Reply to Zhang et al.: The differential role of LRRK2 variants in nested leprosy phenotypes

Abstract

We thank Dr. Zhang et al. (1) for their thought-provoking comments and addition of exciting results to our recent study that identifies an overlap in the genetic control of type-1 reaction (T1R) and Parkinson's disease (PD) (2). To put the comments by Zhang et al. into context, the purpose and design of our study is to analyze the contribution of rare variants to T1R by contrasting T1R-affected with T1R-free leprosy patients. Our study is not designed to test for common variants or the impact of genetic variants on leprosy per se susceptibility. Rather, our study deals with the role of specific genetic variants in the development of T1R among leprosy patients, and we never state or imply that the PRKN and LRRK2 genes have an exclusive impact on T1R but not leprosy. Indeed, we have published extensively on the role of common PRKN variants in leprosy susceptibility (3,4) As for PRKN, the two markers listed by Zhang et al.(1) do not show evidence for significant association with T1R in our study (2). We find that the V380L marker, which is not significant on its own, contributes to the rare variant analysis but not to an extent that impacts the overall conclusion about the contribution of rare PRKN variants to T1R risk. Given the nonsignificant effect of V380L, we do not attempt to do any functional validation of this particular variant.Stimulated by the data of Zhang et al.(1) for LRRK2, we compared the R1628P distribution between T1R-affected and T1R-free leprosy cases of our sample against 472 ethnically matched healthy controls. For T1R-free

Underwhelming or Misunderstood? Genetic Variability of Pattern Recognition Receptors in Immune Responses and Resistance to Mycobacterium tuberculosis

“…Most studies define TB as a single entity combining cases regardless of their clinical and biological characteristics. While this approach has worked for leprosy ( 210 , 211 ), in other instances combining all leprosy cases has proven troublesome due to the presence of well-defined endophenotypes ( 212 , 213 ). Common endophenotypes in leprosy are excessive host inflammatory responses, so-called lepra reactions, that sub-divide the overall group of patients.…”

“…Endophenotypes can result in misclassification of genetic effects ( 213 , 214 ). Indeed, the genetic associations can be in opposite direction between endophenotype and disease per se ( 212 , 215 ).…”

Early onset leprosy reveals a joint effect of LRRK2 and NOD2 variants

“…By applying unbiased WGS analysis on a family with monozygotic twins with extreme early-onset leprosy, we identified three coding variants in the LRRK2 and NOD2 genes as strong candidates for contributing to early-onset leprosy susceptibility. Rare and common variants in both genes had previously been associated with leprosy and leprosy reactions by candidate and genome-wide association studies (3,6,7,(24)(25)(26)(27)(28)(29)(30). Intriguingly, the same coding variants identified in the leprosy family have been implicated in reduced susceptibility to PD and CD (8).…”

“…In previous work, it was shown that the LRRK2 1628P mutation was a risk factor for leprosy but protective for T1R (6,7). The antagonistic pleiotropic effect of the 1628P LRRK2 mutation is a reflection of the two sides of the anti-pathogen host response.…”

“…A recent study discovered significant pleiotropy of amino acid mutations of the PRKN gene for Parkinson’s disease (PD) and T1R while amino acid mutations of the LRRK2 gene displayed significant antagonistic pleiotropy for T1R and PD ( 6 ). The same amino acid change protected from leprosy per se demonstrating how the same genetic variant can protect from infectious disease while predisposing to host damaging inflammatory responsiveness ( 6, 7 ). Recently, pleiotropic effects were also observed for amino acid mutations in the LRRK2 and NOD2 genes between CD and PD ( 8 ).…”