Genetics of lupus-related phenotypes

Lupus Foundation of America

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What is the topic?

Genes do play a role in the predisposition to the development of lupus, but much of the genetic susceptibility remains to be explained. More research on factors related to the heritability of lupus could facilitate greater understanding of the disease, including that of the excessive production of interferon-alpha that is characteristic of about half of adult lupus patients.

What did the researchers hope to learn?

The researchers hoped to learn about the genetic contributions to lupus susceptibility and how this might relate to specific lupus-related phenotypes, such as the presence of specific autoantibodies.

Who was studied?

The researchers used public databases to obtain and analyze genetic data relevant to lupus. The initial study analyzed genetic data from 104 lupus patients from the Hospital for Special Surgery Lupus Registries, which was part of a genome-wide association study. A follow-up validation study was conducted using data from 453 lupus patients obtained from the University of Chicago Translational Research registry and Rush University Medical Center.

How was the study conducted?

The initial study was designed to identify and compare the frequencies of single-nucleotide polymorphisms (SNPs), or genetic variations, in individuals with lupus having high vs. low interferon-alpha levels and those with and without lupus-associated autoantibodies. The top 200 SNPs were examined in detail by expert review of public databases, and the seven top SNPs were chosen for further study in an independent cohort.

A follow-up validation study was conducted in an independent sample of individuals with lupus. This study compared expression levels of 15 lupus-related genes between individuals with lupus and people with no autoimmune diseases. The 15 genes studied here were identified in a public database containing SNP genotype data.

The following were measured in all study samples: anti-Ro, anti-La, anti-Smith, and anti-ribonucleoprotein autoantibodies, as well as anti-double-stranded DNA (anti-dsDNA) antibodies.

What did the researchers find?

The researchers used advanced statistical methods to determine the relationship between autoantibody traits (i.e., their presence of absence) and genetic data regarding 11 SNPs in individuals with lupus from two different sets of ancestral backgrounds. Of these, three SNPs were significantly associated with the presence of specific lupus-related autoantibodies. In addition, two SNPs were also significantly associated with blood levels of interferon-alpha.

A search of a public genetic database revealed that, among four SNPs associated with specific lupus-related phenotypes, each was associated with a unique phenotype in lupus patients of African-American or European descent. Specifically, one SNP was associated with anti-rubonucleoprotein antibodies in African-Americans, one was associated with anti-Smith antibodies in Europeans, one SNP was associated with anti-Ro antibodies in Europeans, and one SNP was associated with interferon levels in both African-Americans and Europeans.

What were the limitations of the study?

First, the study only compared the genetic data between that of African-American and European lupus patients found in the public genetic database. Whether the observed trends are also present in lupus patients of other ethnicities cannot be determined from the present study. Also, the genetic data was organized according to whether the samples came from lupus patients having low or high levels of interferon-alpha, but similar analyses were not done with other kinds of measures (such as, low or high levels of anti-dsDNA antibodies). Lastly, while the results suggest that similar, additional research efforts could facilitate personalized medicine for individuals with lupus, exactly how this information could be used to bring that to fruition is yet to be determined.

What do the results mean for you?

This study identified novel genetic variants associated with specific lupus-related phenotypes in individuals from two different ancestral backgrounds. The results suggest that while many features can be common to a wide range of lupus patients, dysregulation of similar molecular pathways in lupus patients of different ancestral backgrounds can yield different lupus-related phenotypes in different ethnic groups.

Gene-expression-guided selection of candidate loci and molecular phenotype analyses enhance genetic discovery in systemic lupus erythematosus
Koldobskaya Y, Ko K, Kumar AA, Agik S, Arrington J, Kariuki SN, Franek BS, Kumabe M, Utset TO, Jolly M, Skol AD, and Niewold TB. 
Clinical & Developmental Immunology. 2012. July 25. doi: 10.1155/2012/682018.