAT4 ditetapkan gen kerentanan, ada bukti
kuat bagi keberadaan lokus risiko tambahan.
Kami genotyped lebih dari 500.000 polimorfisme nukleotida tunggal (SNP) dalam
sampel DNA dari 1.311 subyek kasus dengan SLE dan 1.783 peserta kontrol, semua
mata pelajaran adalah Amerika Utara keturunan Eropa. Genotipe dari 1.557 subyek
kontrol tambahan yang diperoleh dari repositori data publik. Kami mengukur
hubungan antara SNP dan SLE setelah menerapkan ketat kontrol kualitas filter
untuk mengurangi artefak teknis dan untuk mengoreksi adanya stratifikasi populasi.
Replikasi dari lokus atas dilakukan pada 793 subyek kasus dan 857 subyek kontrol
dari Swedia.
Variasi genetik di wilayah hulu dari situs inisiasi transkripsi gen yang mengkode
tirosin kinase B limfoid (BLK) dan C8orf13 (kromosom 8p23.1) dikaitkan dengan
risiko penyakit di Amerika Serikat dan Swedia kasus-kontrol seri (rs13277113; rasio
odds , 1,39; P = 1 10-10) dan juga dengan perubahan tingkat RNA di B-sel garis.
Selain itu, varian pada kromosom 16p11.22, dekat gen penyandi integrin alpha M
(ITGAM, atau CD11b) dan integrin alpha X (ITGAX), dikaitkan dengan SLE dalam
sampel gabungan (rs11574637, rasio odds, 1,33, P = 3 10-11).
Kami diidentifikasi dan kemudian dikonfirmasi melalui replikasi dua lokus genetik
baru untuk SLE: alel promotor-wilayah yang terkait dengan ekspresi penurunan BLK
dan peningkatan ekspresi C8orf13 dan varian di wilayah ITGAM-ITGAX

http://www.nejm.org/doi/pdf/10.1056/NEJMoa0707865

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