HLA haplotype sharing in rheumatoid arthritis sibships: Risk estimates subdivided by proband genotype

There is a well-known association between rheumatoid arthritis (RA) and HLA-DR4. Recent research has indicated that both DR4 haplotypes are important in disease predisposition (favoring a recessive mode of inheritance). Others have suggested that certain combinations of genotypes, in particular Dw4/Dw14 heterozygotes, may be more important than others. We examined the mode of inheritance of RA using data from the Arthritis and Rheumatism Council's national repository of family material [Worthington et al. (1994) Br J Rheumatol 33:970–976]. There were 85 affected sibships consisting of 77 sib pairs, 6 trios, 1 quintuplet, and 1 sextuplet. The affected sibs shared two, one, and zero parental HLA haplotypes in a ratio of 0.42:0.43:0.15, which was significantly different from random expectations (P = 0.00009). Risk estimates for RA to sibs were calculated based on an overall sibling recurrence risk of 3.9%. Risks for those sharing two, one, and zero parental HLA haplotypes were 6.5% [95% confidence interval (CI) = 5.1–7.9%], 3.3% (95% CI = 2.6–4.0%), and 2.5% (95% CI = 1.5–3.5%), respectively. We also examined the risk of RA based on the DRβ1 genotype status of sib and proband. After excluding genotypic combinations with small numbers, the highest genotype-specific risks were seen for sibs sharing two haplotypes with either a DRβ1*0401/DRβ1*0404 (12.5%, 95% CI = 6.9–15.2%) or a DRβ1*0401/DRβ1*0408 (11.1%, 95% CI = 4.5–15.1%) proband. An independent assessment based on the AGFAP methodology confirmed the increase in risk for these genotypes, in particular for DRβ1*0401/DRβ1*0408. The excess being due to *0401/*0408 rather than to *0401/*0404 may explain why the Dw4/Dw14 effect is not always observed. Genet. Epidemiol. 15:403–418,1998. © 1998 Wiley-Liss, Inc.     

Epistatic modeling in rheumatoid arthritis: An application of the Risch theory

Rheumatoid arthritis (RA) is a disease of unknown etiology but with a presumed complex pattern of inheritance. Risch [Am J Hum Genet 46:222–228, 1990] has shown that the recurrence risk ratio, λ_R, (which is defined as the risk to type R relatives vs. the population prevalence) can be used to evaluate patterns of inheritance in genetically complex diseases. We have used the Risch theory to examine some multiple locus models of inheritance in RA. Recurrence risk ratios in MZ twins and in 1st, 2nd, and 3rd degree relatives are summarized from the literature. The limited data available supports at least a two-locus model of inheritance for RA (assuming that one locus is HLA). Better estimates of the recurrence risk ratios in RA families are required so that the Risch theory can be pursued further. © 1993 Wiley-Liss, Inc.     

AGFAP Method: Applicability under different ascertainment schemes and a parental contributions test

The antigen/allele genotype frequencies among patients (AGFAP) method has been powerful in discriminating between modes of inheritance, and detecting heterogeneity effects, for a number of diseases associated with the HLA system. The method is not dependent on the high level of polymorphism seen in the HLA system, but does require a marker allele association with disease. With recent rapid advances in mapping of the human genome, the method is increasingly relevant in all disease studies. Extension of the AGFAP method to ascertainment schemes other than random sampling of patients is presented here. The method is shown to be robust for distinguishing between incompletely penetrant recessive vs. additive or dominant models if affected children are obtained from nuclear families selected on the basis of at least two affected members: two affected sibs, or an affected parent and affected child. The method can lead to false conclusions for data from families ascertained for at least one affected parent and two affected children. A new test, termed the parental contributions test, applicable in families selected for the presence of an affected parent, and one or more affected children, is presented. The test, based on the expected symmetry (recessive) vs. asymmetry (additive and dominant) of parental marker allele contributions to an affected offspring in these pedigrees, is powerful in distinguishing between these modes of inheritance when there is a marker allele association with disease. Sporadic cases of disease are shown to cause deviations from AGFAP expectations for the recessive model, but not for the additive model. These results will aid in study of the genetics, and hence molecular basis, of complex diseases. © 1993 Wiley-Liss, Inc.     

Trends in the use of emergency contraception: an epidemiological study in Barcelona, Spain (1994-2002)

We conducted a retrospective review of the medical records of women requesting emergency contraception (EC) at our emergency department over a 9-year period (1994-2002). EC accounted for 5.9% of all visits (n = 95,288) and increased from 1.26% in 1994 to 9.82% in 2002 (p < 0.001). Reasons for EC were condom problems in 79.5% of cases. EC was used only once by 93% of women. The mean daily number of visits was significantly higher in August (2.46), July (2.01) and September (2.02) than in other months (p < 0.05), and was more frequent on Sunday (3.26), Saturday (2.92) and Monday (2.05) compared to other week days (p < 0.001). New Year's Day and the St. John's Night registered the highest number of visits (mean of 17.2 and 11.7, respectively), with significant differences compared to the remaining days of the year (p < 0.001).