Evidence for a susceptibility gene (SLEH1) on chromosome 11q14 for systemic lupus erythematosus (SLE) families with hemolytic anemia

Abstract

Hemolytic anemia is a forme fruste of systemic lupus erythematosus (SLE), being observed months or even years before the onset of other clinical manifestations in some patients. We hypothesized that hemolytic anemia in those SLE-affected patients would identify a group of SLE pedigrees that share a high degree of genetic homogeneity. From 160 multiplex SLE pedigrees, we sought evidence for linkage in 35 (16 AfricanAmerican, 17 European-American, and 2 Hispanic) who had at least one SLE-affected patient with hemolytic anemia. Significant linkage was present at 11q14 in the 16 African-American pedigrees, yielding a maximum two-point logarithm of odds (LOD) score of 4.5 at D11S2002. The segregation pattern of SLE in these African-American pedigrees suggested a dominant mode of inheritance and, when maximized across penetrance and disease allele frequencies, produced a multipoint LOD of 4.7. Multipoint analysis yielded a multipoint heterogeneity LOD score of 3.6 (␣ ‫؍‬ 0.63), again with maximum LOD at D11S2002. Finally, markers typed 7 centimorgans to either side of D11S2002 achieved LOD scores of 3 or better by using the maximized model, supporting linkage to 11q14. Clearly, pedigree ascertainment based on select clinical manifestations is an important tool, capable of revealing otherwise cryptic genetic linkages in complex genetic diseases. Thus, we show strong evidence for an SLE susceptibility gene, SLEH1, near D11S2002 in African-American pedigrees multiplex for SLE that have at least one SLE-affected patient with hemolytic anemia.

Stratification of pedigrees multiplex for systemic lupus erythematosus and for self‐reported rheumatoid arthritis detects a systemic lupus erythematosus susceptibility gene (SLER1) at 5p15.3

“…No doubt, the clinical features of SLE have the potential to reveal many genetic effects, of which only a subset is now known (37)(38)(39)(40)(41)(42). These linkage effects, which now include the powerful evidence for linkage at 5p15.3 presented here, along with the 6 reported linkages established using SLE without stratification on clinical features (6)(7)(8), show SLE to be a richly complicated disease phenotype that is now ripe for discovery through a genetic approach.…”

“…An effect at 17p13 (SLEV1) was found in European American pedigrees stratified by having SLEaffected family members with vitiligo (37). Effects were found by stratifying African American pedigrees multiplex for lupus with thrombocytopenia (at 11p13; SLET1) (38) and for lupus with hemolytic anemia (at 11q14; SLEH1) (39). Linkage effects in SLE have been found by stratification according to positivity for anti-doublestranded DNA (by Crithidia luciliae assay) at 18q21.1 for African American pedigrees (SLED2) and at 19p13.2 for European American pedigrees (SLED1) (40).…”

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

“…[53][54][55][56][57][58][59][60][61][62][63] In nearly all of these studies, linkage analyses were carried out using phenotypes defined by fulfillment of the ACR criteria for classification of SLE to determine affected individuals. As a result, substantial phenotypic heterogeneity among individuals considered as affected is inherent in these studies.…”

The genetic etiology of systemic lupus erythematosus: a short dispatch from the combat zone

“…[14][15][16][17][18][19] In this approach, one assumes that the clinical variation in lupus has either a genetic or environmental (or both) origin. In some situations, sub-grouping pedigrees on the basis of the clinical findings of one (or more) affected(s) in the pedigree will sufficiently increase the genetic homogeneity so that previously unimpressive linkage signals become convincing.…”

“…In some situations, sub-grouping pedigrees on the basis of the clinical findings of one (or more) affected(s) in the pedigree will sufficiently increase the genetic homogeneity so that previously unimpressive linkage signals become convincing. Linkages established exceed a LOD of 3.3 at 11q14 with thrombocytopenia, 12 at 5p15 with multiplex self-reported rheumatoid arthritis, 13 at 11p13 with anti-nucleolar antibodies or hemolytic anemia, 14,15 at 17p13 with vitiligo, 16 at 18q21 and 19p13 with anti-double stranded DNA antibodies, 17 and at 2q34-35, 10q22.3, and 11p15.6 with nephritis. 18 Kaufman et al confirm the 11p13 linkage in pedigrees stratified by thrombocytopenia using polymorphisms within the CD44 gene, which has been an unsuccessful candidate gene for genetic association.…”