The Importance of C4A Null Genes in Norwegian Patients with Systemic Lupus Erythematosus

Skarsvåg, S

doi:10.1111/j.1365-3083.1995.tb03698.x

Cited by 14 publications

(4 citation statements)

References 27 publications

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“… 6 Indeed, the association of SLE and HLA-DRB1*0301 was observed in our patients and this finding is consistent with common genetic features of other Northern European lupus samples. 26 , 27 In contrast, HLA-DRB1*1501 did not increase the risk for SLE in our cohort. These findings are in accord with studies indicating that the association with HLA-DRB1*1501/HLA-DR2 is either less strong 28 , 29 or even not significantly increased 30 in Caucasian or Hispanic cohorts, whereas the strongest evidence of the role of HLA-DR2 in SLE appears to be found in patients of Asian origin.…”

Section: Discussioncontrasting

confidence: 73%

Low copy numbers of complement C4 and homozygous deficiency of C4A may predispose to severe disease and earlier disease onset in patients with systemic lupus erythematosus

Jüptner¹,

Flachsbart

Caliebe

et al. 2017

Lupus

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ObjectivesLow copy numbers and deletion of complement C4 genes are potent risk factors for systemic lupus erythematosus (SLE). However, it is not known whether this genetic association affects the clinical outcome. We investigated C4 copy number variation and its relationship to clinical and serological features in a Northern European lupus cohort.MethodsWe genotyped the C4 gene locus using polymerase chain reaction (PCR)-based TaqMan assays in 169 patients with SLE classified according to the 1997 revised American College of Rheumatology (ACR) criteria and in 520 matched controls. In the patient group the mean C4 serum protein concentrations nephelometrically measured during a 12-month period prior to genetic analysis were compared to C4 gene copy numbers. Severity of disease was classified according to the intensity of the immunosuppressive regimens applied and compared to C4 gene copy numbers, too. In addition, we performed a TaqMan based analysis of three lupus-associated single-nucleotide polymorphisms (SNPs) located inside the major histocompatibility complex (MHC) to investigate the independence of complement C4 in association with SLE.ResultsHomozygous deficiency of the C4A isotype was identified as the strongest risk factor for SLE (odds ratio (OR) = 5.329; p = 7.7 × 10−3) in the case-control comparison. Moreover, two copies of total C4 were associated with SLE (OR = 3.699; p = 6.8 × 10−3). C4 serum levels were strongly related to C4 gene copy numbers in patients, the mean concentration ranging from 0.110 g/l (two copies) to 0.256 g/l (five to six copies; p = 4.9 × 10−6). Two copies of total C4 and homozygous deletion of C4A were associated with a disease course requiring cyclophosphamide therapy (OR = 4.044; p = 0.040 and OR = 5.798; p = 0.034, respectively). Homozygous deletion of C4A was associated with earlier onset of SLE (median 24 vs. 34 years; p = 0.019) but not significant after correction for multiple testing. SNP analysis revealed a significant association of HLA-DRB1*0301 with SLE (OR = 2.231; p = 1.33 × 10−5).ConclusionsOur findings confirm the important role of complement C4 genes in the development of SLE. Beyond the impact on the susceptibility for lupus, C4 copy numbers may be related to earlier onset and a more severe course of the disease. The association of homozygous deletion of C4A and SLE is accompanied by the presence of HLA-DRB1*0301 without a proven pathophysiological mechanism.

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Section: Discussioncontrasting

confidence: 73%

Low copy numbers of complement C4 and homozygous deficiency of C4A may predispose to severe disease and earlier disease onset in patients with systemic lupus erythematosus

Jüptner¹,

Flachsbart

Caliebe

et al. 2017

Lupus

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“…[11][12][13] Meanwhile, the presence of a C4A*Q0 has been shown to confer a higher risk for SLE in numerous studies performed in Anglo-Saxon, African-American, Chinese, Japanese, European and Korean populations, when compared with race-matched controls of healthy individuals from the same geographical location. 18,19,[25][26][27][28][29][30] On the contrary, a lack of association between C4A*Q0 and SLE has also been reported in several studies, ie, in French/French-Canadian, American, and Spanish samples. This could be due to the presence of genetic heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

A study of association of the complement C4 mutations with systemic lupus erythematosus in the Malaysian population

Puah

Lh²,

Chew

et al. 2007

Lupus

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The aim of the present study was to investigate the association of C4 gene mutations with systemic lupus erythematosus, in 130 Malaysian SLE patients and 130 healthy controls. Generally, various PCR approaches were used to screen the mutations of the C4 genes, which included 2 bp (+TC) insertions at codon 1213 in exon 29, 1 bp deletions (-C) at codon 811 in exon 20, 1 bp (-C), 2 bp (-GT) deletions at codons 522 and 497 in exon 13 and null alleles. No mutations located at exons 13, 20 and 29 of the C4 gene, were detected amongst the patient and control samples in this study. C4A*Q0 was found in two out of the 130 control samples, while C4B*Q0 was present in two out of the 130 SLE patients. Overall, our results do not demonstrate a significant association to these known C4 mutations identified by previous studies, in the Malaysian scenario.

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“…27 An association between the C4A null allele (C4A*Q0) and SLE susceptibility has been demonstrated in a Caucasian population. [28][29][30][31][32][33][34] C4A*Q0 is also associated with SLE susceptibility in multiethnic Asian populations, including Japanese and Chinese. 35 This result has been replicated in Korean, 19 Japanese 36 and Chinese, 37 but also not in Chinese 16 and Malaysian.…”

Section: Resultsmentioning

confidence: 99%

Genetic studies of systemic lupus erythematosus in Asia: where are we now?

Kim

et al. 2009

Genes Immun

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There have been many genetic studies of systemic lupus erythematosus (SLE) in Asia, but the status of SLE in Asia remains unclear. Genes that have been associated with SLE in Caucasians have shown both consistent and inconsistent results in Asians. This prompted us to review studies of SLE-associated genes and compare the degree of consistency according to ethnicity in Asia. We searched PubMed and the national databases in Korea and Japan for SLE genetic studies. A total of 755 articles were found and after applying various exclusion criteria, 442 studies including 17 linkage studies, 2 genome-wide association studies and 423 candidate-gene analyses were reviewed. Nine linkage loci were confirmed to be associated with SLE susceptibility in non-Asians, but the risk locus (16q12) has been identified in only one Asian study. A total of 156 candidate genes were analyzed, of which 92 were studied in Asians. Although there were allelic (HLA-DRB1 and IRF5) or genetic heterogeneity (FCGR gene family), HLA-DRB1, the FCGR gene family, IRF5, STAT4 and MECP2 showed consistent associations with SLE susceptibility across ethnicities. In conclusion, genetic associations often vary with ethnicity, requiring validation in different ethnic groups, and hence future SLE genetic studies will require strong worldwide collaborations.

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The Importance of C4A Null Genes in Norwegian Patients with Systemic Lupus Erythematosus

Cited by 14 publications

References 27 publications

Low copy numbers of complement C4 and homozygous deficiency of C4A may predispose to severe disease and earlier disease onset in patients with systemic lupus erythematosus

Low copy numbers of complement C4 and homozygous deficiency of C4A may predispose to severe disease and earlier disease onset in patients with systemic lupus erythematosus

A study of association of the complement C4 mutations with systemic lupus erythematosus in the Malaysian population

Genetic studies of systemic lupus erythematosus in Asia: where are we now?

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