Systemic lupus erythematosus (SLE) and chromosome 16: confirmation of linkage to 16q12–13 and evidence for genetic heterogeneity

Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with significant morbidity and mortality, characterized by remarkable clinical variability with unknown etiology. Genetic contribution to the development of SLE is well established. Recently, we found evidence (Po0.004) of linkage at 16p13 and 16q12 -13 in a genome scan based on 37 Hispanic families. The main objective of this study is to replicate and confirm the linkage at these two genomic locations in two large independent replication data sets designated as, group-1 and group-2, consisting of 172 and 120 multiplex SLE families, respectively. We have found a significant evidence of linkage with high heterogeneity (HLOD ¼ 4.85, a ¼ 35%) at 16q12-13 in group-2. Other independent research groups also reported the SLE susceptibility at or close to 16q12-13 previously. Therefore, independent published reports, together with our initial linkage with Hispanics and followed by significant evidence from group-2, provide a strong and confirmed evidence for an SLE susceptibility locus at 16q12 -13.

Fine mapping chromosome 16q12 in a collection of 231 systemic lupus erythematosus sibpair and multiplex families

“…27 The reduction in LOD score following the addition of 44 pedigrees with both the genome-screen and fine-mapping markers is likely to be explained by increased genetic heterogeneity introduced by the addition of unlinked pedigrees. This is consistent with the evidence for heterogeneity described by Nath et al 24 in which maximum evidence for linkage was observed in only 35% of pedigrees (HLOD ¼ 4.85). The reduction in overall evidence for linkage could also result from an increase in genotyping errors, or MT4 MT1X MT3 MT2A MT1E MT1K MT1J MT1A MT1B MT1F MT1G MT1H NOD27 CPNE2 TM4SF11 CCL22 CX3CL1 POLR2C DOK4 MMP15 CSNK2A2 BART1 NDRG4 BCGF1 GOT2 KATNB1 CDH8 inaccuracies of marker order.…”

“…[6][7][8][9][10][11] Linkage studies in human SLE pedigrees have identified multiple regions that meet Lander and Kruglyak's 12 strict criteria for significant linkage: 1q23, 1q31, 1q41-42, 2q37, 4p16, 6p21, 16q12-13, and 17p13. [13][14][15][16][17][18][19][20][21][22][23][24] Chromosome 16q12 is among the most consistently replicated regions in SLE linkage studies. We provided the first evidence for linkage at 16q12 (D16S415, LOD ¼ 3.47) in 105 pedigrees 15 and increased evidence for linkage (D16S415, LOD ¼ 3.85) with the addition of data from 82 independent pedigrees.…”

“…Second, Tsao et al 22 identified linkage (P ¼ 0.001) to this same region (between D16S3136 and D16S415) in non-Caucasian (N ¼ 68) as opposed to Caucasian (N ¼ 77) affected sibpairs. Third, Nath et al 24 found evidence for linkage to chromosome 16q12 (D16S3253, P ¼ 0.000005) in a combination of European-American (N ¼ 82) and African-American (N ¼ 38) families using parametric linkage analysis methods. Finally, evidence for family-based association at 16q12 was reported in a Chinese population (N ¼ 157) (D16S409, P ¼ 0.0278; D16S517, Po0.0001).…”

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

“…[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.…”

Polymorphisms in the Hsp70 gene locus are genetically associated with systemic lupus erythematosus

“…The aetiology of SLE remains elusive, but an interplay of genetic and environmental factors is considered to ultimately cause immune dysregulation, resulting in clinical symptoms. Many genetic variants on different chromosomes together with more than 31 different candidate genes have been reported and were confirmed as susceptibility loci for SLE by replication studies 17–20. A well-known susceptibility locus for SLE is the major histocompatibility complex (MHC) region on chromosome 6p21, which is linked to multiple autoimmune diseases 21.…”