Pleiotropy of systemic lupus erythematosus risk alleles and cardiometabolic disorders: A phenome-wide association study and inverse-variance weighted meta-analysis

Vivian K. Kawai*, Mingjian Shi, Ge Liu, Qi Ping Feng, Wei Qi Wei, Cecilia P. Chung, Theresa L. Walunas, Adam S. Gordon, James G. Linneman, Scott J. Hebbring, John B. Harley, Nancy J. Cox, Dan M. Roden, C. Michael Stein, Jonathan D. Mosley

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: To test the hypothesis that genetic predisposition to systemic lupus erythematosus (SLE) increases the risk of cardiometabolic disorders. Methods: Using 41 single nucleotide polymorphisms (SNPs) associated with SLE, we calculated a weighted genetic risk score (wGRS) for SLE. In a large biobank we tested the association between this wGRS and 9 cardiometabolic phenotypes previously associated with SLE: atrial fibrillation, ischemic stroke, coronary artery disease, type 1 and type 2 diabetes, obesity, chronic kidney disease, hypertension, and hypercholesterolemia. Additionally, we performed a phenome-wide association analysis (pheWAS) to discover novel clinical associations with a genetic predisposition to SLE. Findings were replicated in the Electronic Medical Records and Genomics (eMERGE) Network. To further define the association between SLE-related risk alleles and the selected cardiometabolic phenotypes, we performed an inverse variance weighted regression (IVWR) meta-analysis. Results: The wGRS for SLE was calculated in 74,759 individuals of European ancestry. Among the pre-selected phenotypes, the wGRS was significantly associated with type 1 diabetes (OR [95%CI] =1.11 [1.06, 1.17], P-value = 1.05x10−5). In the PheWAS, the wGRS was associated with several autoimmune phenotypes, kidney disorders, and skin neoplasm; but only the associations with autoimmune phenotypes were replicated. In the IVWR meta-analysis, SLE-related risk alleles were nominally associated with type 1 diabetes (P = 0.048) but the associations were heterogeneous and did not meet the adjusted significance threshold. Conclusion: A weighted GRS for SLE was associated with an increased risk of several autoimmune-related phenotypes including type I diabetes but not with cardiometabolic disorders.

Original languageEnglish (US)
Pages (from-to)1264-1272
Number of pages9
JournalLupus
Volume30
Issue number8
DOIs
StatePublished - Jul 2021

Keywords

  • Systemic lupus erythematosus
  • genetic risk score
  • pleiotropy

ASJC Scopus subject areas

  • Rheumatology

Fingerprint

Dive into the research topics of 'Pleiotropy of systemic lupus erythematosus risk alleles and cardiometabolic disorders: A phenome-wide association study and inverse-variance weighted meta-analysis'. Together they form a unique fingerprint.

Cite this