Efforts to examine the genetics of SLE have resulted in large collections of families in which more than one person is affected with the disease. We have collected over 500 such families and our colleagues at UCLA have collected nearly 450 such families. Among both these cohorts of SLE families, about 1% consist of only SLE affected men. Considering the rarity of men with SLE, that there are families with only men is initially unexpected. On the other hand, in an idealized situation, if men represent 10% of SLE patients and each family has 2 SLE patients, then by chance alone one expects 1% of families to be male only. Nevertheless, even if not greater than expected by chance, study of families with only males affected by SLE may be fruitful.
In addition to the 5 male-only SLE families in the LFRR, we also found one family where we could confirm one SLE patient who had a brother with incomplete lupus (that is, less than 4 criteria), and yet another family with a confirmed SLE patient who had a brother with reported SLE,. This brother declined to participate in the study, however. No women in either family had member a putative or a confirmed diagnosis of SLE. While perhaps interesting, these two families with putative all-male SLE were not considered further, and were not included in the analyses.
SLE in men is different than that found in women, although all studies do not agree on this point (30
). In general, SLE is more severe in men, with renal disease, serious haematological disease such as thrombocytopenia and autoimmune haemolytic anemia as well as neurological disease more likely in men than women (31
). Several studies have found that SLE in men is more likely to present with serositis than SLE in women (33
). An explanation of why SLE is more severe in men has not been achieved, but genetics may play a role. Stein and colleagues found that women with SLE who had a SLE-affected male relative had more severe disease than women without a SLE-affected male relative (7
). This finding was in fact made in the LFRR cohort, which the present study has examined.
There are only a few past reports of male SLE families. Lahita and colleagues reported three families in which there were father-son pairs and no other SLE-affected members (40
). In 1973, 2 sets of brother with SLE were described (41
). While this report is prior to the 1982/1997 revised ACR classification criteria (21
), upon review of this paper, these men have convincing SLE by present-day criteria (41
). Arnett and Shulman's classic paper from 1976 described a father-son pair with SLE (42
). One set of identical male twins, which were concordant for SLE, has been described (43
). Thus, the twins reported herein bring the total to three sets, all of which are concordant for disease. While the number is low of course, this SLE concordance rate is far above that found for female identical twins.
SLE is a complex genetic disease where a large number of genes contribute to the risk but each individual one of these susceptibility genes imparts only a small increase in relative risk (reviewed in 44). In genetic association studies using single nucleotide polymorphism (SNP) typing, the relative risk for SLE associated with the presence of a specific SNP allele may be only 1.2 to 1.4 (see 45
). The men in our families share a Y chromosome but we did not find a yaa
gene equivalent (46
) among these families (). These results confirm a recent finding in a cohort of unrelated men with SLE where no significant concordance between the number of relative TLR7 gene copies and the SLE phenotype was found (17
). Furthermore, this group did not find any difference in variation by ethnic group. These data suggest that the murine genomic segmental duplication in the TLR7 gene and the translocation of this segment to produce the yaa
gene cannot be translated directly to humans with SLE. The contributory role of genetic variants in TLR7 gene on the human SLE phenotype has yet to be explored.
The genetics of autoimmune disease may act at several levels. This has been suggested by study of mice with a lupus-like illness in that an individual susceptibility gene may act by breaking tolerance to self-antigens, by affecting lymphocyte activity or by increasing likelihood of certain manifestations (49
). The associations of HLA are stronger for specific autoantibodies than for SLE itself (see 50
and reviewed in 51
). So, there may genetics for autoimmune disease in general, for specific diseases, for specific serological or clinical manifestations of a disease (19
Could there be genetic factors that contribute to autoimmune disease that only operate in one sex or the other? The data are clear that this is the case for type 1 diabetes mellitus in which men with the disease are much more likely to have offspring with the disease than are women with type 1 diabetes (53
). This effect may be mediated through genetic imprinting on chromosome 11 at the susceptibility locus IDDM2, for which allelic variations of the insulin-like growth factor II have been implicated (54
Our data demonstrate that men with SLE are more likely to be the parents of children eventually affected by SLE than expected. There are several possible reasons to explain this observation. Women with SLE may have infertility problems because of recurrent spontaneous abortion associated with anti-phospholipid antibodies (55
). Because of lupus nephritis, women may be told by the physicians to not have children, but this is obviously not the case for men with SLE. Conversely, there may be genetic causes for an increase in SLE-affected men fathering children with SLE. There is at least one example of an SLE genetic effect that operates in men but not in women (57
). However, not all studies agree on which sex is affected by alleles within this gene (58
). In a linkage study the effect was seen only in families with a male SLE patient (59
). That men with SLE are more likely to be parents of SLE affected offspring than women may also be explained by the so-called Carter effect, which is defined as a polygenic inheritance model with a sexual dimorphic threshold such that the lesser affected sex is more likely to have children with the phenotype (60
). The Carter effect is known to operate in multiple sclerosis (62
Our data suggest that there are factors, genetic or otherwise, that contribute risk to SLE only for men. First, the SLE-unaffected women in the male-only SLE families almost universally had a positive ANA. Their rate of ANA positivity was higher than that found in SLE-unaffected relatives among families with female SLE patients. One can interpret this finding to mean that the break in tolerance that leads to autoimmunity is common between men and women in these male-only families. However, the factor or factors leading to disease are only acting in the men within these families. In addition, we have examined parent-offspring pairs with SLE in the LFRR collection of over 600 families with SLE. We find that men are more likely to be parents of SLE-affected offspring than are women, but that this difference was present only among American White men and not found among American Black men. It is possible that SLE in men is more genetic than in women. That is, men need to have more susceptibility genes than women because maleness is protective. One such protective factor might be the presence of one X chromosome instead of two (10
). Determining that there are male-specific genetics may be a difficult task in that the number of men with SLE needed for such a study will be large. Notwithstanding, the data presented herein along with previous reports (57
) suggest that genetic susceptibility factors act in a sex specific manner. Sorting this out in a genetically complex human disease will be challenging.
In summary, we report that in about 1% of families with SLE all the SLE patients are men. SLE-unaffected women in these families universally have autoantibodies. Along with data that SLE men tend to have children with SLE compared to women with SLE, these data imply that there are susceptibility factors operating in men but not in women in these families.