Purpose: XRCC1and XPD play key roles in the repair of DNA lesions and adducts. Contrasting findings have been reported on the effect of polymorphisms of these genes on the response to platinum-based chemotherapy in advanced non^small-cell lung cancer (NSCLC). This study aimed to investigate the relationship between the XPD Lys751Gln and XRCC1 Arg399Gln genotypes and outcome in lung cancer patients. Experimental Design: We genotyped 203 NSCLC and 45 small-cell lung carcinoma (SCLC) patients for the two polymorphisms. Most of the patients (81%) received a platinum-based chemotherapy. Results: The patients' genotype frequencies did not significantly differ from controls and both groups were in Hardy-Weinberg equilibrium for the two polymorphisms. The XRCC1399 Gln/Gln variant genotype was associated with a higher median survival time (80 weeks versus 54.6 weeks for the Arg/Gln heterozygous and 55.6 weeks for the wild-type Arg/Arg genotype; P = 0.09). At the multivariable analysis adjusted for histology, stage of the disease, performance status, age, and gender, the Gln/Gln genotype was associated with a better survival of borderline significance in the subgroup of patients treated with cisplatin (hazard ratio, 0.55; 95% CI, 0.30-1.00); this association became significant for those with grade 3-4 clinical toxicity (hazard ratio, 0.46; 95% CI, 0.22-0.98). No association between XPD Lys751Gln genotype and clinical outcome was found. Conclusion: This prospective investigation provides suggestive evidence of a favorable effect of the XRCC1399 Gln/Gln genotype on survival in platinum-treated NSCLC and, for the first time, in SCLC patients also. This contrasts with other authors who did not include non^platinum-treated patients, but it does fit the expectation for a suboptimal ability to remove DNA adducts.

Two subjects, of 11,000 healthy individuals screened, were found to be missing three and four immunoglobulin isotypes, respectively (IgAl, IgG2, and IgG4; IgAl, IgG2, IgG4, and IgE), and have beei analyzed at the DNA level by means of Southern blotting and Ig heavy-chain-specific probes. A broad deletion within the heavy-chain constant region (C) gene cluster was found on chromosome 14 of both probands. Two different haplotypes are described: the first has lost the Cai,, Cty, Cy2, Cy4, and CE genes; the second lacks the Cp,> Ca., Cy,1 C.,2, andhCy4 genes. These findings confirm the reciprocal order of the Ig heavy-chain genes as derived by molecular cloning. The inclusion of the C*, gene within the deleted regions confirms its location between Ca, and Cy2.From the observed frequency of the homozygous genotype, 1%-3% of healthy subjects from our population are expected to be heterozygous for multiple heavy-chain gene deletions. Cross-over between mispaired homologous regions seems to be the favored mechanism of multiple Ig gene deletions and duplications, and, generally, in the evolution of the human Ig heavy-chain gene family.

SUMMARY The association of HLA-A,B,C, DR polymorphisms and of Bf and GLO with coeliac disease was analysed in 100 Italian children. Primary involvement of HLA-DR3 and DR7 is apparent, while specificities of nearby loci are probably associated secondarily, because of linkage disequilibrium. Direct assessment of D/DR genotype through family studies and mixed lymphocyte cultures led to the recognition of two high risk genotypes DR3/3 and DR3/7, and of two lower risk genotypes DR3/X and DR7/X. The different weight of the HLA-dependent genetic factors is to some extent correlated with the clinical and immunological parameters, suggesting that the low-risk genotypes induce a milder expression of coeliac disease. Furthermore, other genetic factors, such as sex, appear to contribute to the penetrance of the disease, especially in the case of DR3/X and DR7/X. Both genetic and environmental factors contribute to the onset and to clinical progression of coeliac disease. The role of genetic factors has long been substantiated by a high concordance rate in monozygotic twins, and an increased incidence of overt malabsorption or of asymptomatic histological lesions in first-degree relatives.' 2 More recently, the association between markers of the HLA system and coeliac disease has provided new evidence of the importance of genetic factors in this disease. 8 Different genetic models have been put forward, which propose dominant or recessive expression of HLA-linked gene(s), or in addition assume the involvement of non-HLA gene(s).9 I() In susceptible individuals, exposure to dietary gluten, or to purified gliadin fractions under experimental conditions, is the leading known environmental factor. Clinical and/or histological improvement on a gluten-free diet and relapse after gluten challenge have thus been established as fixed diagnostic criteria.11 Nevertheless, the protean nature of the clinical picture is adequately shown by the significant proportion of atypical cases.'2 As part of an ongoing study, the present report (1) provides further evidence of the association of

The molecular bases of classical serological immunoglobulin allotypes are progressively uncovered through detailed characterization of the relevant genes. Here we describe two isoallotypic determinants of the G4 gene. In the first, Leu 309, as in G1 and G3, is changed to Val, as in G2; studies on myeloma proteins have long assigned the immunologically defined nG4 m(a)/(b) to the same position. The two molecular variants, here called IGHG4*L309 and IGHG4*V309, are allelic in IGHC haplotypes with a single G4 gene, but can be found together in cis in G4-duplicated haplotypes. A second isoallotypic variant was found at codon 409, where either Arg, as in G1 and G3, or Lys, as in G2, can be found. Both isoallotypes are associated with several 'silent isoallotypic' substitutions dispersed through the hinge, CH2 and CH3 domains. This suggests segmental gene conversion as the common mechanism of origin.

A group of 45 children affected with Coeliac Disease (CD) was typed for HLA—A, B, C, D, and DR specificities. The most significant associations were found with two alleles of the D series, with both cellular and serological typing. It is suggested that the susceptibility to CD is determined by two different genes within the HLA region, the first in common with organ‐specific autoimmune diseases and associated with Dw3, the second possibly specific for CD and associated with Dw7.