Association of angiotensin-converting enzyme polymorphisms with systemic lupus erythematosus and nephritis: analysis of 644 SLE families

Angiotensin II is a strong candidate for the perpetuation of autoimmunity, nephritis and visceral damage in systemic lupus erythematosus (SLE). Our goal was to determine whether angiotensin-converting enzyme (ACE) gene polymorphisms are associated with SLE and/or lupus nephritis (LN). We genotyped 644 SLE patients and 1130 family members for three ACE gene polymorphisms: Alu insertion/deletion (I/D), 23949 (CT),I, and 10698 (G)(3/4). All patients met the American College of Rheumatology (ACR) criteria for SLE, and all LN patients met ACR renal criteria and/or had biopsy evidence of LN. We used the transmission/disequilibrium test (TDT) to examine associations between each polymorphism and SLE, including Caucasian, non-Caucasian, and LN subgroups. We also examined transmission of haplotypes defined by these polymorphisms. The ACE I/D polymorphism was associated with SLE among non-Caucasians (61% transmission, P = 0.026) and the 23949 (CT)(2/3) polymorphism was associated with LN among non-Caucasians (69% transmission, P = 0.014). Several haplotypes defined by these 2 markers demonstrated strikingly increased transmission among non-Caucasians (81% - 66% transmission, P = 0.0046 to 0.010). Due to the choice of study design and analytic method these results are unlikely to be due to population admixture. Our findings suggest that DNA sequence variation in the ACE gene influences the risk of developing SLE and LN.