An RFLP map for 2q33‐q37 from multicase mycobacterial and leishmanial disease families: no evidence for an Lsh/Ity/Bcg gene homologue influencing susceptibility to leprosy

Abstract

The mycobacterial diseases leprosy and tuberculosis (TB) and the leishmaniases are characterized by a wide spectrum of disease phenotypes, and by the fact that the majority of individuals exposed to the causative organisms Mycobacterium leprae, M. tuberculosis and Leishmania sp. become infected but do not present with clinical disease. In order to determine whether a human homologue to the murine macrophage resistance gene Lsh/Ity/Bcg influences susceptibility to human disease, multicase families for all three diseases have been collected, and linkage analysis performed using a panel of markers in the region of human chromosome 2q33-q37 known to be conserved with the Lsh/Ity/Bcg-containing region of murine chromosome 1. Because of the paucity of available polymorphic markers/linkage information for 2q33-q37, data from 35 multicase leprosy, TB and visceral leishmaniasis families (310 individuals) were first pooled to produce a detailed RFLP map of the region. Peak LOD scores well in excess of 3 were observed for linkage between adjacent pairs of a more proximal (2q33-q35) set of markers CRYGP1, MAP2, FN1, TNP1, VIL1 and DES, and between adjacent pairs of a more distal (2q35-q37) set COL6A3, D2S55 and D2S3. These peak LOD scores and the corresponding values for theta were used in the MAP92 program to generate a multiple two-point map with gene order/map intervals (cM) of: CRYGP1-4.65-MAP2-3.45-FN1-5.95-TNP1-3.41-VIL1-3. 01- DES-20.14-COL6A-10.91-D2S55-3.67-D2S3. Although local support for the placement of loci in this order was weak (LOD < 2, except for DES-COL6A3 where LOD = 6.02), the map is consistent with the gene order for those loci (Cryg, Fn-1, Tp-1, Vil, Des, Col6a3) previously mapped in the mouse. Data from 17 multicase leprosy families (149 individuals) were further analysed for linkage between a putative disease susceptibility locus (DSL) controlling susceptibility to leprosy per se and each of the marker loci. Assuming 100% penetrance for the susceptibility allele, no positive LOD score was obtained for linkage between the DSL and any of the marker genes. Instead, the data provide convincing evidence (LOD scores < -2) that a DSL does not fall within 10-20 cM of CRYGP1, MAP2, TNP1, VIL1, DES or D2S55, or within 5-10 cM of FN1, COL6A3 or D2S3. This effectively excludes a putative DSL controlling susceptibility to leprosy per se from the entire region 2q33-q37.(ABSTRACT TRUNCATED AT 400 WORDS)

Association of NRAMP1 polymorphism with leprosy type but not susceptibility to leprosy per se in west Africans.

“…Family studies in Polynesia and Pakistan found no evidence for linkage of NRAMP1 to leprosy, 19,20 but a more recent study of Vietnamese families found weak evidence for linkage. 14 The small size of these studies was only sufficient to detect linkage to a major gene accounting for a substantial proportion of the genetic variance.…”

Allelic association between the NRAMP1 gene and susceptibility to tuberculosis in Guinea–Conakry

“…Its identification followed the discovery by positional cloning of the homologous gene in mice, Nramp1, that determined susceptibility to certain strains of Mycobacterium bovis, Salmonella and Leishmania (Vidal, 1993). Linkage studies between NRAMP1 and leprosy have been reported by Shaw et al (1993) in multicase families from Pakistan and Brazil, and by Roger et al (1997) in multicase pedigrees from Polynesia. Neither of these two studies found any evidence in favour of NRAMP1 playing a role in susceptibility to leprosy.…”

Polimorfismo do gene humano NRAMP1, níveis de anticorpos anti-PGL-1 e suscetibilidade para hanseníase em áreas endêmicas do Estado do Pará, Brasil

“…Outros estudos de associação genética não encontraram significância na suscetibilidade para hanseníase em famílias da Polinésia Francesa e Paquistão 34,35 , mas esse fato não invalida estudos que encontraram esta diferença e não significa que não há associação com hanseníase, pois a validação na estratificação e tamanho da população de pacientes e o fato das variações testadas não serem polimórficas nessas populações são fatos importantes a serem considerados 36 .…”

“…Shaw e colaboradores 35 utilizaram um painel de marcadores na região do cromossomo humano 2q33-Q37, conhecido por ser conservado e conter região do cromossomo murino 1. Conjuntos de marcadores utilizados foram CRYGP1, MAP2, FN1, TNP1, VIL1 e DES e, entre os pares adjacentes de região mais distal (2q35-Q57) definiram COL6A3, D2S55 e D2S3, e também não encontraram significância na associação deste polimorfismo com hanseníase.…”

“…Associação do genótipo do NRAMP1 tipado neste estudo, como a maioria dos estudos de associação genética com hanseníase, não encontrou significância estatística para hanseníase per se (p = 0,51, tabela 2) 14,28,34,35 , porém, quando esta análise foi ampliada com dados de sorologia positiva para anti-PGL-1, observou-se significância estatística para hanseníase per se (p = 0,0087) e risco relativo (RR) considerado de efeito moderado (RR = 1,80, IC95% -1,13 -2,85; X² = 6.87, tabela 3). Achado semelhante foi também encontrado no estudo de Ferreira et al 37 , os quais utilizaram a reação de Mitsuda para determinar indivíduos com predominância de resposta imunológica do tipo Th1 (celular) e, desta forma, separando com maior precisão casos PB dos MB.…”