title: CUBN and NEBL common variants in the chromosome 10p13 linkage region are associated with multibacillary leprosy in Vietnam.
abstract: Leprosy is caused by infection with Mycobacterium leprae and is classified clinically into paucibacillary (PB) or multibacillary (MB) subtypes based on the number of skin lesions and the bacillary index detected in skin smears. We previously identified a major PB susceptibility locus on chromosome region 10p13 in Vietnamese families by linkage analysis. In the current study, we conducted high-density association mapping of the 9.5 Mb linkage peak on chromosome region 10p13 covering 39 genes. Using leprosy per se and leprosy subtypes as phenotypes, we employed 294 nuclear families (303 leprosy cases, 63 % MB, 37 % PB) as a discovery sample and 192 nuclear families (192 cases, 55 % MB, 45 % PB) as a replication sample. Replicated significant association signals were revealed in the genes for cubilin (CUBN) and nebulette (NEBL). In the combined sample, the C allele (frequency 0.26) at CUBN SNP rs10904831 showed association [p = 1 × 10(-5); OR 0.52 (0.38-0.7)] with MB leprosy only. Likewise, allele T (frequency 0.42) at NEBL SNP rs11012461 showed association [p = 4.2 × 10(-5); OR 2.51 (1.6-4)] with MB leprosy only. These associations remained valid for the CUBN signal when taking into account the effective number of tests performed (type I error significance threshold = 2.4 × 10(-5)). We used the results of our analyses to propose a new model for the genetic control of polarization of clinical leprosy.
authors.affiliation: Laboratoire de Génétique Humaine des Maladies Infectieuses, Branche Necker, Institut National de la Santé et de la Recherche Médicale, U980, Paris, France, audrey.grant@inserm.fr.
authors.forename: Audrey V
authors.initials: AV
authors.lastname: Grant
authors.forename: Aurelie
authors.initials: A
authors.lastname: Cobat
authors.forename: Nguyen
authors.initials: N
authors.lastname: Van Thuc
authors.forename: Marianna
authors.initials: M
authors.lastname: Orlova
authors.forename: Nguyen Thu
authors.initials: NT
authors.lastname: Huong
authors.forename: Jean
authors.initials: J
authors.lastname: Gaschignard
authors.forename: Andrea
authors.initials: A
authors.lastname: Alter
authors.forename: Nguyen Ngoc
authors.initials: NN
authors.lastname: Ba
authors.forename: Vu Hong
authors.initials: VH
authors.lastname: Thai
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcaïs
authors.forename: Erwin
authors.initials: E
authors.lastname: Schurr
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics*; D056006:Leprosy, Multibacillary / Q000235:genetics*; D008297:Male; D009166:Mycobacterium leprae; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*; D014744:Vietnam
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D060588:LIM Domain Proteins; C486890:NEBL protein, human; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor