A study in Korean patients found five new gene variants associated with the development of Sjögren’s syndrome, which may provide biomarkers for precision medicine, the scientists said.
The research, “Variants at potential loci associated with Sjogren’s syndrome in Koreans: A genetic association study,” appeared in the journal Clinical Immunology.
Large-scale tests have revealed genes associated with Sjögren’s syndrome, with differences comparing European to Han Chinese patients. However, these studies did not explain the genetic basis of some of the characteristic symptoms of the condition.
An approach that may help address this gap is whole-exome sequencing (WES), which sequences the protein-coding regions of genes — their exons — and compares them with a reference sequence. As such, it may detect rare mutations of different types.
The team from Yonsei University and Pohang University of Science and Technology, in South Korea, used WES in 15 Korean women and 100 healthy controls. The patients’ mean age was 61.3 years and their disease duration was eight to 27 months. Clinical signs, symptoms, complications, and laboratory tests were analyzed.
Unstimulated salivary flow was collected with the patients sitting still; the Schirmer’s I test assessed tear production by the lacrimal glands, and gustometry evaluated the patients’ sense of taste.
The results showed that 60% of the participants had hyposalivation (below normal) and 20% had low salivary flow, meaning a flow inferior to 0.1 ml/min or within 0.1-0.2 ml/min, respectively.
As for gustometry, 12 patients could identify sucrose (sweet), 13 could identify sodium chloride (salt), 13 had a normal response to quinine hydrochloride (bitter), and five scored in the normal range for citric acid (sour).
Six patients had poor lacrimal gland function, as defined by a length of wetting (in strips) inferior to 5 mm in five minutes.
The genetic analysis of salivary samples found seven genes with missense variants associated with Sjögren’s syndrome. Only two of these genes, MSH5 and RELN, had previously been linked to the disease. Missense variants are changes in the building blocks of DNA, called nucleotides, which lead to a different amino acid.
Using an approach called SIFT, two variants were predicted to be damaging: rs72552705 in UGT2B28 — a gene associated with another autoimmune disorder called Addison’s disease — and rs2075789 in MSH5. Besides UGT2B28, the other genes newly correlated with the condition were TRBV5-6, NAPB, PRAMEF13, and TARBP1, previously linked with multiple sclerosis and systemic lupus erythematosus.
Subsequent analyses revealed that the variants in MSH5, PRAMEF13, and NAPB were not identified in patients with low salivary flow. In contrast, TARBP1, MSH5, and RELN were the genes most likely linked with hyposalivation; variants in PRAMEF13 and MSH5 were more likely in women with lacrimal gland dysfunction, and the NAPB gene variant had the strongest association with sucrose insensitivity.
Taking these seven variants along with those previously reported in Europeans and Han Chinese, the researchers identified the cellular Golgi network — most importantly involved in modifying, sorting, and packaging proteins for secretion — as likely involved in Sjögren’s syndrome disease processes.
“Despite the small number of samples, this study may support future research based on a larger reference population by elucidating more precisely which genes are related to certain subtypes of complications,” the researchers stated. “We hope our discovery will eventually enable clinicians to treat patients based on their individual genetic characteristics.”