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PubMed2005

Analysis of case-control studies of genetic and environmental factors with missing genetic information and haplotype-phase ambiguity.

Case-control studies of unrelated subjects are now widely used to study the role of genetic susceptibility and gene-environment interactions in the etiology of complex diseases. Exploiting an assumption of gene-environment independence, and treating the distribution of environmental exposures as completely nonparametric, Chatterjee and Carroll recently developed an efficient retrospective maximum-likelihood method for analysis of case-control studies. In this article, we develop an extension of the retrospective maximum-likelihood approach to studies where genetic information may be missing on some study subjects. In particular, special emphasis is given to haplotype-based studies where missing data arise due to linkage-phase ambiguity of genotype data. We use a profile likelihood technique and an appropriate expectation-maximization (EM) algorithm to derive a relatively simple procedure for parameter estimation, with or without a rare disease assumption, and possibly incorporating information on the marginal probability of the disease for the underlying population. We also describe two alternative robust approaches that are less sensitive to the underlying gene-environment independence and Hardy-Weinberg-equilibrium assumptions. The performance of the proposed methods is studied using simulation studies in the context of haplotype-based studies of gene-environment interactions. An application of the proposed method is illustrated using a case-control study of ovarian cancer designed to investigate the interaction between BRCA1/2 mutations and reproductive risk factors in the etiology of ovarian cancer.

Algorithms↗
PubMed2006

A quality assessment survey of SNP genotyping laboratories.

To survey the quality of SNP genotyping, a joint Nordic quality assessment (QA) round was organized between 11 laboratories in the Nordic and Baltic countries. The QA round involved blinded genotyping of 47 DNA samples for 18 or six randomly selected SNPs. The methods used by the participating laboratories included all major platforms for small- to medium-size SNP genotyping. The laboratories used their standard procedures for SNP assay design, genotyping, and quality control. Based on the joint results from all laboratories, a consensus genotype for each DNA sample and SNP was determined by the coordinator of the survey, and the results from each laboratory were compared to this genotype. The overall genotyping accuracy achieved in the survey was excellent. Six laboratories delivered genotype data that were in full agreement with the consensus genotype. The average accuracy per SNP varied from 99.1 to 100% between the laboratories, and it was frequently 100% for the majority of the assays for which SNP genotypes were reported. Lessons from the survey are that special attention should be given to the quality of the DNA samples prior to genotyping, and that a conservative approach for calling the genotypes should be used to achieve a high accuracy.

Clinical Laboratory Techniques↗
PubMed2004

Genotyping and haplotyping of the dopamine D4 receptor gene by capillary electrophoresis.

In this paper we report on simultaneous genotyping of adjacent polymorphisms (referred to as haplotyping) by combining double-tube allele-specific polymerase chain reaction, restriction fragment length polymorphism and capillary gel electrophoresis analysis of the resulting fragments. Direct molecular haplotyping is of particular importance in the case of double heterozygote samples, since in these instances the haplotype structure cannot be constructed based on genotype data. Our approach provided a powerful tool for coincidental genotype analysis of the 48 base pair (bp) variable number of tandem repeats of the third exon and haplotype investigation of the -616CG and -521CT single nucleotide polymorphisms of the dopamine D4 receptor (DRD4) gene. The linear polyacrylamide sieving matrix was optimized for the size range of the double-stranded DNA fragments of interest varying from 35 to 763 bp. We demonstrated that capillary gel electrophoresis in combination with laser induced fluorescence detection offers a sensitive and accurate tool for automated haplotyping in clinical settings.

Base Sequence↗
PubMedDate not supplied

Combined analysis of cytokine genotype polymorphism and the level of expression with allograft function in African-American renal transplant patients.

Cytokine gene polymorphism and expression levels were evaluated in a group of African-American patients who had undergone renal transplantation. It was hypothesized that possession of specific cytokine alleles might be influential in predisposing the recipient to allograft rejection. Thus, we sought to establish a relationship between cytokine gene polymorphism, the levels of cytokine expression, and the outcome of allograft function. Cytokine genotypes and mRNA transcript levels of IL-2, TNF-alpha, TGF-beta1, IL-10, IL-6 and IFN-gamma were determined using peripheral blood cells. Genomic DNA samples from 77 transplant recipients and 77 controls were tested by a multiplex PCR with specific primers for the above cytokines. The frequency distributions of cytokines were analyzed in respect to the clinical characterization, including delayed graft function (DGF), rejection episodes (REs) and stable graft function (SGF). The mRNA transcript level was tested both at pre- and early post-transplantation (day 1 and day 4) with primers for coding regions of the above cytokines in a RT-PCR assay. The majority of recipients with successful graft function were matched with their donors for only three out of the six HLA alleles. We have shown that the TGF-beta1 T/C G/G high producer and IFN-gamma T/A intermediate producer genotypes were associated with allograft rejection, whereas low IFN-gamma producer and high IL-10 producer genotypes were significantly protective of the allograft. There was some correlation between the TGF-beta1 high producer genotype and DGF, but it was not statistically significant. Overall, 77% of those who experienced REs carried the TGF-beta1 T/C G/G, high producer genotype as compared with 52% who experienced DGF, 39% with SGF (P<0.01, RR=2.0), and 27.3% of controls (P<0.003, RR=2.6). The IFN-gamma T/A intermediate producer genotype was found in 69.2% of patients with REs as compared with 26.8% of patients with SGF (P<0.008, RR=2.85). The IL-10, ATA/ATA low producer genotype was found in 38.5% of recipients with REs and 14.6% of recipients without REs (P<0.04, RR=0.53). Expression levels of mRNA transcript were correlated with genotype data, except for the TGF-beta1 high producer genotype where there was no significant difference between the level of mRNA transcript at pre- and post-transplantation. Low DRbeta1 and high DPbeta1 expression by recipient peripheral blood mononuclear cells before transplantation was associated with more SGF, whereas high DRbeta1 and low DPbeta1 expression at pretransplantation was associated with more REs (DRbeta1, P<0.001 and DPbeta1, P<0.05, respectively). We concluded that, dual analysis of cytokine genotype and expression levels by peripheral cells may be an important clue to understanding the contribution of the recipient's immune response to an allograft pre- and post-transplantation. Identification of peripheral markers diagnostic of rejection could allow advance anticipation of clinical outcome, and might reduce the need for tissue biopsy.

Black or African American↗
PubMed2003

Liver transplantation for HCV-associated liver cirrhosis: predictors of outcomes in a population with significant genotype 3 and 4 distribution.

End-stage liver disease associated with hepatitis C virus (HCV) infection is now the leading indication for liver transplantation in adults. However, reinfection of the graft is universal. We aimed to determine predictors of outcome of HCV-liver transplant recipients in the Australian and New Zealand communities. The following variables were analysed: demographic factors, coexistent pathology at the time of transplantation, HCV genotype, and donor age. Outcomes measures were: 1. mortality; 2. development of HCV-related complications, which were stage 3 or 4 fibrosis, or mortality from HCV-related graft failure, or both. Between January 1989 and December 30, 1999, 182 patients were transplanted for HCV-associated cirrhosis. The median follow-up period was 4 years (range, 0 to 13 years). Genotype data were available on 157 patients. The distribution of genotypes among the 157 patients was as follows: 36 (23%) genotype 1a, 30 (19%) genotype 1b, 4 (9%) genotype 1, 17 (11%) genotype 2, 41 (26%) genotype 3a, and 16 (10%) genotype 4. Eight (5%) patients were HCV-polymerase chain reaction (PCR)-negative (but HCV-antibody-positive). Donor age and genotype 4 were associated with an increased risk of retransplantation or death (P <.001 and.05, respectively). Meanwhile, donor age, genotype 4, and pretransplant excess alcohol were risk factors for the development of HCV-related complications (P =.004,.008, and.02, respectively). In contrast, patients with genotype 3a were less likely to develop HCV-related complications (P =.05). In a population of HCV liver transplant recipients with a heterogeneous genotype distribution, donor age, and genotype 4, were predictors of a worse outcome, whereas genotype 3 was associated with a more favorable outcome.

Adult↗
PubMed2005

The International HapMap Project Web site.

The HapMap Web site at http://www.hapmap.org is the primary portal to genotype data produced as part of the International Haplotype Map Project. In phase I of the project, >1.1 million SNPs were genotyped in 270 individuals from four worldwide populations. The HapMap Web site provides researchers with a number of tools that allow them to analyze the data as well as download data for local analyses. This paper presents step-by-step guides to using those tools, including guides for retrieving genotype and frequency data, picking tag-SNPs for use in association studies, viewing haplotypes graphically, and examining marker-to-marker LD patterns.

Computational Biology↗
PubMed2006

A comparison of phasing algorithms for trios and unrelated individuals.

Knowledge of haplotype phase is valuable for many analysis methods in the study of disease, population, and evolutionary genetics. Considerable research effort has been devoted to the development of statistical and computational methods that infer haplotype phase from genotype data. Although a substantial number of such methods have been developed, they have focused principally on inference from unrelated individuals, and comparisons between methods have been rather limited. Here, we describe the extension of five leading algorithms for phase inference for handling father-mother-child trios. We performed a comprehensive assessment of the methods applied to both trios and to unrelated individuals, with a focus on genomic-scale problems, using both simulated data and data from the HapMap project. The most accurate algorithm was PHASE (v2.1). For this method, the percentages of genotypes whose phase was incorrectly inferred were 0.12%, 0.05%, and 0.16% for trios from simulated data, HapMap Centre d'Etude du Polymorphisme Humain (CEPH) trios, and HapMap Yoruban trios, respectively, and 5.2% and 5.9% for unrelated individuals in simulated data and the HapMap CEPH data, respectively. The other methods considered in this work had comparable but slightly worse error rates. The error rates for trios are similar to the levels of genotyping error and missing data expected. We thus conclude that all the methods considered will provide highly accurate estimates of haplotypes when applied to trio data sets. Running times differ substantially between methods. Although it is one of the slowest methods, PHASE (v2.1) was used to infer haplotypes for the 1 million-SNP HapMap data set. Finally, we evaluated methods of estimating the value of r(2) between a pair of SNPs and concluded that all methods estimated r(2) well when the estimated value was >or=0.8.

Algorithms↗
PubMedDate not supplied

Hepatitis B virus genotype A is more often associated with severe liver disease in northern India than is genotype D.

BACKGROUND: The clinical outcome of chronic hepatitis B may depend on hepatitis B virus (HBV) genotype. Data from India on this aspect are limited and contradictory. We studied the frequency of HBV genotypes and their clinical significance. METHODS: Stored sera from patients with chronic HBV infection were tested for HBV genotype using PCR-RFLP. Clinical data, and biochemical and serological parameters were retrieved from medical records; patients were classified as having chronic hepatitis or cirrhosis. RESULTS: Of 70 patients studied (mean age [SD] 38.4 [17.0] years; 63 men; ALT 140 [177] U/L), 32 had chronic hepatitis and 38 had cirrhosis. HBeAg was positive in 50/67 (75%), and anti-HBe in 12/66 (18%). Genotype A was the commonest (37; 53%), followed by D (32; 46%) and C (1; 1%). Patients with genotype A more often had ALT elevation exceeding 1.5 times normal (30/37 [81%] than those with genotype D (18/31 [58%]; p< 0.05). They also more often had positive HBeAg (32/37; 86%) and negative anti-HBe (33/36; 92%) than those with genotype D (18/29 [62%] and 21/29 [72%], respectively; p< 0.05 each). Of 37 patients with genotype A, 23 (62%) had cirrhosis and 14 (38%) had chronic hepatitis; of 32 patients with genotype D, 15 (47%) had cirrhosis and 17 (53%) had chronic hepatitis (p=ns). In the subgroup aged> 25 years, genotype A patients more often had cirrhosis than those with genotype D (23/28 [82%] vs 13/23 [57%]; p < 0.05). CONCLUSION: HBV genotypes A and D were the commonest in our population. Genotype A was more often associated with ALT elevation, HBeAg positivity, absence of anti-HBe and, among those aged 25 years and above, cirrhosis of liver, than was genotype D.

Adult↗
PubMed2003

Phenotypic and genotypic characterization of Oenococcus oeni strains isolated from Italian wines.

A phenotypic and genotypic characterization of 84 Oenococcus oeni isolates from Italian wines of different oenological areas was carried out. Numerical analysis of fatty acid profiles grouped the isolates into two clusters at low level of similarity (63%), the minor cluster containing seven isolates besides the type and the reference strains. Forthy-eight O. oeni isolates, representative of the two clusters, showed no differences in their metabolic properties (heterolactic fermentation pattern, citrate degradation capability and formation of some secondary metabolites). Moreover, the analysis of species-specific randomly amplified polymorphic DNA and 16S-23S rDNA intergenic spacer region polymorphism as well as the sequence-specific separation of V3 region from 16S rDNA by denaturing gradient gel electrophoresis demonstrated a substantial homogeneity among the isolates. On the basis of ApaI Pulsed Field Gel Electrophoresis (PFGE) restriction patterns, the 84 isolates were grouped into five different clusters at 70% similarity, but no correlation with the phenotypic groups could be demonstrated. However, by combining phenotypic and genotypic data, the 84 O. oeni isolates grouped into eight phenotypic-genotypic combined profiles and a relationship between the origin of the isolates and their combined profile became evident, so that a sort of strain specificity can be envisaged for each wine-producing area.

Base Sequence↗
PubMed2000

Estimation of admixture and detection of linkage in admixed populations by a Bayesian approach: application to African-American populations.

We describe a novel method for analysis of marker genotype data from admixed populations, based on a hybrid of Bayesian and frequentist approaches in which the posterior distribution is generated by Markov chain simulation and score tests are obtained from the missing-data likelihood. We analysed data on unrelated individuals from eight African-American populations, genotyped at ten marker loci of which two (FY and AT3) are linked (22 cM apart). Linkage between these two loci was detected by testing for association of ancestry conditional on parental admixture. The strength of this association was consistent with European gene flow into the African-American population between five and nine generations ago. To mimic the mapping of an unknown gene in an 'affecteds- only' analysis, a binary trait was constructed from the genotype at the AT3 locus and a score test was shown to detect linkage of this 'trait' with the FY locus. Mis-specification of the ancestry-specific allele frequencies - the probabilities of each allelic state given the ancestry of the allele - was detected at three of the ten marker loci. The methods described here have wide application to the analysis of data from admixed populations, allowing the effects of linkage and population structure (variation of admixture between individuals) to be distinguished. With more markers and a more complex statistical model, genes underlying ethnic differences in disease risk could be mapped by this approach.

Bayes Theorem↗
PubMed2000

Pharmacogenetic diagnostics of cytochrome P450 polymorphisms in clinical drug development and in drug treatment.

The current use and future perspectives of molecular genetic characterisation of cytochrome P450 enzymes (CYP) for drug development and drug treatment are summarised. CYP genes are highly polymorphic and the enzymes play a key role in the elimination of the majority of drugs from the human body. Frequent variants of some enzymes, CYP2A6, 2C9, 2C19 and 2D6, should be analysed in participants of clinical trials whenever these enzymes may play a role. It is suggested that a CYP genotype certificate is handed out to the volunteers or patients to avoid replicate analyses, and to allow that this information is available for future research and also for treatment with eventually needed drugs. Guidelines on what CYP alleles have to be analysed in drug development, as well as on analytical validation and CYP genotype data handling will be required. Treatment with several drugs may be improved by prior genotyping. The concepts and problems of CYP genotype-based clinical dose recommendations are presented and illustrated for selected drugs. The requirement for prospective trials on the medical and economic benefits of routine CYP genotyping is emphasised. Specific operationally defined recommendations dependent on genotype are a prerequisite for such studies and this review presents tentative CYP genotype-based dose recommendations systematically calculated from published data. Because of the multiplicity of factors involved, these doses will not be the optimal doses for each given individual, but should be more adequate than doses generally recommended for an average total population. Those CYP alleles and polymorphically metabolised drugs which are currently most interesting in drug development and drug treatment are reviewed, and more complete information is available from websites cited in this article.

Animals↗
PubMed1999

Quantitative trait loci for bone density in C57BL/6J and CAST/EiJ inbred mice.

Genetic analyses for loci regulating bone mineral density have been conducted in a cohort of F(2) mice derived from intercross matings of (C57BL/6J x CAST/EiJ)F(1) parents. Femurs were isolated from 714 4-month-old females when peak adult bone density had been achieved. Bone mineral density (BMD) data were obtained by peripheral quantitative computed tomography (pQCT), and genotype data were obtained by Polymerase Chain Reaction (PCR) assays for polymorphic markers carried in genomic DNA of each mouse. Genome-wide scans for co-segregation of genetic marker data with high or low BMD revealed loci on eight different chromosomes, four of which (Chrs 1, 5, 13, and 15) achieved conservative statistical criteria for suggestive, significant, or highly significant linkage with BMD. These four quantitative trait loci (QTLs) were confirmed by a linear regression model developed to describe the main effects; none of the loci exhibited significant interaction effects by ANOVA. The four QTLs have been named Bmd1 (Chr 1), Bmd2 (Chr 5), Bmd3 (Chr 13), and Bmd4 (Chr 15). Additive effects were observed for Bmd1, recessive for Bmd3, and dominant effects for Bmd2 and Bmd4. The current large size of the QTL regions (6-->31 cM) renders premature any discussion of candidate genes at this time. Fine mapping of these QTLs is in progress to refine their genetic positions and to evaluate human homologies.

Age Factors↗
PubMed1995

Isolation and characterization of Rhodovulum strictum sp. nov. and some other purple nonsulfur bacteria from colored blooms in tidal and seawater pools.

Several strains of phototrophic purple nonsulfur bacteria were isolated from colored blooms occurring in tidal and seawater pools in Japan. All of these isolates had ovoid to rod-shaped cells that were motile by means of single polar flagella and contained vesicular intracytoplasmic membranes together with bacteriochlorophyll a and carotenoids of the spheroidene series. They produced ubiquinone 10 as the major quinone and contained straight-chain fatty acids, with C18:1 predominating. They were mesophilic, halophilic, and photoheterotrophic, utilized sulfide and thiosulfate as electron donors for phototrophic growth, and photoassimilated a wide variety of organic compounds as carbon sources. Our results suggested that all of these isolates are members of the recently described genus Rhodovulum. The isolates were classified into four groups (designated groups I through IV) on the basis of phenotypic and genotypic data. The group I isolates, which were the most abundant purple nonsulfur bacteria recovered from the blooms, grew in the presence of NaCl concentrations ranging from 0.5 to 3.0% (optimum NaCl concentration, 0.8%) and at pH values ranging from 7.5 to 9.0 (optimum pH, 8.0 to 8.5). On the basis of these unique physiological traits, together with genotypic and phylogenetic data, we propose that the group I isolates should be classified as members of a new species, Rhodovulum strictum. The group II isolates were identified definitely as Rhodovulum sulfidophilum, and the group III and IV isolates were phenotypically most similar to R. sulfidophilum and Rhodovulum adriaticum, respectively, but could be differentiated from these species by DNA-DNA pairing data.

Bacteria↗
PubMed1998

Genetic studies on chromosome 12 in late-onset Alzheimer disease.

CONTEXT: The only genetic locus universally accepted to be important as a risk factor for late-onset Alzheimer disease (AD) is the apolipoprotein E (APOE) locus on chromosome 19. However, this locus does not account for all the risk in late-onset disease, and a recent report has suggested a second locus on chromosome 12p11-12. OBJECTIVE: To look for evidence of linkage on chromosome 12 and to test for the presence of the new locus in an independent sample of familial late-onset AD cases. DESIGN: Retrospective cohort study. As part of a 20-centimorgan genome screen (approximately equal to 200 markers), we tested a series of 18 genetic markers on chromosome 12 and carried out multipoint, nonparametric lod score and exclusion analyses. SETTING: Clinic populations in the continental United States selected from the National Institute of Mental Health AD Genetics Consortium. PATIENTS: We selected samples for DNA analysis from affected sibling pairs, 497 subjects from 230 families with 2 or more affected individuals with probable or definite AD with onset ages older than 60 years (mean+/-SD, 75+/-6 years). Within the families, we used the 2 probable or definitely affected individuals. In families with more than 2 such cases available, we used all of them; in families with only 2 such cases in which unaffected individuals were available, we also sampled the oldest unaffected individual and used genotype data from this unaffected individual to check for nonpaternity and genotyping errors. MAIN OUTCOME MEASURE: Presence of linkage or locus on chromosome 12. RESULTS: Although linkage analyses confirmed the presence of a genetic susceptibility factor at the APOE locus in these families with late-onset AD, we were unable to confirm the presence of a locus close to the marker D12S1042. A moderate lod score (1.91) was found near D12S98 close to the alpha2-macroglobulin locus in the affected pairs in which both members did not possess an APOE epsilon4 allele. CONCLUSIONS: APOE remains the only locus established to be a risk factor for late-onset AD. We were unable to confirm that a locus on chromosome 12p11-12 has a major effect on risk for late-onset AD, although an effect smaller than that for APOE cannot be excluded.

Age of Onset↗
PubMed2005

Phylogenetic analysis of classical swine fever virus (CSFV) field isolates from outbreaks in South and Central America.

To date, there is little information concerning the epidemiological situation of classical swine fever (CSF) in the Americas. Besides summarizing the available data, genotyping of isolates from outbreaks in domestic pigs in several countries of South and Central America was performed. For this, a 190 base fragment of the E2 envelope glycoprotein gene was used. European strains and isolates, and historical isolates from the United States (US) were included for comparison. In contrast to the situation in most parts of Europe, where group 2 isolates predominate, it was found that all the isolates from the American continent analyzed belonged to group 1 and were further resolved into three subgroups. The Cuban isolates clustered in subgroup 1.2, whereas the isolates from Honduras and Guatemala clustered in subgroup 1.3. The remaining isolates from Argentina, Brazil, Colombia and Mexico generated four poorly resolved clusters in subgroup 1.1, together with the vaccine strains, with historical European and US isolates, and with a recent Russian isolate. While the vaccine strains and the historical European isolates formed a relatively distinct cluster, one of the US isolates clustered together with the Mexican, and another one with Colombian isolates. Historically, CSF (hog cholera) was observed almost simultaneously in the US and in Europe in the first half of the 19th century, and its origin remains a matter of discussion. Our results showed that the US isolates are closely related to isolates from South America, while appearance of isolates in Cuba on one hand and in Honduras and Guatemala on the other hand, seems to have been due to unrelated events. This allows to speculate that at least in the American continent, CSF virus may have appeared independently in several regions, and spreading may have been a secondary effect.

Animals↗
PubMed2003

Power evaluations for family-based tests of association with incomplete parental genotypes.

While a variety of methods have been developed to deal with incomplete parental genotype information in family-based association tests, sampling design issues with incomplete parental genotype data still have not received much attention. In this article, we present simulation studies with four genetic models and various sampling designs and evaluate power in family-based association studies. Efficiency depends heavily on disease prevalence. With rare diseases, sampling affecteds and their parents is preferred, and three sibs will be required to have close power if parents are unavailable. With more common diseases, sampling affecteds and two sibs will generally be more efficient than trios. When parents are unavailable, siblings need not be phenotyped if the disease is rare, but a loss of power will result with common diseases. Finally, for a class of complex traits where other genetic and environmental factors also cause phenotypic correlation among siblings, little loss of efficiency occurs to rare disease, but substantial loss of efficiency occurs to common disease.

Data Interpretation, Statistical↗
PubMed2006

Vitamin D receptor gene polymorphisms and susceptibility of hand osteoarthritis in Finnish women.

We examined whether polymorphisms of the vitamin D receptor (VDR) gene was associated with individual risk of hand osteoarthritis (OA). Radiographs of both hands of 295 dentists and of 248 teachers were examined and classified for the presence of OA using reference images. The VDR ApaI and TaqI genotypes were determined by PCR-based methods. No association was observed between the VDR polymorphisms and the odds of overall hand OA. However, the carriers of the VDR t allele or At haplotype were at almost half the odds of symmetrical hand OA (odds ratio [OR] = 0.60, 95% confidence interval [CI] = 0.38-0.94 and OR = 0.59, 95% CI = 0.38-0.93, respectively) compared with the carriers of the T allele and of the non-At haplotype, respectively. Increased odds of this disease, on the contrary, was observed for women with two copies of the VDR a allele (OR = 1.93, 95% CI = 1.99-3.70) compared with women with the AA genotype. Conversely, the VDR a allele carriage was associated with a tendency of lowered odds of osteophyte (OR = 0.51, 95% CI = 0.25-1.03). When the genotype data were used to construct haplotypes, the VDR AaTt joint genotype appeared to pose a remarkably lower odds (OR = 0.26, 95% CI = 0.08-0.91) of osteophyte compared with the AAtt joint genotype. As a novel finding we observed a joint effect of a low calcium intake and VDR polymorphisms on symmetrical OA; the OR was 2.64 (95% CI = 1.29-5.40) for carriers of the aT haplotype with low daily calcium intake compared with non-carriers of the haplotype with high daily calcium intake. Our results suggest that VDR gene polymorphisms play a role in the etiology of symmetrical hand OA. Moreover, the association between the VDR gene and OA may be modified by calcium intake.

Female↗
PubMed2006

Globally, CYP1B1 mutations in primary congenital glaucoma are strongly structured by geographic and haplotype backgrounds.

PURPOSE: To obtain a global perspective on the distribution and evolution of CYP1B1 mutations in primary congenital glaucoma (PCG) worldwide. METHODS: Five intragenic single-nucleotide polymorphisms in CYP1B1-R48G, A119S, V432L, D449D, and N453S-were used to generate haplotype data from 138 Indian patients with PCG and 132 ethnically matched normal controls, which were then analyzed in conjunction with data from other populations. Maximum-likelihood estimates of haplotype frequencies were estimated from the genotype data. Subsets of patients and normal control subjects were also genotyped with respect to eight short tandem repeat (STR) markers around the CYP1B1 locus (D2S305, D2S165, D2S367, D2S2259, D2S391, D2S3337, D2S23678, and D2S286), to gain evolutionary insights. RESULTS: Common mutations in CYP1B1 that are causal of PCG occurred on a uniform haplotype background among Indian patients, which is completely distinct from the modal haplotype background found among unaffected control subjects. Comparison of these data with data from other global regions reveals strong clustering of CYP1B1 mutations by geographic and haplotype backgrounds. The two distinct modal haplotypes found among Indian patients with PCG and control subjects are both ancient with ages of similar magnitudes, as indicated by large variances in the number of repeats at eight STR loci. Together with data from chimpanzee and normal control subjects from India and other global regions, it was possible to make a parsimonious reconstruction of the evolution of these haplotypes. CONCLUSIONS: The strong association of specific haplotypes with some predominant CYP1B1 mutations underlying PCG and the observed geographical clustering, probably due to founder effects, may be useful for predictive testing.

Africa↗