02235nas a2200301   4500000000100000008004100001653001200042653003600054653001100090653002400101100001100125700001000136700001300146700001500159700001300174700001200187700001400199700001000213700001200223700001300235700001200248700001400260700001100274700001300285245009900298856007700397520145900474       2019                            d10aleprosy10aLeprosy type-1 reactions (T1Rs)10aParkin10aParkinson's disease1 aFava V1 aXu YZ1 aLettre G1 aVan Thuc N1 aOrlova M1 aThai VH1 aCambri GE1 aTao S1 aLahir R1 aAdams LW1 aCobat A1 aAlcaïs A1 aAbel L1 aSchurr E00aPleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson’s disease  uhttps://www.biorxiv.org/content/biorxiv/early/2019/01/02/507806.full.pdf3 a<p>Type-1 reactions (T1Rs) are pathological inflammatory episodes and main contributors to nerve damage in leprosy. Here, we evaluate the gene-wise enrichment of rare protein altering variants in seven genes where common variants were previously associated with T1R. We selected 474 Vietnamese leprosy-patients of which 237 were T1R-affected and 237 were T1R-free matched controls. Gene-wise enrichment of nonsynonymous variants was tested with both kernel based (SKAT) and burden methods. Of the seven genes tested two showed statistical evidence of association with T1R. For the LRRK2 gene an enrichment of nonsynonymous variants was observed in T1R-free controls (p SKAT-O= 1.6x10-4). This gene-wise association was driven almost entirely by the gain of function variant R1628P (p = 0.004; OR = 0.29). The second gene-wise association was found for the Parkin coding gene PRKN (formerly PARK2) where seven rare variants were enriched in T1R-affected cases (p SKAT-O = 7.4x10<sup>-5</sup>). Mutations in both PRKN and LRRK2 are known causes of Parkinson's Disease (PD). Hence, we evaluated to what extent such rare amino acid changes observed in T1R are shared with PD. We observed that nonsynonymous T1R-risk mutations in Parkin were enriched for amino acid mutations implicated in PD (p = 1.5x10<sup>-4</sup>). Hence, neuro-inflammation in PD and peripheral nerve damage due to inflammation in T1R share overlapping mechanisms of pathogenicity.</p>