To the Editor: Naumova et al. (1998) reported a deviation from the expected Mendelian 1:1 ratio of grandpaternal/grandmaternal alleles at loci in Xp11.4-p21.1 in the children of 47 families not selected on the basis of the disease status of the children. The transmission-ratio distortion (TRD) was found only among male offspring and was manifested as a bias in favor of the inheritance of the alleles of the maternal grandfather. The critical region, containing the putative TRD locus, named “DMS1,” was mapped to an interval bounded by DXS538 and DXS7 and peaking at DXS1068. These observations might have an impact on the results of a study in which we have provided evidence of linkage to type 1 diabetes mellitus (MIM 222100), in the same region of chromosome X (Cucca et al. 1998). The possibility of TRD at chromosome Xp gives rise to the question of whether the diabetes-linkage results are indeed disease specific. The following evidence suggests that it is highly unlikely that the DMS1 locus is responsible for the chromosome Xp linkage to type 1 diabetes. We genotyped DXS1068 (a marker that was at the peak of our linkage curve) in two sample sets of control families not ascertained on the basis of the disease status of the children. These control families were from the Centre d'Etude du Polymorphisme Humaine (Fondation Jean Dausset/CEPH) and from a population-based sample from the town of Busselton, Australia, and included 61 large pedigrees with 603 children and 220 families with 525 children, respectively (Hill et al. 1995). Single-point allele sharing in these families with multiple sibships was corrected by means of the method proposed by Hodge (1984), as implemented in the software GENOME ANALYSIS SYSTEM, version 2.0. We obtained 51% sharing, by sib pairs, of one allele identical by descent (252.6 sharing one allele and 243.4 sharing no alleles; P=.68). This compares with 60.5% sharing for DXS1068 in 580 type 1 diabetic sib pair families (193 sharing one allele identical by descent and 126 sharing no alleles in a single-point analysis; P=2×10-4). Hence, there is no evidence of TRD in these nondiabetic families that were analyzed in the same way that we analyzed the diabetic families. We typed both 255 discordant (affected/unaffected) independent sib pairs from the United Kingdom and Sardinian families for DXS1068. We obtained identity-by-descent values of 77 and 86 for sharing one and no alleles, respectively, for all discordant pairs (47.6%); the corresponding values were 25 and 29 for male/male pairs only (46.3%). The trend toward <50% allele sharing in discordant sib pairs is consistent with a type 1 diabetes–specific effect. The putative DMS1 TRD locus near the DXS1068 locus affects only male progeny, whereas the strongest linkage that we observed for DXS1068 was in male/female pairs (Cucca et al 1998). The linkage of the DXS1068 region to type 1 diabetes was strongly concentrated in the 97 of 580 families that had human leukocyte antigen (HLA) DR3/X (X is not DR4) sib pairs (multipoint MLS = 3.5 at DXS1068). Some weak evidence of linkage was present also in the 195 DR3/4 sib pairs (multipoint MLS = .75 at DXS1068), and no evidence of linkage was obtained in the other 288 families with affected sib pairs (Cucca et al. 1998). We evaluated linkage on chromosome X, conditioning the data according to the genotype at the HLA IDDM1 major locus on chromosome 6p21, because, in a large data set from Sardinia, the United Kingdom, and the United States, there was a strong increase in the male:female (M:F) ratio, which was almost exclusively restricted to patients with the DR3/X genotype (M:F ratio = 1.7; P=4.7×10-7), compared with a ratio of 1.0 in the DR4/Y category (Y is not DR3), with a small effect in DR3/4 patients (M:F ratio = 1.2; P=.03) (Cucca et al. 1998). Hence, both the evidence of linkage and the bias in the M:F ratio were concentrated in the families with patients positive for the HLA-DR3, which is one of the two main predisposing haplotypes at the HLA/IDDM1 major locus. These data suggest an interaction between HLA-DR3 haplotypes and the diabetes locus on chromosome X, which is unlikely to be caused by an effect of the putative DMS1 locus. Furthermore, both in the unaffected parents and siblings of the United Kingdom and in the Sardinian families who were DR3/3 homozygotes, the ratio was reversed: 56 males and 80 females (0.7; P=.04) compared with an M:F ratio of 2.2 in DR3/3 patients (P=1.3×10-6), thereby providing another control for our results (Cucca et al. 1998). These results indicate that it is unlikely that the type 1 diabetes linkage that we have observed is explained by the DMS1 locus. TRD could, however, have a significant effect on the interpretation of linkage studies of polygenes in common diseases in which increases in allele sharing at the disease locus may be very small. The possibility of TRD should be ruled out in disease studies (Eaves et al. 1999).