Chromosome 17p12-q11 harbors susceptibility loci for systemic lupus erythematosus

Johansson, Cecilia; Žunec, Renata; García, Mercedes; Scherbarth, Hugo R.; Tate, Guillermo; Paira, Sergio; Navarro, Sandra; Perandones, Carlos E.; Gamron, Susana; Alvarellos, Alejandro; Graf, César; Manni, Jorge A.; Berbotto, Guillermo; Palatnik, Simon A.; Catoggio, Luís J.; Battagliotti, Cristina; Sebastiani, Gian Domenico; Migliaresi, S.; Gargiulo, Mauro; Pons-Estel, Bernardo A.; Alarcón‐Riquelme, Marta E.

doi:10.1007/s00439-004-1145-3

Cited by 33 publications

(24 citation statements)

References 31 publications

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“…34 Multiple genome-wide screens for SLE susceptibility loci have been performed, producing nine chromosomal locations that reach the threshold for significant linkage: 35 1q23, 1q31-32, 1q41-42, 2q37, 4p16, 6p21-p12, 12q24, 16q12 and 17q11. [36][37][38][39][40][41][42][43] Each of these loci has been confirmed in at least one independent collection. 39,40,[43][44][45][46][47][48][49][50][51] Sixteen additional intervals with suggestive evidence for linkage to SLE have been identified in more than one data set and include 1p36, 1q24-25, 6q25-27, 7p22-21, 7q21, 7q36, 9p24, 13q32, 14q22-23, 15q26, 16p13, 17q21, 19q13, 20p12, 20q13 and 22q11-12.…”

Section: Introductionmentioning

confidence: 70%

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Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus

et al. 2006

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Autoantibodies are clinically relevant biomarkers for numerous autoimmune disorders. The genetic basis of autoantibody production in systemic lupus erythematosus (SLE) and other autoimmune diseases is poorly understood. In this study, we characterized autoantibody profiles in 1506 individuals from 229 multiplex SLE pedigrees. There was strong familial aggregation of antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-La/SSB, anti-Ro/SSA, anti-Sm, antinRNP (nuclear ribonucleoprotein), IgM antiphospholipid (aPL) antibodies (Abs) and rheumatoid factor (RF) across these families enriched for lupus. We performed genome-wide linkage analyses in an effort to map genes that contribute to the production of the following autoantibodies: Ro/SSA, La/SSB, nRNP, Sm, dsDNA, RF, nuclear and phospholipids. Using an approach to minimize false positives and adjust for multiple comparisons, evidence for linkage was found to anti-La/SSB Abs on chromosome 3q21 (adjusted P ¼ 1.9 Â 10 À6 ), to anti-nRNP and/or anti-Sm Abs on chromosome 3q27 (adjusted P ¼ 3.5 Â 10 À6 ), to anti-Ro/SSA and/or anti-La/SSB Abs on chromosome 4q34-q35 (adjusted P ¼ 3.4 Â 10 À4 ) and to antiIgM aPL Abs on chromosome 13q14 (adjusted P ¼ 2.3 Â 10 À4). These results support the hypothesis that autoantibody production is a genetically complex trait. Identification of the causative alleles will advance our understanding of critical molecular mechanisms that underlie SLE and perhaps other autoimmune diseases.

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Section: Introductionmentioning

confidence: 70%

“…Minimal evidence for linkage of SLE to chromosome 3q27 has previously been described in a small cohort of 12 Italian pedigrees (LOD ¼ 2.00). 43 Significant evidence was also found on chromosome 4q34.3-35.1 with the anti-Ro/La trait in the EuropeanAmerican pedigrees (P ¼ 3.4 Â 10…”

Section: à4mentioning

confidence: 94%

Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus

et al. 2006

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“…8 A total of 12 published genome scans of SLE families were identified through review of the literature and through a PubMed search. [9][10][11][12][13][14][15][16][17][18][19][20] Only original genome scan results were considered, whereas partial scans and follow-up studies in candidate regions were excluded. Some studies were performed on expanded, nonindependent collections of families by the same research group.…”

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confidence: 99%

“…For the most significant bin (bin 3_6, cytogenetic band 3q22.1-q25.31) or for the flanking bin 3_7 (cytogenetic band 3q25.31-q27.3), where a P SR of 0.0266 was obtained, individual studies have shown evidence of linkage, in particular in Caucasian families, 12,18,19 although only of marginal significance. GSMA thus provided greater power to identify the region that showed only weak evidence for linkage in individual studies.…”

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confidence: 99%

Meta-analysis of genome-wide linkage studies of systemic lupus erythematosus

et al. 2006

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A genetic contribution to the development of systemic lupus erythematosus (SLE) is well established. Several genome-wide linkage scans have identified a number of putative susceptibility loci for SLE, some of which have been replicated in independent samples. This study aimed to identify the regions showing the most consistent evidence for linkage by applying the genome scan meta-analysis (GSMA) method. The study identified two genome-wide suggestive regions on 6p21.1-q15 and 20p11-q13.13 (P-value ¼ 0.0056 and P-value ¼ 0.0044, respectively) and a region with P-valueo0.01 on 16p13-q12.2. The region on chromosome 6 contains the human leukocyte antigen cluster, and the chromosome 16 and 20 regions have been replicated in several cohorts. The potential importance of the identified genomic regions are also highlighted. These results, in conjunction with data emerging from dense single nucleotide polymorphism typing of specific regions or future genome-wide association studies will help guide efforts to identify the actual predisposing genetic variation contributing to this complex genetic disease.

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“…To date, several genome scans have been performed to detect SLE susceptibility loci (Cantor et al 2004;Gaffney et al 1998;Gray-McGuire et al 2000;Johansson et al 2004;Koskenmies et al 2004;Lindqvist et al 2000;Moser et al 1998;Nath et al 2004a, b;Shai et al 1999). Although several susceptibility loci have been identified from individual genome scans, most linkage results remain inconsistent across studies.…”

Section: Introductionmentioning

confidence: 97%

Systemic lupus erythematosus susceptibility loci defined by genome scan meta-analysis

2005

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To date, several susceptibility loci for systemic lupus erythematosus (SLE) have been identified by individual genome-wide scans, but many of these loci have shown inconsistent results across studies. Additionally, many individual studies are at the lower limit of acceptable power recommended for declaring significant linkage. The genome search meta-analysis (GSMA) has been proposed as a valid and robust method for combining several genome scan results. The aim of this study is to investigate whether there is any consistent evidence of linkage across multiple studies, and to identify novel SLE susceptibility loci by using GSMA method. Twelve genome scan results generated from nine independent studies have been used for the present GSMA. All together, the data consists of 605 families with 1,355 SLE affected individuals from three self-reported ethnicities; Caucasian, African-American, and Hispanic. For each study, the genome was divided into 120 bins (30 cM) and ranked according to the maximum evidence of linkage within each bin. The ranks were summed and averaged across studies following which the significance was assessed by the permutation tests. The present study identified two genomic locations at 6p22.3-6p21.1 and 16p12.3-16q12.2 that met genome-wide significance (p<0.000417). The identified region at 6p22.3-6p21.1 contains the HLA region. The combined p-values using Fisher's method also supported the significance in these regions. Clustering of significant adjacent bins was observed for chromosomes 6 and 16. Additionally, there are 12 other bins with two point-wise p-values (Psumrnk and Pord) <0.05, suggesting that these bin regions are highly likely to contain SLE susceptibility loci. Among them, present GSMA also identified two novel regions at 4q32.1-4q34.3 and 13q13.2-13q22.2. However, separate analysis using only Caucasian populations identified the strongest evidence for linkage at chromosome 6p21.1-6q15 (Psumrnk=0.00021). One interesting novel region suggests that 3q22.1-3q25.33 (Psumrnk=0.01376) may be an ethnicity-specific SLE linkage. In summary, the present GSMA have identified two statistically significant genomic regions that reconfirmed the SLE linkage at chromosomes 6 and 16.

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Chromosome 17p12-q11 harbors susceptibility loci for systemic lupus erythematosus

Cited by 33 publications

References 31 publications

Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus

Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus

Meta-analysis of genome-wide linkage studies of systemic lupus erythematosus

Systemic lupus erythematosus susceptibility loci defined by genome scan meta-analysis

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