Leprosy is caused by Mycobacterium leprae and affects about 700,000 individuals each year. It has long been thought that leprosy has a strong genetic component, and recently we mapped a leprosy susceptibility locus to chromosome 6 region q25-q26 (ref. 3). Here we investigate this region further by using a systematic association scan of the chromosomal interval most likely to harbour this leprosy susceptibility locus. In 197 Vietnamese families we found a significant association between leprosy and 17 markers located in a block of approx. 80 kilobases overlapping the 5' regulatory region shared by the Parkinson's disease gene PARK2 and the co-regulated gene PACRG. Possession of as few as two of the 17 risk alleles was highly predictive of leprosy. This was confirmed in a sample of 975 unrelated leprosy cases and controls from Brazil in whom the same alleles were strongly associated with leprosy. Variants in the regulatory region shared by PARK2 and PACRG therefore act as common risk factors for leprosy.
Leprosy, a chronic infectious disease caused by Mycobacterium leprae, affects an estimated 700,000 persons each year. Clinically, leprosy can be categorized as paucibacillary or multibacillary disease. These clinical forms develop in persons that are intrinsically susceptible to leprosy per se, that is, leprosy independent of its specific clinical manifestation. We report here on a genome-wide search for loci controlling susceptibility to leprosy per se in a panel of 86 families including 205 siblings affected with leprosy from Southern Vietnam. Using model-free linkage analysis, we found significant evidence for a susceptibility gene on chromosome region 6q25 (maximum likelihood binomial (MLB) lod score 4.31; P = 5 x 10(-6)). We confirmed this by family-based association analysis in an independent panel of 208 Vietnamese leprosy simplex families. Of seven microsatellite markers underlying the linkage peak, alleles of two markers (D6S1035 and D6S305) showed strong evidence for association with leprosy (P = 6.7 x 10(-4) and P = 5.9 x 10(-5), respectively).
Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-alpha (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P = 0.007 and P = 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P = 0.000024), which increased to 5.63 (P = 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 years of age. In addition to identifying LTA as a major gene associated with early-onset leprosy, our study highlights the critical role of case- and population-specific factors in the dissection of susceptibility variants in complex diseases.
Dental decay is a complex, chronic disease and one of the most common illnesses in dentistry today. Several dental decay risk factors have been identified during the last years; however, these variables alone may not entirely explain the disease development. Genetic research applied to dental decay began in the 1930s with experimental reports in animals and human observational research. Only recently, have some studies begun to search for genetic polymorphisms in humans and apply linkage analysis. However, due to the complex characteristics of the disease, the strong influence from several biological and environmental factors, and the small number of genetic studies related to dental caries, the genetic basis still requires further study. Therefore, the aim of this review is to provide a brief description of the current methodology for genetic analysis of complex traits, followed by a comprehensive evaluation of the literature related to genetic susceptibility/resistance to dental decay and a discussion of different aspects of the applied methodology. Advances towards the elucidation of the dental decay genetic basis may contribute to the understanding of the disease etiopathogenesis and to the identification of high risk groups, thus providing potential targets for effective screening, prevention and treatment.
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