Unlocking the reasons why lupus is more common in women

Lupus Foundation of America

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Lupus is thought to develop due to an interaction between genetic susceptibility and environmental triggers. Previous studies have identified a number of genes referred to as “lupus susceptibility genes,” the presence of which are thought to increase the likelihood of developing lupus.

Importantly, lupus is about nine times more common in women than in men. This increased susceptibility may be made possible, at least in part, due to differences related to hormones and sex chromosomes. However, to what extent these sex differences contribute to the development of lupus is largely unknown.

What did the researchers hope to learn?

The researchers hoped to learn about the degree to which sex-specific genetic differences contribute to the susceptibility to developing lupus. They also investigated possible sex-related differences in levels of anti-double-stranded DNA antibodies (anti-dsDNA) between men and women with lupus.

Who was studied?

3936 people with lupus (3592 females and 344 males), as well as 3491 healthy people (2340 females and 1151 males), of European descent were studied.

How was the study conducted?

Genetic samples were processed according to strict quality guidelines to determine the frequency of small but important changes in 18 known lupus susceptibility genes found on non-sex chromosomes (portions of DNA) in both men and women with and without lupus. Based on differences from this analysis, including a subset of the genetic samples (2982 women and 287 men with lupus), a genetic risk was calculated for the lupus patients in a sex-specific manner.

What did the researchers find?

Initial studies showed that changes in 10 of the 18 susceptibility genes in men and 15 of the 18 in women were found to be significantly different between lupus patients and healthy people. Three of the 18 genes did not meet these criteria, were not associated with lupus in the current study, and were thus excluded from further analyses.

Comparison of the frequency of changes in the 18 lupus susceptibility genes between men and women with lupus indicated that four of them differed significantly in a sex-specific fashion. Two of these genes are found in the human leukocyte antigen (HLA) region (hereafter referred to as “HLA genes”) and two are found outside of the HLA region (hereafter called “non-HLA genes”). The HLA genes encode for proteins that are essential for proper functioning of the immune system and help to elicit powerful and specific immune responses.

Interestingly, the frequency of the two HLA genes (plus one of the non-HLA genes, IRF5, a gene involved in the interferon pathway which is important in the pathogenesis of lupus) was significantly greater in men than in women with lupus. Only one of the four genes of interest here, one of the non-HLA genes (KIAA1542, a gene of unknown function), was significantly greater in frequency in women than in men. Importantly, the frequency of these three genes did not differ between men and women without lupus.

No significant sex-related differences were found in levels of anti-dsDNA between men and women with lupus. Further statistical comparisons showed that the frequency of changes in the four aforementioned lupus susceptibility genes were not associated with differences in disease severity (using kidney involvement and decreased blood platelets as indicators of disease severity) in men or women with lupus.

Comparisons of sex-specific differences in genetic risk showed that men with lupus require, on average, a greater cumulative genetic load of lupus-susceptibility genes than women in order to develop lupus.

What were the limitations of the study?

The study participants were all of European descent, so it is unknown whether the results are applicable to other populations of people with lupus. In addition, the current study did not address any environmental contributions to the development of lupus in the patients studied, nor a possible gender-specific difference in possible environmental contributions.

What do the results means for you?

The results indicate that men need to inherit a greater number of lupus susceptibility genes than women in order to develop lupus. Since the genes analyzed in this study were only genes outside of the sex chromosomes, the findings suggest that sex differences in lupus susceptibility genes are at least partially related to factors beyond sex chromosomes and hormonal differences. These results help to explain, at least in part, why fewer men get lupus than women.

Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus
Hughes T, Adler A, Merrill JT, Kelly JA, Kaufman KM, Williams A, Langefeld CD, Gilkeson GS, Sanchez E, Martin J, Boackle SA, Stevens AM, Alarcón GS, Niewold TB, Brown EE, Kimberly RP, Edberg JC, Ramsey-Goldman R, Petri M, Reveille JD, Criswell LA, Vilá LM, Jacob CO, Gaffney PM, Moser KL, Vyse TJ, Alarcón-Riquelme ME; BIOLUPUS Network, James JA, Tsao BP, Scofield RH, Harley JB, Richardson BC, and Sawalha AH. Annals of the Rheumatic Diseases. 2011 Nov 21.