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PubMed2004

Sporadic cryptosporidiosis case-control study with genotyping.

We report a case-control study of sporadic cryptosporidiosis with genotyping of isolates from case-patients. A postal questionnaire was completed by 427 patients and 427 controls. We obtained genotyping data on isolates from 191 patients; 115 were Cryptosporidium hominis, and 76 were C. parvum. When all cryptosporidiosis cases were analyzed, three variables were strongly associated with illness: travel outside the United Kingdom, contact with another person with diarrhea, and touching cattle. Eating ice cream and eating raw vegetables were both strongly negatively associated with illness. Helping a child <5 years of age to use the toilet and the number of glasses of tap water drunk at home each day were also independently positively associated with risk. Eating tomatoes was negatively associated. For C. hominis infections, the strongly significant risk factors were travel abroad and changing diapers of children <5 years of age. For C. parvum, eating raw vegetables and eating tomatoes were strongly negatively associated with illness; touching farm animals was associated with illness.

Adolescent↗

PubMed1985

High frequency of nonclassical steroid 21-hydroxylase deficiency.

Nonclassical steroid 21-hydroxylase deficiency is an autosomal recessive disorder that is defined by clinical and hormonal criteria that distinguishes it from the classical 21-hydroxylase deficiency. No estimates of the gene frequency of nonclassical 21-hydroxylase deficiency, also called attenuated, late-onset, acquired, and cryptic adrenal hyperplasia, have been published thus far. Here, we have used HLA-B genotype data in families containing multiple members affected with nonclassical 21-hydroxylase deficiency together with the results of quantitative hormonal tests to arrive at estimates of gene and disease frequencies for this disorder. We found nonclassical 21-hydroxylase deficiency to be a far more common disorder than classical 21-hydroxylase deficiency, which occurs in 1/8,000 births. The prevalence of the disease in Ashkenazi Jews was 3.7%; in Hispanics, 1.9%; in Yugoslavs, 1.6%; in Italians, 0.3%; and in the diverse Caucasian population, 0.1%. The gene for nonclassical 21-hydroxylase deficiency is in genetic linkage disequilibrium with HLA-B14 in Ashkenazi Jews, Hispanics, and Italians, but not in Yugoslavs or in a diverse, non-Jewish, Caucasian group. The penetrance of nonclassical 21-hydroxylase deficiency gene in the HLA-B14 containing haplotypes was incomplete. Thus, nonclassical 21-hydroxylase deficiency is probably the most frequent autosomal recessive genetic disorder in man and is especially frequent in Ashkenazi Jews, Hispanics, Italians, and Yugoslavs.

Adrenal Hyperplasia, Congenital↗

PubMed2006

A new method of estimating the pollen dispersal curve independently of effective density.

We introduce a novel indirect method of estimating the pollen dispersal curve from mother-offspring genotypic data. Unlike an earlier indirect approach (TwoGener), this method is based on a normalized measure of correlated paternity between female pairs whose expectation does not explicitly depend on the unknown effective male population density (d(e)). We investigate the statistical properties of the new method, by comparison with those of TwoGener, considering the sensitivity to reductions of d(e), relative to census density, resulting from unequal male fecundity and asynchronous flowering. Our main results are: (i) it is possible to obtain reliable estimates of the average distance of pollen dispersal, delta, from indirect methods, even under nonuniform male fecundity and variable flowering phenology; (ii) the new method yields more accurate and more precise delta-estimates than TwoGener under a wide range of sampling and flowering scenarios; and (iii) TwoGener can be used to obtain approximate d(e) estimates, if needed for other purposes. Our results also show that accurately estimating the shape of the tail of the pollen dispersal function by means of indirect methods remains a very difficult challenge.

Flowers↗

PubMed2005

Accounting for haplotype uncertainty in matched association studies: a comparison of simple and flexible techniques.

Population-based case-control studies measuring associations between haplotypes of single nucleotide polymorphisms (SNPs) are increasingly popular, in part because haplotypes of a few "tagging" SNPs may serve as surrogates for variation in relatively large sections of the genome. Due to current technological limitations, haplotypes in cases and controls must be inferred from unphased genotypic data. Using individual-specific inferred haplotypes as covariates in standard epidemiologic analyses (e.g., conditional logistic regression) is an attractive analysis strategy, as it allows adjustment for nongenetic covariates, provides omnibus and haplotype-specific tests of association, and can estimate haplotype and haplotype x environment interaction effects. In principle, some adjustment for the uncertainty in inferred haplotypes should be made. Via simulation, we compare the performance (bias and mean squared error of haplotype and haplotype x environment interaction effect estimates) of several analytic strategies using inferred haplotypes in the context of matched case-control data. These strategies include using only the most likely haplotype assignment, the expectation substitution approach described by Stram et al. ([2003b] Hum. Hered. 55:179-190) and others, and an improper version of multiple imputation. For relatively uncomplicated haplotype structures and moderate haplotype relative risks (</=2), all methods performed comparably well (small bias with appropriately-sized confidence intervals). For larger relative risks, the most likely haplotype and multiple imputation strategies showed noticeable bias towards the null; the expectation substitution strategy still performed well. When there was more uncertainty in the inferred haplotypes, the most likely and multiple imputation strategies showed even more bias towards the null, while the expectation substitution method had slightly smaller than nominal confidence intervals for larger relative risks (>/=5). An application to progesterone-receptor haplotypes and endometrial cancer further illustrates that the performance of all these methods depends on how well the observed haplotypes "tag" the unobserved causal variant.

Algorithms↗

PubMed2026

Diet-responsive proteogenomic effects following short-term restriction of animal products in humans.

The effect of diet on genetic regulation in humans remains largely unexplored. Here, we investigate gene-diet interactions in a unique group of healthy individuals (N = 200) who alternate between omnivory and dietary restriction of animal products for religious reasons. Using longitudinal proteomic and genotype data, we identify diet-responsive cis-pQTLs and highlight regulatory effects on LBR and MSRA, proteins involved in cholesterol and methionine metabolism respectively. LBR-associated cis-pQTL rs74148404 colocalizes with obesity exclusively under dietary restriction, suggesting diet-dependent modulation of genetic risk. We also show that a diet-dependent cis-pQTL for metabolic regulator FGF21 colocalizes with eosinophil and platelet traits pointing to diet-sensitive immunometabolic signalling. By parallel profiling of a continuously omnivorous control group (N = 211), we uncover seasonally dynamic genetic regulation for proteins linked to apoptosis in immune system pathways (MAVS, CASP3, PDLIM7, IL12RB1), effects likely masked by animal product restriction. These findings reveal dynamic diet- and season-sensitive regulatory mechanisms with implications for precision nutrition and individualized disease prevention strategies, and underscore the need to integrate environmental context into genetic studies of health and disease.

Humans↗

PubMed2004

Comparison of prospective and retrospective methods for haplotype inference in case-control studies.

We compare bias and power of three methods for haplotype inference on disease risk using unphased genotype data from a case-control study. We examine the prospective score test of Schaid et al., a novel modification of the prospective estimating equations of Zhao et al. and the retrospective likelihood of Epstein and Satten. We find that all three approaches are roughly comparable when the haplotype effect on disease odds follows a multiplicative model. However, for dominant and recessive models of haplotype effect, the retrospective-likelihood method has increased efficiency with respect to the prospective methods. As all three methods assume haplotype frequencies are in Hardy-Weinberg Equilibrium (HWE), we compare the robustness of each procedure to departures from HWE. We find the prospective methods are robust to departure from HWE, while the retrospective-likelihood method is biased for dominant and recessive models of haplotype effect. To remedy this limitation of the retrospective-likelihood method, we propose a modification that allows for a non-negative fixation index (common to all haplotype pairs) and show it dramatically reduces the bias of the retrospective likelihood when HWE is violated.

Algorithms↗

PubMed2007

Clonal and parallel evolution of primary lung cancers and their metastases revealed by molecular dissection of cancer cells.

PURPOSE: Several models of cancer progression, including clonal evolution, parallel evolution, and same-gene models, have been proposed to date. The purpose of this study is to investigate the authenticity of these models by comparison of accumulated genetic alterations between primary and corresponding metastatic lung cancers. EXPERIMENTAL DESIGN: A whole-genome allelic imbalance scanning using a high-resolution single nucleotide polymorphism array and mutational analysis of the p53, EGFR, and KRAS genes were done on eight sets of primary and metastatic lung cancers. Based on the genotype data, the natural history of each case was deduced, and candidate metastasis suppressor loci were determined. RESULTS: Five to 20 chromosomal regions showed allelic imbalance in each tumor. Accumulated genetic alterations were similar between primary and corresponding metastatic tumors, and the majority(>67%) of genetic alterations detected in metastatic tumors was also detected in the corresponding primary tumors. On the other hand, in seven of the eight cases, there were genetic alterations accumulated only in metastatic tumors. Among these alterations, allelic imbalances at chromosome 11p15 and 11p11-p13 regions were the most frequent ones (4 of 8, 50%). Likewise, four cases showed genetic alterations detected only in primary tumors. CONCLUSIONS: The natural history of each case indicated that the process of metastasis varies among cases, and that all three models are applicable to lung cancer progression. According to the clonal and parallel evolution models, it is possible that a metastasis suppressor gene(s) for lung cancer is present on chromosome 11p.

Adult↗

PubMed2003

Genome-wide mapping of human loci for essential hypertension.

BACKGROUND: Blood pressure may contribute to 50% of the global cardiovascular disease epidemic. By understanding the genes predisposing to common disorders such as human essential hypertension we may gain insights into novel pathophysiological mechanisms and potential therapeutic targets. In the Medical Research Council BRItish Genetics of HyperTension (BRIGHT) study, we aim to identify these genetic factors by scanning the human genome for susceptibility genes for essential hypertension. We describe the results of a genome scan for hypertension in a large white European population. METHODS: We phenotyped 2010 affected sibling pairs drawn from 1599 severely hypertensive families, and completed a 10 centimorgan genome-wide scan. After rigorous quality control, we analysed the genotypic data by non-parametric linkage, which tests whether genes are shared in excess among the affected sibling pairs. Lod scores, calculated at regular points along each chromosome, were used to assess the support for linkage. FINDINGS: Linkage analysis identified a principle locus on chromosome 6q, with a lod score of 3.21 that attained genome-wide significance (p=0.042). The inclusion of three further loci with lod scores higher than 1.57 (2q, 5q, and 9q) also show genome-wide significance (p=0.017) when assessed under a locus-counting analysis. INTERPRETATION: These findings imply that human essential hypertension has an oligogenic element (a few genes may be involved in determination of the trait) possibly superimposed on more minor genetic effects, and that several genes may be tractable to a positional cloning strategy.

Chromosome Mapping↗

PubMed2000

Comprehensive analysis of the renin-angiotensin gene polymorphisms with relation to hypertension in the Japanese.

BACKGROUND: Components of the renin-angiotensin (R-A) system have been repeatedly investigated as candidate genes for essential hypertension. In particular, suggestive or significant association has been detected in some studies for the angiotensinogen M235T, angiotensin I-converting enzyme I/D, angiotensin II type 1 receptor A1166C, and aldosterone synthase C-344T polymorphisms, although the results remain inconclusive. OBJECTIVE AND METHODS: To evaluate the importance of these candidate genes for hypertension, we undertook an extensive association study in the Japanese. This case-control study was conducted in a total of 1476 individuals using the four R-A gene polymorphisms. In the assessment of genotyping data, 843 hypertensive subjects were divided into three case subgroups according to severity of hypertension, while 633 normotensive subjects divided into two control subgroups by the age of enrollment. Each subgroup was further divided by sex. Subsequently, the presence of synergy (or gene-gene interaction) was evaluated among four R-A gene polymorphisms. RESULTS: No significant association was observed between the individual R-A gene polymorphisms and hypertension status in our case-control study. The results were almost unchanged when severity of hypertension, sex-specificity, and synergy were taken into account CONCLUSIONS: Despite a relatively large number of subjects, we did not find significant evidence for disease association in the Japanese population. Given confounding factors in the case-control strategy, the lack of association does not exclude the relevance of the R-A genes to hypertension. Further investigation needs to be performed in large-scale populations, where the use of not only hypertension status, but also 'intermediate' phenotypes would be useful.

Angiotensin II↗

PubMed2000

Absence of zidovudine resistance in antiretroviral-naive patients following zidovudine/lamivudine/protease inhibitor combination therapy: virological evaluation of the AVANTI 2 and AVANTI 3 studies.

OBJECTIVES: To assess the role of resistance mutations in subjects experiencing virological failure on zidovudine (ZDV) and lamivudine (3TC) combined with a protease inhibitor (PI) to those failing on ZDV/3TC alone. DESIGN AND METHODS: Samples were obtained from previously antiretroviral therapy-naive subjects enrolled into two studies, AVANTI 2 and AVANTI 3. Subjects were randomized to receive either: ZDV/3TC or ZDV/3TC plus indinavir (IDV) for 52 weeks (AVANTI 2), and ZDV/3TC or ZDV/3TC and nelfinavir (NFV) for 28 weeks (AVANTI 3). Emergence of viral resistance mutations was monitored by population sequencing and phenotypic resistance was determined by the recombinant virus assay. RESULTS: Genotypic data were obtained for subjects with plasma HIV-1 RNA > 400 copies/ml. In AVANTI 2, ZDV mutations were detected in 27% of ZDV/3TC-treated patients at week 52, but were absent in subjects treated with ZDV/3TC/IDV. No subjects from either arm of AVANTI 3 developed ZDV resistance mutations at week 28. The M184V mutation developed in most ZDV/3TC-treated subjects from both studies. The presence of M184V was, however, associated with significantly lower plasma viral RNA levels when compared with values obtained before initiation of treatment. There was a high frequency (4 of 11) of the protease L10F substitution in ZDV/3TC/IDV-treated patients that was associated with virological failure but did not result in phenotypic resistance to any of the PIs tested. CONCLUSIONS: ZDV mutations were not detected in ZDV/3TC/PI-treated patients and they developed slowly in those treated with ZDV/3TC. Few protease mutations known to confer phenotypic PI resistance developed in the ZDV/3TC/PI arms of either study. The low prevalence of ZDV and PI mutations is encouraging regarding the future treatment options of these patients.

Adult↗

PubMed2005

Population structure of group B streptococcus from a low-incidence region for invasive neonatal disease.

The population structure of group B streptococcus (GBS) from a low-incidence region for invasive neonatal disease (Israel) was investigated using multilocus genotype data. The strain collection consisted of isolates from maternal carriage (n=104) and invasive neonatal disease (n=50), resolving into 46 sequence types. The most prevalent sequence types were ST-1 (17.5 %), ST-19 (10.4 %), ST-17 (9.7 %), ST-22 (8.4 %) and ST-23 (6.5 %). Serotype III was the most common, accounting for 29.2 % of the isolates. None of the serotypes was significantly associated with invasive neonatal disease. burst analysis resolved the 46 sequence types into seven lineages (clonal complexes), from which only lineage ST-17, expressing serotype III only, was significantly associated with invasive neonatal disease. Lineage ST-22 expressed mainly serotype II, and was significantly associated with carriage. The distribution of the various sequence types and lineages, and the association of lineage ST-17 with invasive disease, are consistent with the results of analyses from a global GBS isolate collection. These findings could imply that the global variation in disease incidence is independent of the circulating GBS populations, and may be more affected by other risk factors for invasive GBS disease, or by different prevention strategies.

Carrier State↗

PubMed1996

Impact of sample selection on APOE epsilon 4 allele frequency: a comparison of two Alzheimer's disease samples.

OBJECTIVE: In a highly selected sample of unrelated Alzheimer's disease (AD) patients, we found that the APOE epsilon 4 allele frequency was higher than previously reported. Differing selection and ascertainment criteria may lead to these differences. To address this possibility, we compared the epsilon 4 allele frequency in two samples of AD patients selected from the same geographical area. SETTING AND PARTICIPANTS: Cases (n = 55) and controls (n = 99) from a research clinic-based sample were compared with subjects (n = 537) from a community-based AD patient sample. The samples consisted of unrelated cases who met NINCDS/ADRDA criteria for probable AD. DESIGN AND MEASUREMENTS: Clinical characteristics and APOE genotype data were obtained from AD cases and controls from both samples. RESULTS: Frequency of APOE epsilon 4 allele in the research cases compared with the community cases (0.45 vs 0.36) was nearly significant. We compared demographic and clinical characteristics that might account for this difference and found that the research cases were younger, had an earlier age of onset, and had more advanced disease than the community cases. After onset age was controlled, there was no overall difference between epsilon 4 allele frequency of the two samples. CONCLUSIONS: We found that the epsilon 4 allele frequency tended to be higher in the research AD sample compared the community-based sample. The two samples differed in several demographic and clinical characteristics. We conclude that research-based samples may lead to enrollment of younger patients with more severe disease who have higher APOE epsilon 4 allele load. This potential selection bias must be considered in the interpretation of studies of APOE allele frequency.

Age of Onset↗

PubMed1996

Linkage of autosomal dominant radial drusen (malattia leventinese) to chromosome 2p16-21.

OBJECTIVE: To identify the chromosomal location of the gene involved in the pathogenesis of autosomal dominant radial drusen (malattia leventinese). PATIENTS: Eighty-six members of four families affected with radial drusen; one family of American origin and three families of Swiss origin. METHODS: Family members were clinically examined for the presence of radial drusen. Affected patients and potentially informative spouses were genotyped with short tandem repeat polymorphisms distributed across the autosomal genome. The clinical and genotypic data were subjected to linkage analysis. RESULTS: Fifty-six patients were found to be clinically affected. Significant linkage was observed between the disease phenotype and markers known to lie on the short arm of chromosome 2. The maximum two-point lod score (Zmax) observed for all four families combined was 10.5 and was obtained with marker D2S378. Multipoint analysis yielded a Zmax of 12, centered on marker D2S378. The lod-1 confidence interval was 8 cM, while the disease interval defined by observed recombinants was 14 cM. CONCLUSIONS: The gene responsible for autosomal dominant radial drusen has been mapped to the short arm of chromosome 2. This is an important step toward actually isolating the disease-causing gene. In addition, this information can be used to evaluate other familial drusen phenotypes such as Doyne's macular dystrophy for a possible allelic relationship.

Adolescent↗

PubMed2003

Quantitative trait loci for femoral size and shape in a genetically heterogeneous mouse population.

UNLABELLED: The aim of this study was to examine the genetic effects on cortical bone geometry. Genotypes from 487 mice were compared with geometric traits obtained from microCT. We found 14 genetic markers that associate with geometric traits, showing the complexity of genetic control over bone geometry. INTRODUCTION: Previous studies have shown that genetic background affects bone characteristics, particularly bone mineral density, in both mouse and human populations. Much less is known, however, about the effects of polymorphic genes on bone size, shape, and mechanical integrity. In this study, we investigated the genetic determinants of geometric properties of cortical bone in mice. MATERIALS AND METHODS: This study used a genetically heterogeneous mouse population, which is denoted UM-HET3 stock and is derived as the progeny of (BALB/cJ X C57BL/6J) F1 females and (C3H/HeJ X DBA/2J) F1 males. The experimental group consisted of 487 female UM-HET3 mice. Genotypic data from 99 polymorphic genetic loci was obtained from the mice at 4 weeks of age. At 18 months of age, the mice were humanely killed, and the right femurs were scanned with microcomputed tomography to assess geometric properties of cortical bone. A permutation-based test was used to detect significant associations between genetic markers and geometric traits. This test generates experiment-wise p values, which account for the effect of testing multiple hypotheses. An experiment-wise p < or = 0.05 was considered statistically significant. RESULTS: Fourteen genetic markers were found to significantly associate with one or more geometric traits. Two markers (D3Mit62 and D4Mit155) were associated with traits describing bone size; 2 (D12Mit167 and D14Mit170) were linked with traits describing bone shape; and 10 (D1Nds2, D5Mit95, D6Mit216, D7Mit91, D8Mit51, D9Mit110, D11Mit83, D15Mit100, D15Mit171, and D17Mit46) were associated with both size and shape. CONCLUSIONS: Our results indicate that the genetic control of cortical bone geometry is complex and that femoral size and shape may be influenced by different, although overlapping, groups of polymorphic loci.

Animals↗

PubMed2003

Investigation of interaction between N-acetyltransferase 2 and heterocyclic amines as potential risk factors for colorectal cancer.

Fast N-acetyltransferase 2 (NAT2) acetylators may be at increased risk of colorectal cancer through the activation of carcinogenic heterocyclic amines (HA), which are produced by meat cooked at high temperatures and are found in cigarette smoke. A study of 500 incident colorectal cancer cases and population controls, matched for age, sex and general practitioner, was conducted in the UK to investigate this hypothesis. Usual meat intake and lifetime smoking habits were estimated using a detailed questionnaire administered by interview. Subjects also indicated how well cooked they ate their meat. Subjects were classified as fast or slow NAT2 acetylators on the basis of NAT2 genotype. Complete genotype data were available on 433 matched pairs. The risk of colorectal cancer showed a steady increase with meat intake, rising to an odds ratio of 1.51 [95% confidence interval (1.03, 2.23)] for the highest versus the lowest quartile, after adjustment for total energy intake, and this was even more pronounced for red meat [odds ratio 1.97 (1.30, 2.98)]. However, this effect was not influenced by the preference for well-done meat. Smoking was also associated with an increased risk [odds ratio 1.47 (1.10, 1.98) for ever- versus never-smokers]. In both cases and controls approximately 40% of subjects were classified as fast acetylators, and the risks associated with (red) meat intake and smoking did not vary with NAT2 status. This study provides no support for the hypothesis that fast NAT2 acetylators are at increased risk of colorectal cancer, even if exposed to high levels of HA from well-cooked meat or smoking.

Aged↗

PubMed2004

Ala45Thr polymorphism of the NEUROD1 gene and diabetes susceptibility: a meta-analysis.

A meta-analysis assessed whether the Ala45Thr polymorphism of the neurogenic differentiation 1 (NEUROD1) gene is associated with increased risk of diabetes mellitus type 1 (T1D) or type 2 (T2D). Fourteen case-control studies were analyzed, including genotype data on 3,057 patients with diabetes (T1D n=1,213, T2D n=1,844) and 2,446 controls. Overall and race-specific summary odds ratios (ORs) were obtained with fixed and random effects models. The Thr allele did not significantly increase the overall risk for T1D (OR 1.27 [0.94-1.71], P=0.12) or T2D (OR 1.07 [0.90-1.28], P=0.46). The Thr allele conferred increased susceptibility in subjects of Asian racial descent to T1D (OR 1.88 [1.10-3.21], P=0.020), but not to T2D (OR 1.08 [0.74-1.56], P=0.70). There was no association in subjects of European descent (OR 0.97 [0.76-1.23], P=0.80 for T1D; OR 1.03 [0.88-1.21], P=0.68 for T2D). Larger studies seemed to show more conservative estimates for the association with T1D (P=0.083). The Ala45Thr polymorphism of the NEUROD1 gene has no effect on susceptibility to T2D. It may however be a risk factor for susceptibility to T1D, in particular for subjects of Asian descent, although bias cannot be totally excluded.

Adolescent↗

PubMed2006

Phaeochromocytoma, new genes and screening strategies.

Following recent advances in the genetics of phaeochromocytomas and paragangliomas, the members of the European Network for the Study of Adrenal Tumours (ENS@T) Phaeochromocytoma Working Group have decided to share their genotyping data and to propose European recommendations for phaeochromocytoma/functional paraganglioma (PH/FPGL) genetic testing. Germline DNA from 642 patients was analysed by ENS@T teams. In 166 patients (25.9%) the disease was familial and caused by germline mutations in VHL (56), SDHB (34), SDHD (31), RET (31) or NF1 (14), causing von Hippel-Lindau disease, SDHB- or SDHD-PH/FPGL syndromes, multiple endocrine neoplasia type 2 (MEN 2) and type 1 neurofibromatosis (NF1), respectively. In almost 60% of inherited cases it was possible to formulate a probable genetic diagnosis based on family history and/or typical syndromic presentation. Genetic testing revealed mutations in 12.7% of cases with an apparently sporadic presentation. Several clinical characteristics, such as young age at onset, the presence of bilateral, extra-adrenal or multiple tumours or a malignant tumour, should be seen as indications for genetic testing. The ENS@T Phaeochromocytoma Working Group recommends the genetic testing of all patients with PH and FPGL and suggests a practice algorithm for the management of their exploration.

Adrenal Gland Neoplasms↗

PubMed2005

Genetic origin of lupus in NZB/SWR hybrids: lessons from an intercross study.

OBJECTIVE: (SWR x NZB)F(1) (or SNF(1)) hybrid mice succumb to lupus nephritis. A previous analysis of SNF(1) x NZB backcross mice revealed the existence of 4 SWR loci (H2 on chromosome 17, Swrl-1 on chromosome 1, Swrl-2 on chromosome 14, and Swrl-3 on chromosome 18) and 2 NZB loci (Nba1 and Lbw2/Sbw2, both on chromosome 4). A second study focusing on SNF(1) x SWR backcross offspring uncovered 5 suggestive loci for antinuclear antibody formation, consisting of 3 dominant NZB contributions (Nba4 on chromosome 5, Lbw4 on chromosome 6, and Nba5 on chromosome 7) and 2 recessive SWR contributions (Swrl-1 on chromosome 1 and Swrl-4 on chromosome 10). The present intercross study was executed to replicate the earlier findings, using an independent panel of (SWR x NZB)F(2) offspring. METHODS: A panel of (NZB x SWR)F(2) hybrids were phenotyped (for renal disease, early mortality, and a variety of autoantibodies) and genotyped (using 95 microsatellite primers positioned across all 19 autosomes and the X chromosome). Linkage analysis was conducted using the derived phenotype and genotype data, with the interval-mapping program MapManager. RESULTS: Four suggestive loci were mapped: Swrl-5 on chromosome 1 (peak at 106 cM), linked to hypergammaglobulinemia; an NZB locus on chromosome 5 (Nba4; peak at 15 cM), linked to IgG anti-single-stranded DNA (anti-ssDNA) antibodies, IgG anti-doubled-stranded DNA (anti-dsDNA) antibodies, and glomerulonephritis; an NZB locus on chromosome 13 (Nba6; peak at 28 cM), linked to IgG anti-dsDNA antibodies; and an SWR locus on chromosome 14 (Swrl-2; peak at 30 cM), linked to IgG anti-ssDNA antibodies. Eight additional loci revealed linkage at P < 0.01, of which 7 co-mapped with lupus susceptibility loci previously identified in other models. CONCLUSION: Considering all 3 mapping studies together, lupus in SWR/NZB hybrids appears to be the epistatic end product of several distinct loci, of which 3 SWR-derived loci (Swrl-1, Swrl-2, and Swrl-3) and 5 NZB-derived loci (Nba1, Nba3, Nba4, Nba5, and Lbw4) have been independently confirmed. The immunologic functions and molecular identities of these loci await elucidation.

Animals↗