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PubMed2007

Single nucleotide polymorphisms of tumor necrosis factor-alpha and the susceptibility to bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy. A "New" BPD has been characterized in preterm infants that may begin in utero, and then progress post-natally, resulting in arrested lung development and alveolar hypoplasia. Foundations for this "New" BPD may be derived from pro-inflammatory genes including tumor necrosis factor-alpha (TNFalpha). The hypothesis of the current study is that single nucleotide polymorphisms (SNPs) of the pro-inflammatory TNFalpha gene place preterm infants at increased risk for BPD. Preterm infants (105 in number) with birthweights <or=1 kg, who survived to at least 36 weeks postmenstrual age (PMA) or discharge were enrolled into this study. They were stratified for BPD according to their need for supplemental oxygen at 28 days and at 36 weeks PMA (non-, mild-, moderate-, or severe-BPD). DNA was extracted from these infants and subjected to analyses for the TNFalpha SNPs: -1,031, -863, -857, -308, and -238. The PHASE software (version 2.1) was used to reconstruct haplotypes and estimate their frequencies within the study population. Differences in birth weight (P < 0.001) and gestational age (P < 0.001), but not in racial distribution between the groups were found. Haplotype-specific analysis revealed no significant association between BPD severity and any of the 5-marker common haplotypes with 10 or more copies in this study population. Additionally, no significant association was observed in any three SNP haplotypes at -1,031, -863, and -857, and two SNP haplotypes at -308 and -238. We observed no association between BPD severity and the five TNFalpha SNPs investigated.

Bronchopulmonary Dysplasia↗
PubMed1983

DNA restriction mapping identifies the chromosome carrying the mutant Hb Presbyterian beta-globin gene.

Restriction endonuclease mapping of cellular DNA has been used to identify chromosomes that carry the mutant Hb Presbyterian beta-globin genes in a family with individuals heterozygous for this disease. The presence of the polymorphic Hind III restriction site in the G gamma-globin gene and its absence in the A gamma-globin gene were shown to be in phase with the Hb Presbyterian mutation yielding a haplotype constellation that is diagnostic for any further affected offspring.

Chromosome Mapping↗
PubMed2006

Catechol-O-methyltransferase (COMT) gene variants predict response to bupropion therapy for tobacco dependence.

BACKGROUND: Although bupropion is efficacious for smoking cessation, only a minority of smokers are able to quit. Pharmacogenetic research may improve treatment outcomes through discovery of DNA sequences predictive of successful pharmacotherapy for subgroups of smokers. We investigated variants in the catechol-O-methyltransferase (COMT) gene in a smoking cessation trial of bupropion. METHODS: A double-blind, placebo-controlled, 10-week trial of bupropion and counseling (with a 6-month follow-up period) was conducted at two university-based smoking cessation research programs. Abstinence was biochemically verified at the end of treatment and at 6 months after the target quit date. RESULTS: At the end of the treatment phase, statistically significant interaction effects indicated that COMT haplotypes of two SNPs (rs737865 and rs165599) predicted the efficacy of bupropion compared with placebo. This interaction effect was attenuated at 6-month follow-up. CONCLUSIONS: COMT haplotypes at rs737865 and rs165599 may predict a favorable outcome for bupropion treatment for smoking cessation. European-American smokers with a G allele at both SNPs may not benefit from bupropion treatment. Small numbers of some COMT haplotypes limit interpretation of response. If study findings are confirmed in additional large studies, COMT genotyping could be applied to identify likely responders to bupropion treatment for smoking cessation.

Adult↗
PubMed2007

Evaluation of the beta2-adrenergic receptor gene as a candidate glaucoma gene in 2 ancestral populations.

OBJECTIVE: To determine whether the beta(2)-adrenergic receptor (ADRB2) gene is a glaucoma susceptibility locus. DESIGN AND METHODS: The design was an association study stratified by ancestry (white vs black African) and disease (primary open-angle glaucoma vs control subjects). The ADRB2 single nucleotide polymorphisms were determined by sequencing, and the haplotypes of the common single nucleotide polymorphisms affecting codons 16 and 27 were phased by allele-specific polymerase chain reaction and restriction enzyme digestion. We analyzed the association of single nucleotide polymorphisms and haplotypes by ancestry and disease with the Fisher exact test, chi(2) test, and standardized Pearson residual. RESULTS: A total of 583 subjects underwent genotyping (156 white subjects with primary open-angle glaucoma; 143 subjects of black African ancestry with primary open-angle glaucoma; 148 white controls; and 136 controls of black African ancestry). There were no differences in ADRB2 alleles and haplotypes between the primary open-angle glaucoma and control groups, whether analyzed together or by ancestry. Previously described ancestry-based differences in allele frequencies were found. We also found ancestry-based differences in ADRB2 haplotypes. CONCLUSION: The ADRB2 gene was not a glaucoma susceptibility locus in our study population. CLINICAL RELEVANCE: Because this gene is not a disease locus, we can now study the role of ADRB2 haplotypes in the glaucoma risk factor of intraocular pressure fluctuation and variation in intraocular pressure response to beta-blockers.

Aged↗
PubMed1996

Long-term survival in advanced chronic myelogenous leukemia following bone marrow transplantation from haploidentical related donors.

From 1987 to 1991, 26 patients with CML and a median age of 31 years received allogeneic BMT from a partially mismatched related donor (PMRD) who shared at least one haplotype with the recipient. Nine patients were in accelerated phase (AP), and 11 patients were in blast crisis (BC) at the time of BMT. Patients were mismatched either in graft-versus-host or host-versus-graft directions for one antigen in 3 patients, two antigens in 14 patients, and three antigens in 9 patients. All patients were prepared with a regimen consisting of total body irradiation, etoposide, cytosine arabinoside, cyclophosphamide and methylprednisolone. All marrows were treated ex vivo with T10B91.A-31, a monoclonal antibody directed toward the alpha beta heterodimer of the CD3 receptor, and rabbit complement. Additional GVHD prophylaxis included either the anti-CD5 immunoconjugate XomaZyme-H65, cyclosporine, or both in combination with methylprednisolone. Eight patients did not have sustained engraftment. The 100-day survival was 42%. The incidence of > or = grade II acute GVHD was 29%. The incidence of chronic GVHD was 50% and was limited in all cases. The median survival at 4 years for all 26 patients was 27%. Seven patients (CP 1, AP 3, BC 3) remain in hematologic remission 1297-2241+ days after transplantation. AlloBMT from a PMRD may be considered for patients with advanced CML who lack a matched sibling or unrelated donor.

Adolescent↗
PubMed2006

Haplotype-environment interactions that regulate the human glutathione S-transferase P1 promoter.

Phase II detoxification of carcinogens is reported to mediate some of the anticarcinogenesis effects of candidate chemopreventive agents. We explored the interaction between sequence variation in the GSTP1 gene promoter and candidate chemopreventive exposure in regulating human GSTP1 expression. Polymorphisms along 1.8 kb of the GSTP1 promoter were identified in leukocytes [peripheral blood mononuclear cells (PBMC)] from 40 Caucasian subjects. Ten promoter polymorphisms (9 previously unreported) displayed strong linkage disequilibrium, yielding identification of three frequently observed haplotypes [HAP1 (43%), HAP2 (36%), and HAP3 (8%)]. Each haplotype was cloned into luciferase reporter constructs and transfected into normal human bronchial epithelial cells. Basal HAP3 reporter activity was significantly elevated (1.8-fold) but decreased to the same levels as HAP2 and HAP1 with increasing concentrations of sulforaphane, benzyl isothiocyanate (BITC), and epigallocatechin gallate (EGCG). To confirm native HAP3 functionality, we quantitated mRNA expression in uncultured PBMCs and in laser microdissected normal lung epithelial cells (MNLEC) from the same patients. Basal mRNA expression was higher in HAP3 individuals [1.8-fold (PBMC) and 4-fold (MNLEC) for HAP3 heterozygotes and 2.3-fold (PBMC), and 15-fold (MNLEC) for the HAP3 homozygote] than in the other genotypes. PBMC GSTP1 mRNA expression correlated to MNLEC expression (R2 = 0.77). After culture and in vitro exposure to sulforaphane, BITC, or EGCG, the elevated GSTP1 mRNA expression of PBMCs from HAP3 individuals decreased to common expression levels. Elevated HAP3 function was confirmed at the protein level in PBMCs (5-fold higher for HAP3 heterozygotes and 7.6-fold for the HAP3 homozygote). These data suggest a potentially protective GSTP1 promoter haplotype and unpredicted inhibitory chemopreventive agent-haplotype interactions.

Case-Control Studies↗
PubMed1998

Testing migration patterns and estimating founding population size in Polynesia by using human mtDNA sequences.

The hypervariable 1 region of human mtDNA shows markedly reduced variability in Polynesians, and this variability decreases from western to eastern Polynesia. Fifty-four sequences from New Zealand Maori show that the mitochondrial variability with just four haplotypes is the lowest of any sizeable human group studied and that the frequency of haplotypes is markedly skewed. The Maori sequences, combined with 268 published sequences from the Pacific, are consistent with a series of founder effects from small populations settling new island groups. The distributions of haplotypes were used to estimate the number of females in founding population of New Zealand Maori. The three-step simulation used a randomly selected founding population from eastern Polynesia, an expansionary phase in New Zealand, and finally the random selection of 54 haplotypes. The results are consistent with a founding population that includes approximately 70 women (between 50 and 100), and sensitivity analysis shows that this conclusion is robust to small changes in haplotype frequencies. This size is too large for models postulating a very small founding population of "castaways," but it is consistent with a general understanding of Maori oral history as well as the results of recent canoe voyages recreating early trans-oceanic voyages.

Base Sequence↗
PubMed2004

Comprehensive evaluation of the association between prostate cancer and genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2.

Genes involved in the testosterone biosynthetic pathway - such as CYP17A1, CYP3A4, and SRD5A2 - represent strong candidates for affecting prostate cancer. Previous work has detected associations between individual variants in these three genes and prostate cancer risk and aggressiveness. To more comprehensively evaluate CYP17A1, CYP3A4, and SRD5A2, we undertook a two-phase study of the relationship between their genotypes/haplotypes and prostate cancer. Phase I of the study first searched for single-nucleotide polymorphisms (SNPs) in these genes by resequencing 24 individuals from the Coriell Polymorphism Discovery Resource, 92-110 men from prostate cancer case-control sibships, and by leveraging public databases. In all, 87 SNPs were discovered and genotyped in 276 men from case-control sibships. Those SNPs exhibiting preliminary case-control allele frequency differences, or distinguishing (ie, 'tagging') common haplotypes across the genes, were identified for further study (24 SNPs in total). In Phase II of the study, the 24 SNPs were genotyped in an additional 841 men from case-control sibships. Finally, associations between genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2 and prostate cancer were evaluated in the total case-control sample of 1117 brothers from 506 sibships. Family-based analyses detected associations between prostate cancer risk or aggressiveness and a number of CYP3A4 SNPs (P-values between 0.006 and 0.05), a CYP3A4 haplotype (P-values 0.05 and 0.009 in nonstratified and stratified analysis, respectively), and two SRD5A2 SNPs in strong linkage disequilibrium (P=0.02). Undertaking a two-phase study comprising SNP discovery, haplotype tagging, and association analyses allowed us to more fully decipher the relation between CYP17A1, CYP3A4, and SRD5A2 and prostate cancer.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2006

Haplotype analysis suggest common founders in carriers of the recurrent BRCA2 mutation, 3398delAAAAG, in French Canadian hereditary breast and/ovarian cancer families.

BACKGROUND: The 3398delAAAAG mutation in BRCA2 was recently found to recur in breast and/or ovarian cancer families from the French Canadian population of Quebec, a population that has genetic attributes consistent with a founder effect. To characterize the contribution of this mutation in this population, this study established the frequency of this mutation in breast and ovarian cancer cases unselected for family history of cancer, and determined if mutation carriers shared a common ancestry. METHODS: The frequency was estimated by assaying the mutation in series of French Canadian breast cancer cases diagnosed before age 41 (n = 60) or 80 (n = 127) years of age, and ovarian cancer cases (n = 80) unselected for family history of cancer by mutation analysis. Haplotype analysis was performed to determine if mutation carriers shared a common ancestry. Members from 11 families were analyzed using six polymorphic microsatellite markers (cen-D13S260-D13S1699-D13S1698-D13S1697-D13S1701-D13S171-tel) spanning approximately a 3.6 cM interval at the chromosomal region 13q13.1, which contains BRCA2. Allele frequencies were estimated by genotyping 47 unaffected female individuals derived from the same population. Haplotype reconstruction of unaffected individuals was performed using the program PHASE. RESULTS: The recurrent BRCA2 mutation occurred in 1 of 60 (1.7%) women diagnosed with breast cancer before 41 years of age and one of 80 (1.3%) women with ovarian cancer. No mutation carriers were identified in the series of breast cancer cases diagnosed before age 80. Mutation carriers harboured one of two haplotypes, 7-3-9-3 - [3/4]-7, that varied with marker D13S1701 and which occurred at a frequency of 0.001. The genetic analysis of D13S1695, a polymorphic marker located approximately 0.3 cM distal to D13S171, did not favour a genetic recombination event to account for the differences in D13S1701 alleles within the haplotype. Although mutation carriers harbour genotypes that are frequent in the French Canadian population, neither mutation-associated haplotype was plausible in reconstructed haplotypes of 47 individuals of French Canadian descent. CONCLUSION: These results suggest that mutation carriers share a related ancestry; further supporting the concept that recurrent BRCA1 and BRCA2 mutations in the French Canadian population could be attributed to common founders. This finding provides further support for targeted screening of recurrent mutations in this population before large-scale mutation analyses are performed.

Adult↗
PubMed2005

XPC polymorphisms and lung cancer risk.

Polymorphisms in DNA repair genes may be associated with differences in the capacity to repair DNA damage and thereby influence an individual's susceptibility to smoking-related cancer. To test this hypothesis, we investigated the potential association of 7 XPC polymorphisms (-449G-->C, -371G-->A, -27G-->C, Val499Arg, PAT-/+, IVS11-5C-->A and Lys939Gln) and their haplotypes with lung cancer risk in a Korean population. XPC genotypes were determined in 432 lung cancer patients and 432 healthy controls frequency-matched for age and sex. XPC haplotypes were predicted using a Bayesian algorithm in the Phase program. The combined -27CG+CC genotype was associated with a significantly increased risk for overall lung cancer compared to the -27GG genotype (adjusted OR = 1.97, 95% CI 1.22-3.17, p = 0.005). The other 6 polymorphisms were not significantly associated with overall risk of lung cancer. When lung cancer cases were categorized by tumor histology, the -371AA genotype was associated with a significantly increased risk of squamous cell carcinoma compared to the combined -371GG and GA genotype (adjusted OR = 2.08, 95% CI 1.09-4.00, p = 0.03). The PAT-/+, IVS11-5C-->A and Lys939Gln polymorphisms were associated with a significantly decreased risk of small cell carcinoma (SM) under a dominant model for the polymorphic allele (adjusted OR = 0.49, 95% CI 0.29-0.82, p = 0.006; adjusted OR = 0.60, 95% CI 0.36-1.00, p = 0.05; and adjusted OR = 0.58, 95% CI 0.35-0.97, p = 0.04, respectively). Consistent with genotyping analyses, haplotype 4 (1112222) containing the PAT+/IVS11-5A/939Gln alleles was associated with a significantly decreased risk of SM (adjusted OR = 0.56, 95% CI 0.37-0.85, p = 0.007 and Bonferroni-corrected p = 0.049), whereas haplotype 5 (1122111) containing the -27C allele was associated with a significantly increased risk of SM (adjusted OR = 2.88, 95% CI 1.41-5.87, p = 0.004 and Bonferroni-corrected p = 0.028). These results suggest that XPC polymorphisms/haplotypes may contribute to genetic susceptibility for lung cancer.

Aged↗
PubMed2002

Efficiency of haplotype frequency estimation when nuclear family information is included.

In genetic studies the haplotype structure of the regarded population is expected to carry important information. Experimental methods to derive haplotypes, however, are expensive and none of them has yet become standard methodology. On the other hand, maximum likelihood haplotype estimation from unphased individual genotypes may incur inaccuracies. We therefore investigated the relative efficiency of haplotype frequency estimation when nuclear family information is included compared to estimation from experimentally derived haplotypes. Efficiency was measured in terms of variance ratios of the estimates. The variances were derived from the binomial distribution for experimentally derived haplotypes, and from the Fisher information matrix corresponding to the general likelihood function of the haplotype frequency parameters, including family information. We subsequently compared these variance ratios to the variance ratios for the case of estimation from individual genotypes. We found that the information gained from a single child compensates missing phase information to a high degree, resulting in estimates almost as reliable as those derived from observed haplotypes. Thus, if children have already been genotyped for other reasons, it is highly recommendable to include them into the estimation. If child information is not already present, it depends on the number of loci and the haplotype diversity if it is useful to genotype a single child just to reduce phase ambiguity. In general, if the number of loci is less than or equal to three or if the number of haplotypes with a frequency >5% is less than or equal to four, haplotype estimation from individuals is quite good already and the improvement gained from a single child can not compensate the genotyping effort for it. On the other hand, under scenarios with many loci and high haplotype diversity, haplotype frequency estimation from trios can be more efficient than haplotype frequency estimation from individuals also on a per genotype base.

Data Interpretation, Statistical↗
PubMed1980

Delayed-type hypersensitivity responses to H-Y: characterization and mapping of Ir genes.

This paper examines the delayed-type hypersensitivity (DTH) response to male (H-Y) antigen(s). Female mice of the H-2b haplotype developed delayed footpad reaction to syngeneic or allogenic male thymus and spleen cells after priming with syngeneic male thymus and spleen cells. The reaction peaks at 24 h, has classical DTH histology and is specific to H-Y antigen as it is not elicited with female cells. Cell transfer studies show that donor/recipient matching at the I-Bb subregion is necessary for successful transfer of DTH and that the effective primed population is Thy-1+, Lyt-1+, 2-. DTH response to H-Y antigen appears to be confined to mice of the H-2b haplotype. There appears to be a lack of associative recognition between H-Y antigen and MHC-coded determinants in the effector phase of DTH, and macrophage processing of H-Y seems likely, since nonresponder haplotypes can elicit the DTH response. Studies with H-2b recombinant mouse strains indicate that the dominant Ir gene is located in the I-B region. Female F1 hybrid mice derived from matings of strains not involving H-2b haplotype failed to develop DTH to H-Y. In summary, these data imply that a complete correlation exists between DTH to H-Y and the ability to reject male skin graft, suggesting that the effector mechanisms of skin-graft rejection may closely involve DTH cells.

Animals↗
PubMed2003

Interleukin-6 protects anterior horn neurons from lethal virus-induced injury.

We evaluated the role of interleukin-6 (IL-6) in neuronal injury after CNS infection. IL-6-/- and IL-6+/+ mice of resistant major histocompatibility complex (MHC) H-2b haplotype intracerebrally infected with Theiler's virus cleared the infection normally without development of viral persistence, lethal neuronal infection, or late phase demyelination. In contrast, infection of IL-6-/- mice on a susceptible H-2q haplotype resulted in frequent deaths and severe neurologic deficits within 2 weeks of infection as compared with infected IL-6+/+ H-2q littermate controls. Morphologic analysis demonstrated dramatic injury to anterior horn neurons of IL-6-/- H-2q mice at 12 d after infection. Infectious viral titers in the CNS (brain and spinal cord combined) were equivalent between IL-6-/- H-2q and IL-6+/+ H-2q mice. In contrast, more viral RNA was detected in the spinal cord of IL-6-/- mice compared with IL-6+/+ H-2q mice. Virus antigen was localized predominantly to anterior horn cells in infected IL-6-/- H-2q mice. IL-6 deletion did not affect the humoral response directed against virus, nor did it affect the expression of CD4, CD8, MHC class I, or MHC class II in the CNS. Importantly, IL-6 was expressed by astrocytes of infected IL-6+/+ mice but not in astrocytes of IL-6-/- mice or uninfected IL-6+/+ mice. Furthermore, expression of various chemokines was robust at 12 d after infection in both H-2b and H-2q IL-6-/- mice, indicating that intrinsic CNS inflammatory responses did not depend on the presence of IL-6. Finally, in vitro analysis of virus-induced death in neuroblastoma-spinal cord-34 motor neurons and primary anterior horn cell neurons showed that IL-6 exerted a neuroprotective effect. These data support the hypothesis that IL-6 plays a critical role in protecting specific populations of neurons from irreversible injury.

Animals↗
PubMed2004

Linkage disequilibrium testing when linkage phase is unknown.

Linkage disequilibrium, the nonrandom association of alleles from different loci, can provide valuable information on the structure of haplotypes in the human genome and is often the basis for evaluating the association of genomic variation with human traits among unrelated subjects. But, linkage phase of genetic markers measured on unrelated subjects is typically unknown, and so measurement of linkage disequilibrium, and testing whether it differs significantly from the null value of zero, requires statistical methods that can account for the ambiguity of unobserved haplotypes. A common method to test whether linkage disequilibrium differs significantly from zero is the likelihood-ratio statistic, which assumes Hardy-Weinberg equilibrium of the marker phenotype proportions. We show, by simulations, that this approach can be grossly biased, with either extremely conservative or liberal type I error rates. In contrast, we use simulations to show that a composite statistic, proposed by Weir and Cockerham, maintains the correct type I error rates, and, when comparisons are appropriate, has similar power as the likelihood-ratio statistic. We extend the composite statistic to allow for more than two alleles per locus, providing a global composite statistic, which is a strong competitor to the usual likelihood-ratio statistic.

Alleles↗
PubMed2005

Association of nuclear factor-kappaB in psoriatic arthritis.

OBJECTIVE: To examine the association of single nucleotide polymorphisms (SNP) in the NFKB1 gene, as well as 2 genes in the nuclear factor (NF)-kappaB functional complex (RelA and NFKBIA), in patients with psoriatic arthritis (PsA) from Newfoundland. METHODS: Patients with PsA and controls were genotyped for one 4-base insertion/deletion and 5 SNP in NFKB1, 4 SNP in RelA, and 7 SNP in NFKBIA by time-of-flight mass spectrometry, using the Sequenom platform. Chi-square analysis was used to test the single locus associations between SNP in the NF-kappaB complex and PsA. Associations between multi-locus haplotypes and case or control status were tested using the software PHASE. RESULTS: Two hundred and twenty-four patients with PsA (52% male) and 88 ethnically matched controls (64% male) were genotyped. No association was noted with any of the SNP tested for the single locus associations in NFKB1, RelA, and NFKBIA or with multi-locus haplotypes. In particular, the allele frequency for the NFKB1 -94delATTG was 41.7% in cases and 41.6% in the controls (p = 0.97). CONCLUSION: No association between the NFKB1 -94 ins/delATTG promoter polymorphism or with other NF-kappaB complex SNP in patients with PsA from Newfoundland was observed.

Adult↗
PubMed2001

Modern concepts for the prediction of type 1 diabetes.

Type 1 diabetes results from the destruction of the insulin-producing beta cells of the pancreas. The disease process is thought to be initiated by a complex interaction between genetic and environmental factors leading to a cellular and humoral autoimmune response against beta cell specific components. Over the past decade there has been important progress in identification of several diabetes specific autoantigens. The availability of recombinant antigens, most notably the enzyme glutamic acid decarboxylase (GAD) and the tyrosine phosphatase-like molecule IA-2, made it possible to develop simple, sensitive and specific radioimmunoassays for the detection of autoantibodies on a large scale. It has been shown that the combination of GAD antibodies (GADA) and IA-2 antibodies (IA-2-A) with insulin autoantibodies (IAA) can replace the conventional ICA test. This considerably facilitates screening programmes. Prospective studies in subjects with and without family history of type 1 diabetes conclusively demonstrate that the risk for type 1 diabetes is strongly correlated with the number of positive antibodies. The 5-10-years risk for type 1 diabetes varies from 0-1% in individuals with only one positive antibodies to 62-100% in subjects who were positive for three or more antibodies. Despite the identification of novel genetic markers associated with type 1 diabetes, the major histocompatibility complex, namely HLA-DQ alleles, still represents the strongest genetic risk factor. The analysis of HLA-DQ alleles may be important to discriminate between subjects at high or intermediate risk from antibody positive individuals carrying protective haplotypes. Assessment of the metabolic state using the first phase insulin response to intravenous glucose may provide additional information to predict rapid progression to diabetes. Screening for multiple antibodies is the most specific and sensitive strategy for identifying subject at risk for type 1 diabetes. Second-line genotyping or analysis of the first phase insulin response can serve as useful tool to improve the prediction of type 1 diabetes. The value of additional markers such as isotype specific autoantibodies or T-helper cells subsets measured by ELISPOT assays or FACS remains to be shown.

Autoantibodies↗
PubMed1990

Two step procedure for early diagnosis of polycystic kidney disease with polymorphic DNA markers on both sides of the gene.

Polymorphic DNA markers can now be used for presymptomatic and prenatal diagnosis of the autosomal dominant form of polycystic kidney disease (PKD). A detailed map is known for the chromosomal region around the PKD1 gene on the short arm of chromosome 16. We present here a simple, two step procedure for diagnosis of PKD1 by family studies. Using this approach, at least 92% of random subjects are informative for polymorphic DNA markers bracketing the PKD1 gene. The recombination rate between these flanking markers is on average 10%. In non-recombinants (90% of family members), the accuracy of diagnosis using DNA markers is greater than 99%. We conclude that sufficient well defined DNA markers are now available for routine diagnosis of PKD1. We recommend, however, that prenatal diagnosis of PKD by chorionic villi sampling should be attempted only after the linkage phase of the DNA markers has been established by haplotyping the index family. Since autosomal dominant PKD has been found to be genetically heterogeneous, families should be of sufficient size to rule out the rare form of PKD not caused by a mutation on the short arm of chromosome 16.

Chromosomes, Human, Pair 16↗
PubMed2006

Polymorphisms in the hMSH2 gene and the risk of primary lung cancer.

Polymorphisms in the DNA repair genes may be associated with differences in the capacity to repair DNA damage, and so this can influence an individual's susceptibility to lung cancer. To test this hypothesis, we investigated the association of hMSH2 -118T>C, IVS1+9G>C, IVS10+12A>G, and IVS12-6T>C genotypes and their haplotypes with the risk of lung cancer in a Korean population. The hMSH2 genotypes were determined in 432 lung cancer patients and in 432 healthy controls who were frequency matched for age and gender. The hMSH2 haplotypes were estimated based on a Bayesian algorithm using the Phase program. The presence of at least one IVS10+12G allele was associated with a significantly decreased risk of adenocarcinoma, as compared with the IVS10+12AA genotype [adjusted odds ratio (OR), 0.59; 95% confidence interval (95% CI), 0.40-0.88; P = 0.01], and the presence of at least one IVS12-6C allele was associated with a significantly increased risk of adenocarcinoma, as compared with the IVS12-6TT genotype (adjusted OR, 1.52; 95% CI, 1.02-2.27; P = 0.04). Consistent with the results of the genotyping analysis, the TGGT haplotype with no risk allele was associated with a significantly decreased risk of adenocarcinoma, as compared with the TCAC haplotype with two risk allele [i.e., IVS10+12A and IVS12-6C allele; adjusted OR, 0.49; 95% CI, 0.30-0.78; P = 0.003 and P(c) (Bonferroni corrected P value) = 0.012]. The effect of the hMSH2 haplotypes on the risk of adenocarcinoma was statistically significant in the never smokers and younger individuals (adjusted OR, 0.45; 95% CI, 0.27-0.75; P = 0.002 and P(c) = 0.004; and adjusted OR, 0.44; 95% CI, 0.23-0.85; P = 0.014 and P(c) = 0.028, respectively) but not in the ever-smokers and older individuals. These results suggest that the hMSH2 polymorphisms and their haplotypes may be an important genetic determinant of adenocarcinoma of the lung, particularly in never smokers.

Adenocarcinoma↗