Frontal fibrosing alopecia and lichen planopilaris in HLA-identical mother and daughter.

Frontal fibrosing alopecia (FFA) is a lymphocyte-mediated scarring alopecia thought to be a variant of lichen planopilaris (LPP). We present a 67-year-old woman with frontal fibrosing alopecia whose daughter was diagnosed to have lichen planopilaris. Both patients had identical human leukocyte antigen (HLA) D types, supporting a phenotypical relationship between the two clinical entities. Interestingly, our patient also had of autoimmune chronic atrophic gastritis, a previously unreported association.

A general efficient and flexible approach for genome-wide association analyses of imputed genotypes in family-based designs.

Genotype imputation is a critical technique for following up genome-wide association studies. Efficient methods are available for dealing with the probabilistic nature of imputed single nucleotide polymorphisms (SNPs) in population-based designs, but not for family-based studies. We have developed a new analytical approach (FBATdosage), using imputed allele dosage in the general framework of family-based association tests to bridge this gap. Simulation studies showed that FBATdosage yielded highly consistent type I error rates, whatever the level of genotype uncertainty, and a much higher power than the best-guess genotype approach. FBATdosage allows fast linkage and association testing of several million of imputed variants with binary or quantitative phenotypes in nuclear families of arbitrary size with arbitrary missing data for the parents. The application of this approach to a family-based association study of leprosy susceptibility successfully refined the association signal at two candidate loci, C1orf141-IL23R on chromosome 1 and RAB32-C6orf103 on chromosome 6.

No evidence of linkage between Mitsuda reaction and the NRAMP1 locus.

Thirty sib-pairs were ascertained through unrelated lepromatous probands. They consisted of 22 healthy individuals and 8 leprosy patients. The Mitsuda reactions of all sibs were evaluated both macroscopically and histologically, and high molecular weight genomic DNA was extracted from the white blood cells of all sib-pairs. Three DNA polymorphisms identified by polymerase chain reaction (274C/T, D543N, 1729 + 55del4) were used as chromosome markers at the NRAMP1 locus. Sib-pair comparisons did not disclose any sign of close linkage between the Mitsuda reaction and the genetic markers.

Granulomatous reaction to intradermal injection of lepromin (Mitsuda reaction) is linked to the human NRAMP1 gene in Vietnamese leprosy sibships.

The Mitsuda test, which measures the specific immune response against intradermally injected lepromin, has a high prognostic value for susceptibility or resistance to the lepromatous form of leprosy. A sib-pair linkage analysis between the Mitsuda response and the NRAMP1 gene was done among 20 nuclear families with leprosy (totaling 118 sibs) from Ho Chi Minh City, Vietnam. All family subjects were genotyped for several intragenic and flanking NRAMP1 markers, leading to the definition of a fully informative NRAMP1 haplotype. Significant linkage was observed between NRAMP1 and Mitsuda reaction when considered either as a quantitative (P<.002) or as a categorical (P=.001) trait. Separate analyses among healthy and affected sibs showed evidence for linkage in both subsamples, indicating that linkage between the Mitsuda reaction and NRAMP1 is independent of leprosy status. These results support the view that NRAMP1 plays a regulatory role for the development of acquired antimycobacterial immune responses as determined by in vivo Mitsuda test reaction.

Granulomatous reaction to intradermal injection of lepromin (Mitsuda reaction) is linked to the human NRAMP1 gene in Vietnamese leprosy

The Mitsuda test, which measures the specific immune response against intradermally injected lepromin, has a high prognostic value for susceptibility or resistance to the lepromatous form of leprosy. A sib-pair linkage analysis between the Mitsuda response and the NRAMP1 gene was done among 20 nuclear families with leprosy (totaling 118 sibs) from Ho Chi Minh City, Vietnam. All family subjects were genotyped for several intragenic and flanking NRAMP1 markers, leading to the definition of a fully informative NRAMP1 haplotype. Significant linkage was observed between NRAMP1 and Mitsuda reaction when considered either as a quantitative (P<.002) or as a categorical (P=.001) trait. Separate analyses among healthy and affected sibs showed evidence for linkage in both subsamples, indicating that linkage between the Mitsuda reaction and NRAMP1 is independent of leprosy status. These results support the view that NRAMP1 plays a regulatory role for the development of acquired antimycobacterial immune responses as determined by in vivo Mitsuda test reaction.

Absence of an association between insulin-dependent diabetes mellitus and developmental learning difficulties.

For several years, investigators have been examining the relationship between learning difficulties and a variety of immunological disorders. Two recent studies by Hansen and colleagues reported a negative association between Type 1 diabetes and reading disabilities (dyslexia): subjects with Type 1 diabetes had a lower prevalence of dyslexia than their nondiabetic relatives. In order to control for the impact of environmental variables on learning, we investigated the relationship between Type 1 diabetes and learning problems in 27 sibling pairs, ranging in age from 6 to 20 years. One child in each pair had Type 1 diabetes, and the other child was the unaffected sibling closest in age. Children were assessed for cognitive skills, academic achievement in reading, mathematics, and written language, as well as for speech articulation and motor coordination. Other variables that were examined included handedness, behavioural variables, medical history, and pregnancy and birth complications. We found no significant differences between the 27 children with Type 1 diabetes and their unaffected siblings on any of the cognitive, academic achievement, or speech articulation measures. There were also no significant differences on handedness, behavioural variables, or health history.

The epidemiology of leprosy in a high prevalence village in Papua New Guinea.

In a village of about 1000 people in Papua New Guinea the prevalence of clinical leprosy was 8.6% compared to about 3% in surrounding villages. This exceptionally high prevalence could not be explained by recent introduction of the disease or by social factors. Dapsone-resistant disease and faulty compliance with treatment are considered to be contributory to persistent infectivity of old cases which, together with the presence of 20 previously undiagnosed cases, comprised a large infective source. Social ostracism of cases was not observed and the extensive social mixing of all ages would facilitate widespread dissemination of infection. A high prevalence, particularly in children, of elevated levels of IgM antibody to phenolic glycolipid-1 Mycobacterium leprae specific antigen suggests frequent subclinical infection. The greater prevalence of clinical leprosy following childhood in the village favours altered susceptibility following exposure in childhood. There was a higher prevalence of leprosy in close relatives of cases when compared with the same relatives of age and sex matched leprosy-free controls. The occurrence of familial clustering of leprosy in a hyperendemic area with intense transmission suggests that unidentified inherited factors influence susceptibility to clinical leprosy. It is suggested that the clustering of adverse inherited traits through intermarriage may explain this hyperendemic focus on leprosy.

A test of nonrandom segregation.

Within a family, associations between a disease and a marker locus are often inferred when affected offspring share marker alleles more often than is expected by chance. Generally, this is due to nonrandom parental transmission of marker alleles and specifically could be due to linkage, epistatic gene action, or segregation distortion at the marker locus. In this paper, we discuss the statistical properties of a general test of nonrandom segregation of a marker gene. The exact probability distribution of the test under the null hypothesis of random segregation is derived, as is the distribution under the alternative hypothesis of genetic linkage. We compute the mean and variance of these distributions as a means of judging the adequacy of random segregation to explain disease-marker data but also provide a method for computing the exact significance value under the null hypothesis. These methods have been utilized for studying HLA segregation in families with tuberculoid leprosy. On the assumption that this type of leprosy is autosomal recessive, we find evidence that a gene controlling susceptibility to infection by Mycobacterium leprae resides on human chromosome 6, approximately 13 map units away from the HLA locus in males.