Biomedical subjects

D W Bowden

Publications and source records attributed to D W Bowden.

At least 37 records · Page 2Linked to original sources

PubMed2000

Association of autoimmune thyroid disease with microsatellite markers for the thyrotropin receptor gene and CTLA-4 in Japanese patients.

In a previous study we identified a microsatellite marker near the thyrotropin receptor (TSHR) gene. Studies with this marker, TSHR-CA, revealed a significant association between autoimmune thyroid disease (AITD) in Japanese patients and one specific allele (allele 1; 180 base pair [bp]) of the microsatellite sequence. In addition, weak evidence for association of AITD with two alleles of the CTLA-4 gene was observed. In the present study, TSHR-CA has been mapped to approximately 600 kb of the TSHR gene using radiation hybrid mapping. TSHR-CA and another TSHR microsatellite marker, TSHR-AT, which is located in intron 2 of TSHR gene, were genotyped in a set of 349 unrelated Japanese AITD patients and 218 Japanese controls. The TSHR-AT marker showed association in this Japanese AITD population with a significant increase in allele 5 (294 bp; p < 0.05) and a significant decrease in allele 7 (298 bp; p < 0.05). The association of allele 5 of TSHR-AT was also significant in hypothyroid patients (thyrotropin-binding inhibitory immunoglobulin-positive [TBII+], P < 0.01; thyrotropin-binding inhibitory immunoglobulin-negative [TBII-], p < 0.05). The association of allele 7 of TSHR-AT were also significant for the hypothyroid TBII+ patients (p < 0.05). The CTLA-4 gene was also genotyped in this expanded set of Japanese AITD patients and controls. Association between AITD susceptibility and allele 2 (102 bp; p < 0.01) and allele 4 (106 bp; p < 0.01) were observed. These associations were also observed with GD patients (allele 2, p < 0.01; allele 4, p < 0.01). Associations with TSHR-CA were observed for Hashimoto's thyroiditis (HT) patients with respect to alleles 3 (179 bp; p < 0.05) and 5 (175 bp; p < 0.05) and with hypothyroid TBII- patients for allele 4 (177 bp; p < 0.05). The presence of specific alleles of TSHR-CA, TSHR-AT, and CTLA-4 contribute significant increase in risk of development of AITD. These results confirm and expand on our previous study suggesting that alleles of the TSHR and CTLA-4 genes, or genes near them contribute to AITD susceptibility and set the stage for future studies of interactions between these genes and AITD.

Abatacept↗

PubMed2000

Genetic analysis of nitric oxide and endothelin in end-stage renal disease.

BACKGROUND: Genetic factors have been implicated in the development of the common aetiologies of end-stage renal disease (ESRD), including renal failure attributed to hypertension, diabetes mellitus, systemic lupus erythematosus and human immunodeficiency virus infection. Nitric oxide (NO) and endothelin are powerful vasoactive mediators involved in inflammation and regulation of vascular tone and blood pressure. We evaluated the role of the neuronal constitutive (NOS1) and endothelial constitutive (NOS3) nitric oxide synthase genes and the endothelin-1 (EDN-1) gene in predisposition to chronic renal failure in African-Americans. METHODS: The study population for the linkage and association analyses in ESRD consisted of 361 individuals from 168 multiplex African-American families. These individuals comprised 207 unweighted sibling pairs concordant for all-cause ESRD. Microsatellite markers NOS1B (NOS1), D7S636 (NOS3) and CPHD1-1/2 (EDN-1) were genotyped in the sample. In addition, a mutation, Glu298Asp, in exon 7 of NOS3 and a 27 bp variable number tandem repeat (VNTR) marker in intron 4 of NOS3 were evaluated in the sibling pairs and in an additional 92 unrelated African-Americans with type 2 diabetes mellitus-associated ESRD (singletons). Association analyses utilized the relative predispositional effect method. Model independent linkage analyses were performed using GeneHunter-plus and MapMaker/SIBS (exclusion analysis) software. RESULTS: Significant evidence for association with ESRD was detected for alleles 7 and 9 of the NOS1 gene (11.9 and 34.2%, respectively, in unrelated probands of ESRD families versus 6.5 and 27.5%, respectively, in race-matched controls, both P:<0.01). These associations were maintained when the unrelated first sibling from each family was used in a case-control comparison and was most pronounced in the non-diabetic ESRD cases. The NOS3 and EDN-1 markers failed to provide consistent evidence for association in the sibling pairs and the diabetic ESRD singletons, although we identified two novel endothelial constitutive NOS4 (ecNOS4) VNTR alleles in African-Americans. Significant evidence for linkage was not detected between the NOS genes or the EDN-1 gene in either all-cause ESRD or when the ESRD sibling pairs were stratified by aetiology (type 2 diabetic ESRD or non-diabetic aetiologies). CONCLUSION: Based upon the consistent allelic associations, we believe that further evaluation of the NOS1 gene in ESRD susceptibility in African-Americans is warranted.

Adult↗

PubMed2000

Human Na+/H+ exchanger genes : identification of polymorphisms by radiation hybrid mapping and analysis of linkage in end-stage renal disease.

The Na+/H+ exchangers (NHEs) are membrane-bound transporters that catalyze the electro-neutral movement of extracellular Na+ for intracellular H+. NHE genes play a critical role in pH homeostasis and cellular volume regulation and can be considered candidate genes for essential hypertension and renal disease. This study was performed to determine whether the NHE genes contributed to genetic susceptibility in end-stage renal disease (ESRD). To date, 5 isoforms of NHE have been cloned in mammals (NHE1 to NHE5). The complementary DNA (cDNA) sequences of NHE1 to NHE3 and NHE5 are known in humans. Because the chromosomal structure of the NHE genes is unknown, we used cDNA sequences to design polymerase chain reaction primers for use in radiation hybrid mapping. Radiation hybrid mapping of NHE genes identified nearby polymorphic markers for NHE1 to NHE3 (NHE1: D1S197, D1S2677; NHE2: D2S373, D2S1789; and NHE3: D5S678, D5S2005). We used these markers, and other previously identified polymorphic markers for NHE5, in linkage and association analyses of ESRD. The NHE1 to NHE3 and NHE5 loci did not demonstrate evidence for linkage to ESRD. However, NHE5 showed significant evidence for association (P</=1.0x10(-4)). The strongest evidence for association was observed with allele 6 of NHE5 (P</=0.001 to 0. 01). Allele 6 appeared to have a renoprotective effect, with a frequency of 0.15 in the control population and 0.06 to 0.09 in patients with ESRD. The combined approach of designing primers from cDNA and radiation hybrid mapping has proven successful in identifying polymorphisms for human genes of which only cDNA sequences were previously available. The NHE primers and associated polymorphic loci identified in this study can be used in genomic, linkage, and association analysis of NHE genes in future genetic studies of hypertension and renal failure. Given the allelic association, further evaluation of the role of NHE5 in ESRD susceptibility appears warranted.

Alleles↗

PubMed1999

A physical map of the 20q12-q13.1 region associated with type 2 diabetes.

Several recent genetic studies have suggested linkage of Type 2 diabetes (non-insulin-dependent diabetes mellitus) susceptibility to a region of chromosome 20q12-q13.1. To facilitate the identification and cloning of a diabetes susceptibility gene(s) in this region, we have constructed correlated radiation hybrid and YAC/BAC contig physical maps of the region. A high-resolution radiation hybrid map encompassing 9.5 Mb between the PLC and the CEBPB genes was constructed using 68 markers: 25 polymorphic markers, 15 known genes, 21 ESTs, and 7 random genomic sequences. The physical order of the polymorphic markers within this radiation hybrid map is consistent with published genetic maps. A YAC/BAC contig that gives continuous coverage between PLC and CEBPB was also constructed. This contig was constructed from 24 YACs, 34 BACs, and 1 P1 phage clone onto which 71 markers were mapped: 23 polymorphic markers, 12 genes, 24 ESTs, and 12 random genomic sequences. The radiation hybrid map and YAC/BAC physical map enable precise mapping of newly identified transcribed sequences and polymorphic markers that will aid in linkage and linkage disequilibrium studies and facilitate identification and cloning of candidate Type 2 diabetes susceptibility genes residing in 20q12-q13.1.

Chromosomes, Artificial, Yeast↗

PubMed1999

Race-specific HIV-1 disease-modifying effects associated with CCR5 haplotypes.

Genetic variation in CC chemokine receptor 5 (CCR5), the major HIV-1 coreceptor, has been shown to influence HIV-1 transmission and disease progression. However, it is generally assumed that the same CCR5 genotype (or haplotype) has similar phenotypic effects in different populations. To test this assumption, we used an evolutionary-based classification of CCR5 haplotypes to determine their associated HIV-1 disease-modifying effects in a large well-characterized racially mixed cohort of HIV-1-seropositive individuals. We demonstrate that the spectrum of CCR5 haplotypes associated with disease acceleration or retardation differs between African Americans and Caucasians. Also, we show that there is a strong interactive effect between CCR5 haplotypes with different evolutionary histories. The striking population-specific phenotypic effects associated with CCR5 haplotypes emphasize the importance of understanding the evolutionary context in which disease susceptibility genes are expressed.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Evaluation of markers on human chromosome 10, including the homologue of the rodent Rf-1 gene, for linkage to ESRD in black patients.

There is abundant evidence supporting the contribution of genetic factors to the development of end-stage renal disease (ESRD) in blacks. Two renal failure susceptibility genes, Rf-1 and Rf-2, have been identified in the fawn-hooded rat, an animal model of hypertension and nephrosclerosis. The human homologous region containing the rodent Rf-1 gene has been localized to chromosome 10q. We tested for genetic linkage between 21 polymorphic markers on human chromosome 10 and chronic renal failure in 129 black sibling pairs concordant for ESRD. Two adjacent markers on 10p, D10S1435 and D10S249 (4 centiMorgans from D10S1435), approached significance for linkage to ESRD in sibling pairs with nondiabetic causes of ESRD (P = 0.035 pairwise, P = 0.082 multipoint for D10S1435; P = 0.074 pairwise, P = 0.063 multipoint for D10S249). The markers spanning the homologous region of Rf-1 did not show evidence for linkage to ESRD in sibling pairs concordant for diabetic ESRD, sibling pairs concordant for nondiabetic causes of ESRD, or in the entire family set. These results suggest that the human homologue of Rf-1 is unlikely to contribute substantially to renal failure susceptibility from the common causes of kidney disease in blacks.

Animals↗

PubMed1999

Mutations of the cathepsin C gene are responsible for Papillon-Lefèvre syndrome.

Papillon-Lefèvre syndrome (PLS) is an autosomal recessive disorder characterised by palmoplantar hyperkeratosis and severe early onset periodontitis that results in the premature loss of the primary and secondary dentitions. A major gene locus for PLS has been mapped to a 2.8 cM interval on chromosome 11q14. Correlation of physical and genetic maps of this interval indicate it includes at least 40 ESTs and six known genes including the lysosomal protease cathepsin C gene (CTSC). The CTSC message is expressed at high levels in a variety of immune cells including polymorphonuclear leucocytes, macrophages, and their precursors. By RT-PCR, we found CTSC is also expressed in epithelial regions commonly affected by PLS, including the palms, soles, knees, and oral keratinised gingiva. The 4.7 kb CTSC gene consists of two exons. Sequence analysis of CTSC from subjects affected with PLS from five consanguineous Turkish families identified four different mutations. An exon 1 nonsense mutation (856C-->T) introduces a premature stop codon at amino acid 286. Three exon 2 mutations were identified, including a single nucleotide deletion (2692delA) of codon 349 introducing a frameshift and premature termination codon, a 2 bp deletion (2673-2674delCT) that results in introduction of a stop codon at amino acid 343, and a G-->A substitution in codon 429 (2931G-->A) introducing a premature termination codon. All PLS patients were homozygous for cathepsin C mutations inherited from a common ancestor. Parents and sibs heterozygous for cathepsin C mutations do not show either the palmoplantar hyperkeratosis or severe early onset periodontitis characteristic of PLS. A more complete understanding of the functional physiology of cathepsin C carries significant implications for understanding normal and abnormal skin development and periodontal disease susceptibility.

Adult↗

PubMed1998

Sublocalization of the Papillon-Lefevre syndrome locus on 11q14-q21.

Papillon-Lefevre syndrome (PLS) is an autosomal recessive form of palmoplantar ectodermal dysplasia, characterized by palmoplantar hyperkeratosis and severe early-onset periodontitis. The presence of severe periodontitis distinguishes PLS from other palmoplantar keratodermas. As part of our efforts to study the genetic basis of periodontitis susceptibility, we performed a genome-wide search to identify major loci for PLS in 44 individuals (14 affected) from 10 consanguineous PLS families. We have identified evidence for linkage of a PLS gene on 11q14-q21. A maximum two-point logarithm of the odds (LOD) score of 8.24 was obtained for D11S1367 at a recombination fraction of theta=0.00. Multipoint analysis resulted in a LOD score of 10.45 and placed the gene for PLS within a 4-5 cM genetic interval. This genetic interval, flanked by D11S4197 and D11S931, contains more than 50 cDNAs and 200 expressed sequence tags (ESTs). This refinement of the candidate region for a PLS gene is in agreement with other recent reports of linkage for PLS to chromosome 11q14-q21 and should help in identification of the gene for PLS.

Chromosomes, Human, Pair 11↗

PubMed1998

Genetic initiation of hypertensive and diabetic nephropathy.

The factors initiating the common etiologies of chronic renal failure remain elusive. This article reviews the evidence in support of a generalized genetic susceptibility to human end-stage renal disease, including kidney failure attributed to the systemic diseases of hypertension, diabetes mellitus, and glomerulonephritis. Molecular genetic techniques are powerful tools, assisting in the detection of the initiating factors in many complex diseases. In kidney disease, genetic methodologies complement the available anatomic, epidemiologic, and physiologic analyses. This article provides strategies to allow for the detection of human renal failure susceptibility genes. The identification of human renal failure genes would provide useful markers for disease susceptibility and speed the development of novel therapeutic strategies.

Animals↗

PubMed1998

Genetic linkage of hereditary gingival fibromatosis to chromosome 2p21.

Gingival fibromatosis is characterized by a slowly progressive benign enlargement of the oral gingival tissues. The condition results in the teeth being partially or totally engulfed by keratinized gingiva, causing aesthetic and functional problems. Both genetic and pharmacologically induced forms of gingival fibromatosis are known. The most common genetic form, hereditary gingival fibromatosis (HGF), is usually transmitted as an autosomal dominant trait, although sporadic cases are common and autosomal recessive inheritance has been reported. The genetic basis of gingival fibromatosis is unknown. We identified an extended family (n=32) segregating an autosomal dominant form of isolated gingival fibromatosis. Using a genomewide search strategy, we identified genetic linkage (Zmax=5.05, straight theta=.00) for the HGF phenotype to polymorphic markers in the genetic region of chromosome 2p21 bounded by the loci D2S1788 and D2S441. This is the first report of linkage for isolated HGF, and the findings have implications for identification of the underlying genetic basis of gingival fibromatosis.

Chromosomes, Human, Pair 2↗

PubMed1998

Identification of a mutation in DLX3 associated with tricho-dento-osseous (TDO) syndrome.

Tricho-dento-osseous syndrome (TDO) is an autosomal dominant disorder characterized by abnormal hair, teeth and bone. The main clinical manifestations of TDO include taurodontism, enamel hypoplasia, kinky, curly hair at birth and increased thickness and density of the cranial bones. These pleiotropic clinical features suggest the role of a developmental gene modulating epithelial-mesenchymal interactions. We recently mapped the TDO locus to chromosome 17q21, a region that includes two members of the distal-less homeobox gene family, DLX3 and DLX7. In this paper we describe genomic cloning and sequencing of both human DLX3 and DLX7 and identification of a 4 bp deletion in human DLX3 which correlates with the TDO phenotype in six families. The observed mutation is predicted to cause a frameshift and premature termination codon, resulting in a functionally altered DLX3. This first report of a human mutation in the DLX genes is consistent with murine studies indicating their important role in the development of hair, teeth and bone.

Abnormalities, Multiple↗

PubMed1998

A common DLX3 gene mutation is responsible for tricho-dento-osseous syndrome in Virginia and North Carolina families.

Tricho-dento-osseous syndrome (TDO) is characterised by a variable clinical phenotype primarily affecting the hair, teeth, and bone. Different clinical features are observed between and within TDO families. It is not known whether the variable clinical features are the result of genetic heterogeneity or clinical variability. A gene for TDO was localised recently to chromosome 17q21 in four North Carolina families, and a 4 bp deletion in the human distal-less 3 gene (DLX3) was identified in all affected members. A previous genetic linkage study in a large Virginia kindred with TDO indicated possible linkage to the ABO, Gc, and Kell blood group loci. To examine whether TDO exhibits genetic heterogeneity, we have performed molecular genetic analysis to determine whether affected members of this Virginia kindred have the DLX3 gene deletion identified in North Carolina families. Results show that affected subjects (n=3) from the Virginia family have the same four nucleotide deletion previously identified in the North Carolina families. A common haplotype for three genetic markers surrounding the DLX3 gene was identified in all affected subjects in the North Carolina and Virginia families. These findings suggest that all people with TDO who have been evaluated have inherited the same DLX3 gene deletion mutation from a common ancestor. The variable clinical phenotype observed in these North Carolina and Virginia families, which share a common gene mutation, suggests that clinical variability is not the result of genetic heterogeneity at the major locus, but may reflect genetic heterogeneity at other epigenetic loci or contributing environmental factors or both.

Abnormalities, Multiple↗

PubMed1998

Identification of human plasma kallikrein gene polymorphisms and evaluation of their role in end-stage renal disease.

Kallikreins are serine proteases that release kinins from kininogens. Kinins, via their effects on cardiovascular and renal function, may be involved in the pathogenesis of hypertension and renal failure. Two groups of kallikreins exist, glandular or tissue kallikrein and plasma kallikrein. In this study, we examined the human plasma kallikrein gene KLK3 to determine whether it contributed to end-stage renal disease (ESRD) susceptibility. We identified two novel polymorphic sequences closely linked to the KLK3 gene, designated KLK3b and KLK3c (heterozygosities: 0.64 to 0.68 and 0.48 to 0.52, respectively). We mapped the KLK3 gene and the marker KLK3c to the long arm of human chromosome 4 between F11 and D4S426 using a radiation hybrid panel. The study population consisted of 142 sibling pairs concordant for ESRD from 121 African American families. The 142 sibling pairs were stratified into 78 pairs with hypertension- and chronic glomerulonephritis-associated ESRD and 64 with non-insulin-dependent diabetes mellitus-associated ESRD. Linkage analyses, using SIBPAL of SAGE, and exclusion analysis, using MAPMAKERS/SIBS, were performed. Linkage analysis of affected sibling pairs did not reveal any evidence of linkage of KLK3 to ESRD in all 142 sib-pairs or in the two stratified subsets. Exclusion analysis indicated that the KLK3 gene could be excluded from contributing to ESRD at a relative risk of 3 when the maximum log of the odds score of -2 was used as the criterion for exclusion. However, an association analysis using the relative predispositional effect technique showed that alleles 7 and 9 of KLK3b were consistently associated with ESRD. Alleles 7 and 9 were present in 11.2% and 10.8% of the 113 unrelated ESRD probands and in 6.6% and 6.6% of the 204 race-matched control subjects without renal disease (allele P=.0041 and .0016, respectively). Alleles 7 and 9 were also present in 13% and 10.4% of the proband's first siblings (allele P=.00014 and .0087, respectively). The association of KLK3b alleles with ESRD raises the possibility that polymorphisms in KLK3 may play a role in ESRD susceptibility. The lack of linkage might reflect our relatively small family set.

Alleles↗

PubMed1997

Genetic linkage analysis of growth factor loci and end-stage renal disease in African Americans.

Hypertension, diabetes mellitus and chronic glomerular diseases reportedly cause in excess of 80% of the incident cases of end-stage renal disease (ESRD) in the U.S. The factors that initiate progressive renal failure in patients with these disorders remain unknown. Several investigators have reported enhanced synthesis and activity of cytokines in the kidneys of patients with renal failure. The ensuing inflammation and fibrosis have been postulated to contribute to the development of progressive renal failure. There is also abundant evidence supporting the contribution of genetic factors in ESRD susceptibility based upon the strong familial clustering of ESRD, particularly in African Americans. Therefore, genetic linkage analysis may be useful to evaluate the role of candidate genes in several cytokine cascades that could contribute to the pathogenesis of chronic renal failure. We tested for genetic linkage between eight cytokine candidate genes and chronic renal failure in a collection of African American sibling pairs concordant for ESRD. Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF) beta 1, TGF-beta 2 and TGF-beta 3, and tumor necrosis factor (TNF)-alpha and TNF-beta candidate genes were selected for analysis due to their putative roles in diabetic renal disease and chronic glomerulonephritis. The interleukin-1 receptor antagonist gene (IL1RN) was also genotyped due to its reported association with diabetic nephropathy. Non-parametric (genetic model independent) affected sib pair linkage analysis was used to evaluate evidence for linkage. In order to genotype TGF-beta 3, we identified four closely linked, previously unidentified, highly polymorphic microsatellite loci near the TGF-beta 3 gene. Linkage of ESRD and transforming growth factor beta 2 polymorphisms on human chromosome 1 approached significance for non-diabetic nephropathy (predominantly chronic glomerular disease, hypertensive nephrosclerosis and unknown etiology) (P = 0.08), but showed no linkage to diabetic nephropathy. The other candidate loci did not demonstrate linkage to ESRD in the total population or in the subgroups with diabetic or non-diabetic etiologies of ESRD. The IL1RN gene did not show significant evidence for linkage to ESRD; however, we did confirm an association between allele 2 of IL1RN and ESRD (as reported in diabetic nephropathy). Overall, these results suggest that these growth factor loci do not make major contributions to the pathogenesis of ESRD in African Americans.

Base Sequence↗

PubMed1997

Genetic linkage of the tricho-dento-osseous syndrome to chromosome 17q21.

Tricho-dento-osseous syndrome (TDO), MIM# 190320, is transmitted as a highly penetrant autosomal dominant trait that is characterized by variable clinical expression. The principal clinical features include kinky/curly hair in infancy, enamel hypoplasia, taurodontism, as well as increased thickness and density of cranial bones. Possible genetic linkage has been reported for TDO with the ABO blood group locus, but the gene defect remains unknown. We have identified four multiplex families (n = 63, 39 affected, 24 unaffected) from North Carolina segregating TDO. We previously have excluded a major locus for TDO in the ABO region for these families. Utilizing a genome-wide search strategy, we obtained conclusive evidence for linkage of the TDO syndrome locus to markers on chromosome 17q21 (D17S791, Z max = 10.54, Theta = 0.00) with no indication of genetic heterogeneity. Multipoint analysis suggests the TDO locus is located in a 7 cM chromosomal segment flanked by D17S932 and D17S941. This finding represents the first step towards isolation and cloning of the TDO gene. Identification of this gene has important implications for understanding normal and abnormal craniofacial development of hair, teeth and bone.

Abnormalities, Multiple↗

PubMed1997

Linkage of genetic markers on human chromosomes 20 and 12 to NIDDM in Caucasian sib pairs with a history of diabetic nephropathy.

The potential contribution of maturity-onset diabetes of the young (MODY) genes to NIDDM susceptibility in African-American and Caucasian NIDDM-affected sibling pairs with a history of adult-onset diabetic nephropathy has been evaluated. Evidence for linkage to NIDDM was found with polymorphic loci that map to the long arms of human chromosomes 20 and 12 in regions containing the MODY1 and MODY3 genes. Nonparametric analysis of chromosome 20 inheritance data collected with the MODY1-linked marker D20S197 provides evidence for linkage to NIDDM with a P value of 0.005 in Caucasian sib pairs using affected sibpair (ASP) analyses. Non-parametric analysis of chromosome 12 inheritance data collected with the MODY3-linked markers D12S349 and D12S86 provides evidence for linkage to NIDDM with P values of 0.04 and 0.006, respectively, in Caucasian sib pairs using similar analyses. No evidence for linkage of MODY1 and MODY3 markers to NIDDM in African-American sib pairs was observed. In addition, no evidence for linkage to MODY2 (glucokinase-associated MODY) was observed with either study population. Results of multipoint maximum logarithm of odds (LOD) score analysis were consistent with the ASP results. A maximum LOD score of 1.48 was calculated for linkage to MODY1-linked loci and 1.45 to MODY3-linked loci in Caucasian sib pairs. Tabulation of allele sharing in affected sib pairs with D20S197 and D12S349 suggests that affected sibling pairs may inherit susceptibility genes simultaneously from chromosome 20 and chromosome 12. The results suggest that genes contributing to NIDDM in the general Caucasian population are located in the regions containing the MODY1 and MODY3 genes.

Adult↗

PubMed1997

Association of autoimmune thyroid disease with a microsatellite marker for the thyrotropin receptor gene and CTLA-4 in a Japanese population.

To examine the genetic contribution of the thyroid-stimulating hormone receptor (TSHR, or thyrotropin receptor) gene to autoimmune thyroid disease (AITD), we identified a dinucleotide repeat polymorphism near the TSHR gene that mapped to an 8.6 cM interval between D14S74 and D14S55 on the long arm of human chromosome 14. Association studies revealed a significant difference (p = 3.8 x 10(-5) between the TSHR microsatellite allele frequency distribution in 81 unrelated Japanese AITD patients and 113 Japanese controls, with a significant increase in the 180 pb allele (allele 1) of the microsatellite sequence (p = 5.8 x 10(-7). The risk for AITD with the 180 bp allele was 3.5, with association highly significant in female patients (p = 1.1 x 10(-5) and less dramatic, but still significant, in male patients (p = .02). These results suggest that the 180 bp allele of the TSHR microsatellite is associated with a susceptibility locus for AITD in Japanese patients. Two additional genetic markers have been evaluated for association in the Japanese AITD patients. The TSHR codon 52 (C52-->A52) transition mutation was not observed in the Japanese. A polymorphism for the CTLA-4 gene was genotyped and, while association with AITD was not observed (p = .15), a significant association was observed between CTLA-4 alleles of 110 bp (p = .01) and 106 bp (p = .004) and susceptibility to primary hypothyroidism or idiopathic myxedema, respectively.

Abatacept↗

PubMed1996

Physical and genetic mapping of the muscle phosphofructokinase gene (PFKM): reassignment to human chromosome 12q.

Phosphofructokinase (PFK) is a key rate-limiting enzyme in glycolysis and represents a major control point in the metabolism of glucose. There are at least three known isoforms of PFK in humans, referred to as the muscle, platelet, and liver forms, each of which is differentially expressed in various tissues. The gene for muscle phosphofructokinase, PFKM, is mutated in Tarui disease and conceivably contributes to non-insulin-dependent diabetes mellitus (NIDDM). Based on physical and genetic mapping, we have found that the gene for PFKM does not map to chromosome 1 as previously described, but instead maps to chromosome 12. PCR analysis with a somatic cell hybrid mapping panel using primers derived from intron 6 and exon 18 of the PFKM gene showed consistent amplification of cell lines containing chromosome 12 (concordance, 100%). Fluorescence in situ hybridization analysis with CEPH YAC 762G4, isolated with exon 18 primers, indicated that this clone maps to 12q13, centromeric to the diacylglycerol kinase gene (DAGK) at 12q13. 3. A highly informative genetic marker isolated from YAC 762G4 was used to map PFKM genetically between the CHLC framework markers D12S1090 and D12S390. This placement for 762G4 was significantly proximal to the recently reported locus for a third gene for maturity onset diabetes of the young (MODY). The PFKM-associated microsatellite will be a valuable tool in the evaluation of PFKM in diabetic populations as well as in linkage analysis in families with Tarui disease.

Blotting, Southern↗