FULL PAPER Linkage analysis of susceptibility to leprosy type using an IBD regression method C Wallace 1,2 , J Fitness 3,4 , B Hennig 3 , L Sichali 5 , L Mwaungulu 5 , JM Po ¨ nnighaus 5 , DK Warndorff 5 , D Clayton 6 , PEM Fine 1 and AVS Hill 3 1 London School of Hygiene and Tropical Medicine, UK; 2 Barts and The London, Queen Mary’s School of Medicine, UK; 3 Wellcome Trust Centre for Human Genetics, Oxford, UK; 4 Victoria University of Wellington, New Zealand; 5 Karonga Prevention Study, Malawi; 6 Cambridge Institute for Medical Research, UK Leprosy is a chronic disease caused by infection with Mycobacterium leprae, which is manifested across a wide clinical spectrum. There is evidence that susceptibility both to leprosy per se and to the clinical type of leprosy is influenced by host genetic factors. This paper describes the application of an identity by descent regression search for genetic determinants of leprosy type among families from Karonga District, Northern Malawi. Suggestive evidence was found for linkage to leprosy type on chr 21q22 (Po0.001). The methodological implications of the approach and the findings are discussed. Genes and Immunity (2004) 5, 221–225. doi:10.1038/sj.gene.6364062 Published online 11 March 2004 Keywords: IBD regression; linkage analysis; leprosy; leprosy type; Malawi Introduction Leprosy is a disease of skin and nervous tissue caused by infection with Mycobacterium leprae, and over 700 000 new cases were registered worldwide in 2002. 1 Infection is necessary for disease, but it is thought that only a small proportion (in the order of 10%) of infections lead to recognisable clinical lesions. 2 These may be manifested across a spectrum from paucibacillary (PB), characterised by a high cellular immune response and low bacterial load, to multibacillary (MB) disease, characterised by low to nonexistent cellular immune response and high bacterial load (up to 10 9 bacilli/g of tissue in the dermis). The exact mode of transmission of M. leprae is unknown, but it is favoured by prolonged contact with an infected individual. Linkage analyses have been carried out recently on data from leprosy cases and their families in Vietnam and India. 3–5 These identified regions on chromosomes 6, 10 and 20, which may harbour genes affecting suscept- ibility to leprosy per se or to PB leprosy in particular. Association studies in various populations have found evidence that variants in VDR, HLA-DR2, SLC11A1 and TNF are associated with leprosy or its subtypes. 6–13 However, many of these results have not been replicated in other populations, and in the case of TNF, the same allele has been found to be associated significantly with increased and with decreased risk of disease in Central Indian and Brazilian populations, respectively. 13–15 These results may reflect genetic heterogeneity be- tween populations. Such heterogeneity may also be evident in the apparent differences in relative frequency of MB and PB disease between populations, with the proportion of MB disease being lowest in Africans, higher in Asians and highest amongt Caucasians. This difference has been shown to persist in migrant popula- tions, 16 suggesting that it is related to host response rather than to the environment. However, some authors have suggested that this may be due at least in part to variation in ascertainment of PB disease (characterised by hypopigmented patches, which are most easily seen against a dark skin). 17 Families, with multiple cases of leprosy, have been ascertained from Karonga District in Northern Malawi, in the context of epidemiological studies carried out over the past 20 years, 18 a subset of which are nuclear families. The analysis of linkage to leprosy per se in the subset of nuclear families failed to replicate any of the regions identified above, but found weak evidence for linkage to a region on chr 21 (D21S180, MLS ¼ 1.4) and chr X (DXS990, MLS ¼ 1.1). 19 Here, we present the results of an identity by descent (IBD) regression analysis carried out in order to search for genes that influence leprosy type (as opposed to leprosy per se) in all nuclear and extended multicase families from this population. Results In all, 185 extended pedigrees multiplex for leprosy were ascertained as described in Materials and methods, 83 of Received 31 October 2003; revised 19 December 2003; accepted 23 January 2004 Correspondence: Dr C Wallace (c/o Karonga Programme), IDEU, LSHTM, Keppel St, London WC1E 7HT, UK. E-mail: c.wallace@qmul.ac.uk Genes and Immunity (2004) 5, 221–225 & 2004 Nature Publishing Group All rights reserved 1466-4879/04 $25.00 www.nature.com/gene