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Obesity in childhood: the Muscatine Study.

Beginning in 1971 children in grades kindergarten through the 12th grade were examined on alternate years until 1992 in Muscatine, Iowa, in these examinations the following variables were assessed: height, weight, skinfold thickness, lipids, lipoproteins, smoking behaviors, as well other variables. In order to lend relevance to risk factors in childhood a number strategies have been used. These include: 1) Examination of familial aggregation and mortality; 2) Segregation analysis of genetic mechanisms; 3) Relationship of obesity in childhood to other established risk factors; 4) Examination of the relationship of childhood obesity to the development of coronary artery calcification as assessed by electron beam computed tomography. In these studies we have shown that obese children's siblings, mothers, fathers, aunts and uncles have significant greater body mass indices than leaner children. Children who are obese have significantly higher systolic and diastolic blood pressure, higher plasma triglycerides and lower HDL-cholesterol levels. The first and second degree relatives of obese hypertensive children have a higher mortality rate from cardiovascular disease than leaner children's relatives. From complex segregation analyses about 35% of the population of Muscatine appear to carry a gene for obesity and 6% appear homozygous. Over the past decade we have observed that the children in Muscatine, Iowa have become more obese than previously. Our longitudinal observations indicate that obesity acquired in childhood is predictive of adult obesity and is also predictive of the development of coronary artery calcification. Thus obesity in childhood is not only an important risk factor in children but also a growing public health problem for children and adolescents.

Adolescent↗

Linkage relationships in the bovine MHC region. High recombination frequency between class II subregions.

Class II genes of the bovine major histocompatibility complex (MHC) have been investigated by Southern blot analysis using human DNA probes. Previous studies revealed the presence of bovine DO beta, DQ alpha, DQ beta, DR alpha, and DR beta genes, and restriction fragment length polymorphisms for each of these genes were documented. In the present study, the presence of three additional class II genes, designated DZ alpha, DY alpha, and DY beta, are reported. DZ alpha was assumed to correspond to the human DZ alpha gene while the other two were designated DY because their relationship to human class II genes could not be firmly established. The linkage relationships among bovine class II genes and two additional loci, TCP1B and C4, were investigated by family segregation analysis and analysis of linkage disequilibrium. The results clearly indicated that all these loci belong to the same linkage group. This linkage group is divided into two subregions separated by a fairly high recombination frequency. One region includes the C4, DQ alpha, DQ beta, DR alpha, and DR beta loci and the other one is composed of the DO beta, DY alpha, DY beta, and TCP1B loci. No recombinant was observed within any of these subregions and there was a strong or fairly strong linkage disequilibrium between loci within groups. In contrast, as many as five recombinants among three different families were detected in the interval between these subregions giving a recombination frequency estimate of 0.17 +/- 0.07. The fairly high recombination frequency observed between class II genes in cattle is strikingly different from the corresponding recombination estimates in man and mouse. The finding implies either a much larger molecular distance between some of the bovine class II genes or alternatively the presence of a recombinational "hot spot" in the bovine class II region.

Animals↗

Genotype assignment of haemophilia A by use of intragenic and extragenic restriction fragment length polymorphisms.

We performed DNA analysis in 20 families with haemophilia A in order to evaluate its usefulness for carrier detection and prenatal diagnosis. The polymorphic BclI site within intron 18 of the factor VIII gene and the extragenic TaqI and BglII polymorphic sites which are detected by the random DNA probes designated St14 and DX13, respectively, were investigated for. Two events of recombination were found between the St14 and the haemophilia A locus in 51 informative meioses. In one of these recombinant meioses crossing over had also occurred between the DX13 and the haemophilia A locus. No further crossovers between the DX13 and the haemophilia A locus were found in 20 informative meioses. Segregation analysis of the polymorphic markers and the deleterious mutation within the families allowed a diagnosis at the gene level for 52 out of 57 potential carriers. The new method considerably decreased the uncertainty about carriership for seventeen of the nineteen women with a probability of carriership between 5% and 95% based on pedigree analysis and factor VIII assays. In seven cases chromosome and DNA analysis of a chorionic villus biopsy was carried out. Three of the fetuses were female, four were male. Three of the male fetuses had inherited the normal maternal X-chromosome and were, therefore, not affected. For another male fetus no diagnosis at the gene level was possible since the mother was homozygous for all the known restriction fragment length polymorphisms within or closely linked with the haemophilia A locus.

Carrier State↗

Linkage analysis in families diagnosed with type 1 von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 VWD.

BACKGROUND: von Willebrand disease (VWD) type 1 is a congenital bleeding disorder caused by genetic defects in the von Willebrand factor (VWF) gene and characterized by a reduction of structurally normal VWF. The diagnosis of type 1 VWD is difficult because of clinical and laboratory variability. Furthermore, inconsistency of linkage between type 1 VWD and the VWF locus has been reported. OBJECTIVES: To estimate the proportion of type 1 VWD that is linked to the VWF gene. PATIENTS AND METHODS: Type 1 VWD families and healthy control individuals were recruited. An extensive questionnaire on bleeding symptoms was completed and phenotypic tests were performed. Linkage between VWF gene haplotypes and the diagnosis of type 1 VWD, the plasma levels of VWF and the severity of bleeding symptoms was analyzed. RESULTS: Segregation analysis in 143 families diagnosed with type 1 VWD fitted a model of autosomal dominant inheritance. Linkage analysis under heterogeneity resulted in a summed lod score of 23.2 with an estimated proportion of linkage of 0.70. After exclusion of families with abnormal multimer patterns the linkage proportion was 0.46. LOD scores and linkage proportions were higher in families with more severe phenotypes and with phenotypes suggestive of qualitative VWF defects. About 40% of the total variation of VWF antigen could be attributed to the VWF gene. CONCLUSIONS: We conclude that the diagnosis of type 1 VWD is linked to the VWF gene in about 70% of families, however after exclusion of qualitative defects this is about 50%.

Adolescent↗

Identification and fine mapping of AvrPi15, a novel avirulence gene of Magnaporthe grisea.

Avirulence of Magnaporthe grisea isolate CHL346 on rice cultivar GA25 was studied with 242 ascospore progenies derived from the cross CHL346 x CHL42. Segregation analysis of the avirulence in the progeny population was in agreement with the existence of a single avirulence (Avr) gene, designated as AvrPi15. For mapping the Avr gene, we developed a total of 121 microsatellite DNA markers [simple sequence repeat (SSR)], which evenly distributed in the whole-genome of M. grisea through bioinformatics analysis (BIA) using the publicly available sequence. Linkage analysis of the AvrPi15 gene with these SSR markers showed that six markers on chromosome 6, MS6-1, MS6-2, MS6-3, MS6-7, MS6-8 and MS6-10, were linked to the AvrPi15 locus. To further define the chromosomal location of the AvrPi15 locus, two additional markers, MS6-17 and STS6-6, which were developed based on the sequences of telomeric region 11 (TEL11), were subjected to linkage analysis. The results showed that MS6-17 and STS6-6 were associated with the locus by 3.3 and 0.8 cM, respectively. To finely map the Avr gene, two additional candidate avirulence gene (CAG) markers, CAG6-1 and CAG6-2, were developed based on the gene annotation of the sequence of TEL 11. Linkage analysis of the Avr gene with these two markers revealed that both of them completely cosegregated with the AvrPi15 locus. Finally, this locus was physically mapped into approximately 7.2-kb interval of the TEL11 by BIA using these sequence-ready markers. This is the key step toward positional cloning of the AvrPi15 gene.

Chromosome Segregation↗

Human imprinted chromosomal regions are historical hot-spots of recombination.

Human recombination rates vary along the chromosomes as well as between the two sexes. There is growing evidence that epigenetic factors may have an important influence on recombination rates, as well as on crossover position. Using both public database analysis and wet-bench approaches, we revisited the relationship between increased rates of meiotic recombination and genome imprinting. We constructed metric linkage disequilibrium (LD) maps for all human chromosomal regions known to contain one or more imprinted genes. We show that imprinted regions contain significantly more LD units (LDU) and have significantly more haplotype blocks of smaller sizes than flanking nonimprinted regions. There is also an excess of hot-spots of recombination at imprinted regions, and this is likely to do with the presence of imprinted genes, per se. These findings indicate that imprinted chromosomal regions are historical "hot-spots" of recombination. We also demonstrate, by direct segregation analysis at the 11p15.5 imprinted region, that there is remarkable agreement between sites of meiotic recombination and steps in LD maps. Although the increase in LDU/Megabase at imprinted regions is not associated with any significant enrichment for any particular sequence class, major sequence determinants of recombination rates seem to differ between imprinted and control regions. Interestingly, fine-mapping of recombination events within the most male meiosis-specific recombination hot-spot of Chromosome 11p15.5 indicates that many events may occur within or directly adjacent to regions that are differentially methylated in somatic cells. Taken together, these findings support the involvement of a combination of specific DNA sequences and epigenetic factors as major determinants of hot-spots of recombination at imprinted chromosomal regions.

Chromosomes↗

Initial results of a study into the effectiveness of breast cancer screening in a population identified to be at high risk.

BACKGROUND: Women are frequently referred to genetic clinics because of a family history of breast or ovarian cancer, conferring a moderate increased risk of the disease, but not sufficient in itself to indicate gene mutation analysis. One possible management strategy is to offer regular mammographic screening, possibly earlier in life and more frequently than in the general population. This strategy is used in many parts of the UK, although it has not been formally evaluated. METHODS: In this paper we present some early results on the effectiveness of a programme of mammography in 2,998 women aged 19-71 with a moderate family history of breast cancer in Manchester. We estimated the test and programme sensitivity and sojourn time, using different statistical methods. RESULTS: Fifty breast cancers were diagnosed. The incidence rate observed was 4.46 per thousand person-years. The incidence expected from the segregation analysis of Claus et al. was 3.75 per thousand person-years. Screen-detection rates at first and subsequent screens were 5.00 and 4.93 per thousand respectively. Interval cancer incidence in the first year following a negative screen was 0.91 per thousand person-years. Screening test sensitivity was estimated conservatively as 83%, programme sensitivity as 70%. CONCLUSIONS: Early indications are that the programme is likely to be effective. Further follow-up, analysis of tumour size, node status and malignancy grade, and subsequent mortality from breast cancer is required to confirm this.

Adult↗

High-resolution mapping of loci conferring resistance to sugarcane mosaic virus in maize using RFLP, SSR, and AFLP markers.

Sugarcane mosaic virus (SCMV) is one of the most important virus diseases of maize in Europe. Genetic analysis on backcross five (BC5) progeny derived from the cross FAP1360A (resistant) x F7 (susceptible) confirmed that at least two dominant genes, Scm1 and Scm2, are required for resistance to SCMV in the progeny of this cross. With the aid of RFLP and SSR marker analyses, Scm1 was mapped in the region of 8.7 cM between the nucleolus organizer region (nor) and RFLP marker bnl6.29 on the short arm of chromosome 6, while Scm2 was mapped to an interval of 26.8 cM flanked by the RFLP markers umc92 and umc102 near the centromere region of chromosome 3. Both chromosome regions were further enriched for AFLP markers by successful application of a bulked segregant analysis to this oligogenic trait. A total of 23 linked AFLP markers were identified, clustered in chromosome regions adjacent to either Scm1 or Scm2. Seven AFLP markers linked to Scm1 resided within the nor-bnl6.29 interval, and one of them, E3M8-1, showed no recombination with Scm1. Three AFLP markers linked to Scm2 are located between umc92 and umc102.

Chromosome Mapping↗

Heritability estimate of erythrocyte Na-K-Cl cotransport in normotensive and hypertensive families.

Na-K-Cl cotransport was measured in 209 essential hypertensive patients (EH) and in 114 normotensive controls (NT). The distribution of Na-K-Cl cotransport was bimodal in EH and unimodal in NT. The EH with higher Na-K-Cl cotransport values had increased passive permeability to Na in fresh erythrocytes and increased Li-Na countertransport compared to NT. Li-Na countertransport was significantly increased in the EH as a whole, but the increase was accounted for by some EH individuals with elevated Na-K-Cl cotransport values. A simple biometric analysis of the Na-K-Cl cotransport was performed for 287 individuals of 86 families with different prevalence of hypertension (neither parent hypertensive, 39 families; one, 31 families; or both, 16 families). Na-K-Cl cotransport was not correlated between spouses, but was correlated highly significantly between the average value of the two parents (mid-parent) and offspring. The polygenic additive heritability (h2) was about 50% for all families considered together. It increased slightly for the hypertensive families analyzed alone (no significant correlation was found, and hence genetic heritability, in the normotensive families). Finally, after applying arbitrary cut-off points to the Na-K-Cl cotransport values, segregation analysis showed that some major gene, recessive for the high allele, also contributes to the phenotypic value of Na-K-Cl cotransport.

Alleles↗

Development of a codominant CAPS marker linked to PRSV-P resistance in highland papaya.

Development of resistant papaya varieties is widely considered the best strategy for long-term control of the papaya ringspot virus type P (PRSV-P). Several species of "highland papaya" from the related genus Vasconcellea exhibit complete resistance to PRSV-P, and present a valuable source of resistance genes with potential for application in Carica papaya. The objectives of this study were two fold; to identify molecular markers linked to a previously characterised PRSV-P resistance gene in V. cundinamarcensis (psrv-1), and to develop codominant marker based strategies for reliable selection of PRSV-P resistant genotypes. Using a bulked segregant analysis approach, dominant randomly amplified DNA fingerprint (RAF) markers linked to prsv-1 were revealed in the resistant DNA bulk, which comprised F2 progeny from a V. parviflora (susceptible) x V. cundinamarcensis (resistant) interspecific cross. One marker, Opk4_1r, mapped adjacent to the prsv-1 locus at 5.4 cM, while a second, Opa11_5r, collocated with it. Sequence characterisation of the Opk4_1r marker permitted its conversion into a codominant CAPS marker (PsiIk4), diagnostic for the resistant genotype based on digestion with the restriction endonuclease PsiI. This marker mapped within 2 cM of the prsv-1 locus. Psilk4 was shown to correctly identify resistant genotypes 99% of the time when applied to interspecific F2 progeny segregating for the resistant character, and has potential for application in breeding programs aimed to deliver the PRSV-P resistance gene from V. cundinamarcensis into C. papaya.

Caricaceae↗

Genetic analysis of a group of mentally retarded children.

Genetic analysis of 169 mentally retarded (MR) children from Madras, revealed chromosomal abnormalities in 17%. Down syndrome was the major chromosomal anomaly (24/169 = 14.2%). These included three cases of trisomy-21 mosaics, and one case of de novo Robertsonian translocation. MR children with chromosomal abnormalities were either mildly or moderately retarded. Syndromes with known etiology occurred in 3% of the MR cases. Microcephaly, neonatal anoxia, perinatal stress and pharmacological attempt for abortion were found to be important pathogenic factors associated with MR. Most of the microcephalics (11/169 = 6.5%) were severely retarded, whereas those associated with neonatal anoxia and perinatal stress were either mildly or moderately retarded. Birth-order effects were found only among Down syndrome patients. Segregation analysis of the three groups of proband families (viz. mild, moderate and severe MR) indicated that autosomal recessive mode of inheritance is compatible in moderate and severe MR proband families. The proportion of X-linked instances of MR is estimated to be about 22% of the cases.

Child↗

Efficient fine mapping of the naked caryopsis gene ( nud) by HEGS (High Efficiency Genome Scanning)/AFLP in barley.

The hulled or naked caryopsis character of barley ( Hordeum vulgare L.) is an important trait for edibility and to follow its domestication process. A single recessive gene, nud, controls the naked caryopsis character, and is located on the long arm of chromosome 7H. To develop a fine map around the nud locus efficiently, the HEGS (High Efficiency Genome Scanning) electrophoresis system was combined with amplified fragment length polymorphism (AFLP). From bulked segregant analysis of 1,894 primer combinations, 12 AFLP fragments were selected as linked markers. For mapping, an F(2 )population of 151 individuals derived from a cross between Kobinkatagi (naked type) and Triumph (hulled type) was used. Seven AFLP markers were localized near the nud region. A fine map was developed with one-order higher resolution than before, along with the seven anchor markers. Among the seven linked AFLP markers (KT1-7), KT1, KT2 and KT6 were co-dominant, and the former two were detected for their single-nucleotide polymorphisms (SNPs) in the same length of fragments after electrophoresis with the non-denaturing gels of HEGS. The nud locus has co-segregated with KT3 and KT7, and was flanked by KT2 and KT4, at the 0.3-cM proximal and the 1.2-cM distal side, respectively. Four of these AFLP markers were converted into sequence-characterized amplified region (SCAR) markers, one of which was a dominant marker co-segregating with the nud gene.

Chromosome Mapping↗

A survey of genetic diversity and reproductive biology of Puya raimondii (Bromeliaceae), the endangered queen of the Andes.

Puya raimondii Harms is an outstanding giant rosette bromeliad found solely around 4000 m above sea level in the Andes. It flowers at the end of an 80 - 100-year or even longer life cycle and yields an enormous (4 - 6 m tall) spike composed of from 15,000 to 20,000 flowers. It is endemic and currently endangered, with populations distributed from Peru to the north of Bolivia. A genomic DNA marker-based analysis of the genetic structure of eight populations representative of the whole distribution of P. raimondii in Peru is reported in this paper. As few as 14 genotypes out of 160 plants were detected. Only 5 and 18 of the 217 AFLP marker loci screened were polymorphic within and among these populations, respectively. Four populations were completely monomorphic, each of the others displayed only one to three polymorphic loci. Less than 4 % of the total genomic variation was within populations and genetic similarity among populations was as high as 98.3 %. Results for seven cpSSR marker loci were in agreement with the existence of a single progenitor. Flow cytometry of seed nuclear DNA content and RAPD marker segregation analysis of progeny plantlets demonstrated that the extremely uniform genome of P. raimondii populations is not compatible with agamospermy (apomixis), but consistent with an inbreeding reproductive strategy. There is an urgent need for a protection programme to save not only this precious, isolated species, but also the unique ecosystem depending on it.

Bromeliaceae↗

Risk evaluation of carriers with chromosome reciprocal translocation t(7;13)(q34;q13) and concomitant meiotic segregation analyzed by FISH on ejaculated spermatozoa.

We performed the segregation analysis of a relatively large pedigree of t(7;13)(q34;q13) carriers together with the sperm karyotype analysis of the one carrier using a tri-color fluorescence in situ hybridization (FISH) method. The risk assessments for unfavorable pregnancy outcomes in a series of 36 pregnancies in eight reciprocal chromosome translocation (RCT) couples of carriers were estimated directly from a pedigree after ascertainment correction. The individual probability rate for unbalanced child was predicted according to Stengel-Rutkowski and co-workers. The unbalanced karyotypes in the form of monosomy 7q34-->qter and trisomy 13q13-->qter were detected among stillborn/early death newborns with holoprosencephaly (HPE), cyclopia and other malformations. Based on clinical description of unkaryotyped stillbirth progeny, it can be assumed that the phenotype distinctions were connected with the unbalanced karyotype from 2:2 segregation (monosomy 7q with trisomy 13q) and 3:1 segregation as interchange trisomy 13 (Patau syndrome). Probability rates for miscarriages, stillbirth/early death were 12.9 +/- 6% (4/31) and 29 +/- 8.2% (9/31), respectively. The results of the meiotic segregation pattern indicated the rate of unbalanced spermatozoa for about 60%, with the unusual high rate (29.4%) of 3:1 segregant (i.e., 13.4% of the tertiary segregation and 16% of the interchange segregation). Adjacent-1 segregation followed with 23.5% and adjacent-2 followed with 7.2% of analyzed spermatozoa. The high rate of unbalanced gametes in comparison to the number of stillborn/early death and miscarriages detected in pedigree suggests a strong selection against unbalanced chromosomal constitutions during fetal development. It corresponds to a very small probability rate (about 0.3%) of viable unbalanced progeny from 3:1 meiotic segregation predicted for maternal carriers. This knowledge can be used in genetic counseling of families with similar RCT ascertained in a different way.

Abortion, Spontaneous↗

Coupled mutagenesis screens and genetic mapping in zebrafish.

Forward genetic analysis is one of the principal advantages of the zebrafish model system. However, managing zebrafish mutant lines derived from mutagenesis screens and mapping the corresponding mutations and integrating them into the larger collection of mutations remain arduous tasks. To simplify and focus these endeavors, we developed an approach that facilitates the rapid mapping of new zebrafish mutations as they are generated through mutagenesis screens. We selected a minimal panel of 149 simple sequence length polymorphism markers for a first-pass genome scan in crosses involving C32 and SJD inbred lines. We also conducted a small chemical mutagenesis screen that identified several new mutations affecting zebrafish embryonic melanocyte development. Using our first-pass marker panel in bulked-segregant analysis, we were able to identify the genetic map positions of these mutations as they were isolated in our screen. Rapid mapping of the mutations facilitated stock management, helped direct allelism tests, and should accelerate identification of the affected genes. These results demonstrate the efficacy of coupling mutagenesis screens with genetic mapping.

Animals↗

Molecular diagnosis of Prader-Willi and Angelman syndromes by methylation-specific melting analysis and methylation-specific multiplex ligation-dependent probe amplification.

BACKGROUND: Approximately 99% of Prader-Willi syndrome (PWS) and 80% of Angelman syndrome (AS) cases have deletions at a common region in chromosome 15q11.2-q13, uniparental disomy for chromosome 15 (UPD15), or imprinting center defects affecting gene expression in this region. The resulting clinical phenotype (PWS or AS) in each class of genomic abnormalities depends on the parent of origin. Both disorders are characterized at the molecular level by abnormal methylation of imprinted regions at 15q11.2-q13. Other rare chromosome 15 rearrangements and a few smaller atypical deletions associated with abnormal methylation patterns also have symptoms overlapping with either PWS or AS. METHODS: We designed a methylation-specific melting analysis (MS-MA) method for a rapid screening of PWS/AS and evaluated methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) for diagnosis of PWS/AS associated with deletions, UPD15, or rare duplications. Forty-nine previously genotyped samples were tested by MS-MA. We also tested 26 MS-MA genotyped samples and 1 additional sample with rare duplication of chromosome region 15q11-q12. RESULTS: PWS/AS genotyping results obtained by MS-MA and by MS-MLPA were fully concordant. In addition, MS-MLPA was superior in detecting deletions/rare duplications, possible UPD15, or imprinting center defects, which were usually determined by a laborious fluorescence in situ hybridization method or by chromosomal segregation analysis for the parental-origin using short-tandem repeat makers. CONCLUSIONS: MS-MA appears to be an efficient primary method to diagnose PWS/AS, and use of the quantitative MS-MLPA method provides detailed information about deletions, rare duplications, and possibly UPD.

Angelman Syndrome↗

Population-wide analysis of a QTL affecting milk-fat production in the Israeli Holstein population.

A population-wide linkage disequilibrium on bovine chromosome 14 between microsatellite ILSTS039 and DGAT1, a putative quantitative trait locus affecting milk production traits, was found in the Israeli Holstein population. A total of 394 bulls were genotyped for both DGAT1 and ILSTS039, and 1747 cows were genotyped for ILSTS039. The ILSTS039 allele termed "225," and the DGAT1 K allele (substitution of a lysine residue with alanine), were associated with decreased milk production, and increased fat production and fat and protein percent. The number of 225 ILSTS039 and K DGAT1 alleles per individual were the same for 80% of the bulls genotyped. From the effects associated with cows homozygous for the 225 allele, the effect of the quantitative trait locus appears to be approximately codominant. The substitution effect was 0.16% fat. Genotype probabilities for the quantitative gene were determined for the entire Israeli Holstein milk-recorded population, including 507,725 cows and 1442 bulls, using segregation analysis. Overall frequency of the allele that increased fat percent was 8.9% in cows and 15.5% in bulls. The frequency of this allele decreased from 1981 until 1990, from 15 to 5%, and since has increased to 10%. The effects estimated on the population-wide analyses of both cows and bulls were similar to the effect associated with DGAT1 in the daughters of genotyped bulls. Modified animal model evaluations were computed for the entire population with the effect of this gene included in the model. The correlations between the modified and standard animal model evaluations for all traits were > 0.99.

Acyltransferases↗

Association of HLA-DR5 (DR11) with systemic sclerosis (scleroderma) in Mexican patients.

OBJECTIVE: To study the association between Major Histocompatibility Complex (MHC) haplotypes and systemic sclerosis (SSc) in Mexican mestizo patients. METHODS: Class I, II and III MHC antigens were determined in 41 Mexican mestizo patients with SSc, 113 of their first degree relatives, and 85 ethnically matched controls. The significance of differences between patients and controls was tested by chi-square analysis with Yates' correction. RESULTS: Frequencies of HLA-DR5 and HLA-DRw52 were found to be higher in SSc patients compared to ethnically matched healthy controls (p = 0.007, RR = 3.31; 95% confidence interval: 1.3-8.3 and p = 0.04, RR = 2.4; 95% confidence interval: 1.0-5.7, respectively). Sequence-specific oligotyping in DR5 positive individuals showed that 10 out of 41 patients had the DRB1*1104 subtype (24.3%) as compared to only 6 of the 85 healthy controls (7.0%) (p = 0.01, RR = 4.25). Subdividing patients according to their clinical features showed a significant increase of HLA-DR5 in diffuse (p = 0.013, RR = 3.89, 95% confidence interval: 1.27-12.0) and limited scleroderma (p = 0.0008), but not in the CREST syndrome. Segregation analysis obtained from the families showed that in the patients, DR5 was mostly part of the [HLAB35;DR5] haplotype as opposed to healthy controls. CONCLUSION: These data support the role of DR5 (DRB1*1104) in the genetic susceptibility to develop scleroderma in Mexican patients and also sustain the notion of genetically determined clinical subgroups of SSc.

Base Sequence↗