Evaluation of a SNP map of 6q24–27 confirms diabetic nephropathy loci and identifies novel associations in type 2 diabetes patients with nephropathy from an African-American population

Previously, we performed a genome scan for type 2 diabetes (T2DM) using 638 African-American (AA) affected sibling pairs from 247 families; non-parametric linkage analysis suggested evidence of linkage at 6q24–27 (LOD 2.26). To comprehensively evaluate this region, we performed a two-stage association study by first constructing a SNP map of 754 SNPs selected from HapMap on the basis of linkage disequilibrium (LD) in 300 AAT2DM end-stage renal disease (ESRD) subjects, 311 AA controls, 43 European American controls and 45 Yoruba Nigerian samples (Set 1). Replication analyses were conducted in an independent population of 283 AA T2DM-ESRD subjects and 282 AA controls (Set 2). In addition, we adjusted for the impact of admixture on association results by using ancestry informative markers (AIMs). In Stage 1, 137 (18.2%) SNPs showed nominal evidence of association (P < 0.05) in one or more of tests of association: allelic (n = 33), dominant (n = 36), additive (n = 29), or recessive (n = 34) genotypic models, and 2- (n = 47) and 3-SNP (n = 43) haplotypic analyses. These SNPs were selected for follow-up genotyping. Stage 2 analyses confirmed association with a predicted 2-SNP “risk” haplotype in the PARK2 gene. Also, two intergenic SNPs showed consistent genotypic association with T2DM-ESRD: rs12197043 and rs4897081. Combined analysis of all subjects from both stages revealed nominal associations with 17 SNPs within genes, including suggestive associations in ESR1 and PARK2. This study confirms known diabetic nephropathy loci and identifies potentially novel susceptibility variants located within 6q24–27 in AA. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Genome-wide association study of bronchial asthma in the Volga-Urals region of Russia

Bronchial asthma is a chronic inflammatory respiratory disease caused by a complex interaction of environmental influences and genetic susceptibility. The first genome-wide association study of bronchial asthma discovered a significant association between single nucleotide polymorphisms (SNPs) located within the genomic region 17q12-q21 and childhood bronchial asthma in individuals of European descent. This result was later replicated in a number of independent population samples of European and Asian origin. Here we report the results of the first genome-wide association study of bronchial asthma in the Volga-Urals region of Russia. The study involved 358 unrelated patients with physician-diagnosed bronchial asthma and 369 disease-free control subjects of different ethnicity (Russians, Tatars, and Bashkirs). DNA specimens were genotyped using an Illumina Human610 quad array as a part of the GABRIEL project (EC contract no. LSHB-CT-2006-018996). After QC filtering procedures, a final set of 550 915 SNPs genotyped in 330 patients and 348 controls was tested for association with bronchial asthma. Five markers on chromosome 17q12-21 showed significant association with bronchial asthma (p ≤ 4.79 × 10⁻⁷). The rs7216389 SNP located in GSDMB intron 1 showed the strongest evidence for association (p = 1.01 × 10⁻⁷). Association with childhood asthma (p = 1.97 × 10⁻⁶ for rs7216389) was stronger than with late-onset asthma (p = 1.8 × 10⁻⁴ for rs7216389). A replication study of three SNPs located within GSDMB confirmed association only with childhood asthma. In sum, these results suggest that genetic variants of 17q12–q21 play an important role in susceptibility to bronchial asthma in the Volga-Urals region of Russia.     

Genetic variants on 17q21 are associated with asthma in a Han Chinese population

A genome-wide study has shown an association between SNPs located on 17q21 and asthma. Such associations have been identified in several populations, but little is known about the Han Chinese population. We conducted a case-control study in a Han Chinese population to investigate the relationship between SNPs located on 17q21 and asthma; 241 asthmatic patients and 212 healthy controls were recruited from the outpatient clinics of the Nanfang Hospital, Guangdong Province, southern China. We genotyped six SNPs (rs8067378, rs8069176, rs2305480, rs4795400, rs12603332, and rs11650680) located on 17q21 with the Sequenom MassARRAY iPLEX platform. For two of these six loci (rs2305480 and rs8067378), there was evidence of association with asthma, and there was a weak association of asthma with rs8069176. We confirm that genetic variants on 17q21 are associated with asthma in the Han Chinese population.     

Family-based association analysis of theMAPT gene in Parkinson

The MAPT gene has been shown to be associated with several neurodegenerative disorders, including forms of parkinsonism and Parkinson disease (PD), but the results reveal population differences. We investigated the association of 10 single-nucleotide polymorphisms (SNPs) in the region ofMAPT on chromosome 17q21 with PD and age at onset, by using 443 discordant sib pairs in PD from a public dataset (Mayo-Perlegen LEAPS Collaboration). Association with PD was assessed by the FBAT using generalized estimating equations (FBAT-GEE), while the association with age at onset as a quantitative trait was evaluated using the FBAT-logrank statistic. Five SNPs were significantly associated with PD (P < 0.05) in an additive model, and 9 SNPs were associated with PD (P < 0.05) in dominant and recessive models. Interestingly, 8 PD-associated SNPs were also associated with age at onset of PD (P < 0.05) in dominant and recessive models. The SNP most significantly associated with PD and age at onset was rs17649641 (P = 0.015 and 0.021, respectively). Two-SNP haplotypes inferred from rs17563965 and rs17649641 also showed association with PD (P = 0.018) and age at onset (P = 0.026). These results provide further support for the role of MAPT in development of PD.     

Association of <Emphasis Type="Italic">ADAM33</Emphasis> gene polymorphisms with adult-onset asthma and its severity in an Indian adult population

ADAM33, a member of the ADAM (a disintegrin and metalloprotease) gene family, is an asthma susceptibility gene originally identified by positional cloning. In the present study, we investigated the possible association of five single-nucleotide polymorphisms (SNPs) in the ADAM33 (rs511898, rs528557, rs44707, rs597980 and rs2787094) with adult-onset asthma in an Indian population. The study included 175 patients with mild intermittent (n = 44), mild persistent (n = 108) or moderate persistent (n = 23) subgroups of asthma, and 253 nonasthmatic control individuals. SNPs were genotyped with the help of restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) method, and data were analysed using chi-square test and logistic regression model. Bonferroni’s correction for multiple comparisons was applied for each hypothesis. Genotypes and allele frequencies of SNPs rs511898 and rs528557 were significantly associated with adult-onset asthma (P = 0.010-<0.001). A significant association of the homozygous mutant genotype and mutant alleles of SNPs rs2787094, rs44707 and rs597980 with the asthma was also observed (P = 0.020-<0.001). A positive association between asthma and haplotypes AGCCT, GGCCT, AGACT, GCAGT, GGACT, ACCCC and AGACC were also found (P = 0.036-<0.001, OR = 2.07–8.49). Haplotypes AGCGT, GCAGC, ACAGC, ACAGT, GGAGC and GGCGT appear to protect against asthma (P = 0.013-<0.0001, OR = 0.34–0.10). Our data suggest that ADAM33 gene polymorphisms serve as genetic risk factors for asthma in Indian adult population.     

Genetic variation in CYP17 and endometrial cancer risk

Genetic variation in CYP17 is suspected to be related to endometrial cancer risk based on its role in the regulation of steroid and non-steroid hormone biosynthesis. Reported associations between CYP17 and higher levels of estradiol in some studies suggest that the C allele of a T-to-C single nucleotide polymorphism (SNP) in the 5′UTR of CYP17 (rs743572) may be associated with an increased risk of hormone-related cancers. However, five relatively small epidemiologic studies of endometrial cancer have reported that women with the rs743572 C allele have a decreased risk of endometrial cancer. To examine this association, we genotyped rs743572 and eight other haplotype-tagging SNPs (htSNPs), which are estimated to capture >80% of the variation in CYP17 in a population-based study of 497 endometrial cancer cases and 1,024 controls in Poland. Significant associations were not found for rs743572 (per C allele: OR = 1.12, 95%CI 0.96–1.30; P-trend = 0.15), for individual htSNPs, or for extended haplotypes (global P-value = 0.60). When we pooled data from previously published studies with our own (a total of 1,004 endometrial cases and 1,907 controls), we observed significant study heterogeneity in summary estimates of the association between rs743572 and endometrial cancer, as well as evidence of publication bias. In conclusion, our data are not consistent with a decreased endometrial cancer risk associated with rs743572, as previously reported, or with other haplotype-tagging polymorphisms. Further evaluation in consortia is necessary to confirm potential weak associations between common variation in CYP17 and endometrial cancer risk and to address the concern of publication bias. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

The association of SNPs in ADIPOQ,ADIPOR1, and ADIPOR2 with insulin sensitivity in a cohort of adolescents and their parents

Few studies have examined the association of SNPs in the adiponectin (ADIPOQ) and adiponectin receptor 1 and 2 (ADIPOR1, ADIPOR2) genes with the euglycemic clamp, i.e. the gold standard measure of insulin sensitivity. The association of comprehensive tag SNPs in these genes with insulin sensitivity was examined in a cohort of adolescents and their parents. Probands and siblings (n = 441, mean age = 17.9 years) were recruited along with their parents (n = 262, mean age = 47.9 years). Typed SNPs included 21 SNPs in ADIPOQ, 7 SNPs in ADIPOR1, and 13 SNPs in ADIPOR2. Mixed model linear regression was used to test the association of SNPs with euglycemic-clamp derived insulin sensitivity. All analyses were stratified by race. After corrections to account for multiple testing and the linkage disequilibrium structure of the genes, one SNP in the ADIPOQ gene (rs822393) was significantly associated with insulin sensitivity in white subjects. In whites, six SNPs in ADIPOQ, one SNP in ADIPOR1 and one SNP in ADIPOR2 were associated with insulin sensitivity at the P < 0.05 level. In African Americans, two SNPs in ADIPOR1 were associated with insulin sensitivity at the P < 0.05 level. These results suggest that a variant in the ADIPOQ gene influences levels of insulin sensitivity and age may modify the effects of this variant. There are several other variants in ADIPOQ, ADIPOR1, and ADIPOR2 that may influence insulin sensitivity and these variants should be further investigated in other populations. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Comprehensive evaluation of the estrogen receptor α gene reveals further evidence for association with type 2 diabetes enriched for nephropathy in an African American population

We previously investigated the estrogen receptor α gene (ESR1) as a positional candidate for type 2 diabetes (T2DM), and found evidence for association between the intron 1-intron 2 region of this gene and T2DM and/or nephropathy in an African American (AA) population. Our objective was to comprehensively evaluate variants across the entire ESR1 gene for association in AA with T2DM and end stage renal disease (T2DM–ESRD). One hundred fifty SNPs in ESR1, spanning 476 kb, were genotyped in 577 AA individuals with T2DM–ESRD and 596 AA controls. Genotypic association tests for dominant, additive, and recessive models, and haplotypic association, were calculated using a χ² statistic and corresponding P value. Thirty-one SNPs showed nominal evidence for association (P < 0.05) with T2DM–ESRD in one or more genotypic model. After correcting for multiple tests, promoter SNP rs11964281 (nominal P = 0.000291, adjusted P = 0.0289), and intron 4 SNPs rs1569788 (nominal P = 0.000754, adjusted P = 0.0278) and rs9340969 (nominal P = 0.00109, adjusted P = 0.0467) remained significant at experimentwise error rate (EER) P ≤ 0.05 for the dominant class of tests. Twenty-three of the thirty-one associated SNPs cluster within the intron 4–intron 6 regions. Gender stratification revealed nominal evidence for association with 35 SNPs in females (352 cases; 306 controls) and seven SNPs in males (225 cases; 290 controls). We have identified a novel region of the ESR1 gene that may contain important functional polymorphisms in relation to susceptibility to T2DM and/or diabetic nephropathy. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

The <Emphasis Type="Italic">COL1A1</Emphasis> gene and high myopia susceptibility in Japanese

The collagen type Ι alpha Ι (COL1A1) gene encodes the extracellular matrix component, collagen, and resides in candidate MYP5 for high myopia on the chromosome 17q22–q23.3. This locus has recently been implicated in playing an important role in the pathogenesis of experimental myopia. We investigated the association of disruptions of COL1A1 gene with high myopia by analyzing the frequency of ten SNPs in a Japanese population of 330 subjects with high myopia of −9.25 D or less and 330 randomized controls without high myopia. Two SNPs (rs2075555 and rs2269336) were significantly associated with high myopia (P < 0.05, Pc < 0.1). Two different haplotype blocks in COL1A1 were observed by the pair-wise linkage disequilibrium between the SNPs. The frequency of GGC/GGC diplotype constructed by the three SNPs (rs2075555, rs2269336, rs1107946) was significantly high (OR = 1.6) and associated with high myopia (P = 0.028, Pc< 0.084). Together our results provide the first evidence for COL1A1 as a gene associated with high myopia.     

Genetic effects in the leukotriene biosynthesis pathway and association with atherosclerosis

Leukotrienes are arachidonic acid derivatives long known for their inflammatory properties and their involvement with a number of human diseases, most particularly asthma. Recently, leukotriene-based inflammation has also been shown to play an important role in atherosclerosis: ALOX5AP and LTA4H, both genes in the leukotriene biosynthesis pathway, have individually been shown to be associated with various cardiovascular disease (CVD) phenotypes. To assess the role of the leukotriene pathway in CVD pathogenesis, we performed genetic association studies of ALOX5AP and LTA4H in a family based study of early onset coronary artery disease (EOCAD) (GENECARD, 1,101 families) and in a non-familial dataset of EOCAD (CATHGEN, 656 cases and 405 controls). We found weak to moderate association between single nucleotide polymorphisms (SNPs) in ALOX5AP and LTA4H with EOCAD. The previously reported four-SNP haplotype (HapA) in ALOX5AP showed association with EOCAD in CATHGEN (P = 0.02), while controlling for age, race and CVD risk factors. HapK, the previously reported ten-SNP haplotype in LTA4H was associated with EOCAD in CATHGEN (P = 0.04). Another previously reported four-SNP haplotype in ALOX5AP (HapB) was not significant in our sample (P = 0.39). The overall lack of (or weak) association of single SNPs as compared with the haplotype results demonstrates the need for analyzing multiple SNPs within each gene in such studies. Interestingly, we detected an association of SNPs in ALOX5 (P < 0.05), the target of ALOX5AP, with CVD. Using a pathway-based approach, we also detected statistical evidence for interactions among ALOX5, ALOX5AP and LTA4H using RNA expression data from a collection of freshly harvested human aortas with varying degrees of atherosclerosis. The GENECARD families did not demonstrate evidence for linkage or association with ALOX5, ALOX5AP or LTA4H. Our results support a modest role for the leukotriene pathway in atherosclerosis pathogenesis, reveal important genomic interactions within the pathway, and suggest the importance of using pathway-based modeling for evaluating the genomics of atherosclerosis susceptibility. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Genetic variants in telomere‐maintenance genes are associated with ovarian cancer risk and outcome

Most ovarian cancer patients present at an advanced stage with poor prognosis. Telomeres play a critical role in protecting chromosomes stability. The associations of genetic variants in telomere maintenance genes and ovarian cancer risk and outcome are unclear. We genotyped 137 single nucleotide polymorphisms (SNPs) in telomere‐maintenance genes in 417 ovarian cancer cases and 417 matched healthy controls to evaluate their associations with cancer risk, survival and therapeutic response. False discovery rate Q‐value was calculated to account for multiple testing. Eleven SNPs from two genes showed nominally significant associations with the risks of ovarian cancer. The most significant SNP was TEP1: rs2228026 with participants carrying at least one variant allele exhibiting a 3.28‐fold (95% CI: 1.72‐6.29; P < 0.001, Q = 0.028) increased ovarian cancer risk, which remained significant after multiple testing adjusting. There was also suggested evidence for the associations of SNPs with outcome, although none of the associations had a Q < 0.05. Seven SNPs from two genes showed associations with ovarian cancer survival (P < 0.05). The strongest association was found in TNKS gene (rs10093972, hazard ratio = 1.88; 95% CI: 1.20‐2.92; P = 0.006, Q = 0.076). Five SNPs from four genes showed suggestive associations with therapeutic response (P < 0.05). In a survival tree analysis, TEP1:rs10143407 was the primary factor contributing to overall survival. Unfavourable genotype analysis showed a cumulative effect of significant SNPs on ovarian cancer risk, survival and therapeutic response. Genetic variations in telomere‐maintenance genes may be associated with ovarian cancer risk and outcome.     

Role ofADRB2 gene polymorphism in asthma and response to β2-agonists in Polish children

The aims of this study were: (1) to find associations of asthma with single-nucleotide polymorphisms (SNPs) within theADRB2 gene: Arg16Gly, Gln27Glu, −1023 G/A, −367 T/C, −47 C/T ; (2) to define linkage disequilibrium in the gene region, basing on the analyzed SNPs; and (3) to analyze the importance ofADRB2 polymorphism for response to bronchodilator drugs in children diagnosed with bronchial asthma. We compared 113 asthmatic children and 123 healthy subjects from the Polish population. Genotyping was performed by PCR-RFLP. We found an association of the A allele of −1023A/GADRB2 polymorphism with asthma (P = 0.024). No significant associations with other SNPs were detected. Moderate linkage was found between Gln27Glu and −47C/T polymorphisms in linkage disequilibrium analysis (D’ = 0.85,r ² = 0.429, LOD = 31.97). No significant differences were found in haplotype frequencies in comparison to the control group, implicating that they are not associated with susceptibility to asthma in the analyzed population. There was no significant correlation between the analyzed SNPs of theADRB2 gene and the response to β₂-agonists. This is the first report providing suggestive evidence for association of —1023A/GADRB2 polymorphism with an increased risk of asthma. The analyzed SNPs may not play a major role in response to β₂-agonists in asthmatic children.     

Multilocus OCA2 genotypes specify human iris colors

Human iris color is a quantitative, multifactorial phenotype that exhibits quasi-Mendelian inheritance. Recent studies have shown that OCA2 polymorphism underlies most of the natural variability in human iris pigmentation but to date, only a few associated polymorphisms in this gene have been described. Herein, we describe an iris color score (C) for quantifying iris melanin content in-silico and undertake a more detailed survey of the OCA2 locus (n = 271 SNPs). In 1,317 subjects, we confirmed six previously described associations and identified another 27 strongly associated with C that were not explained by continental population stratification (OR 1.5–17.9, P = 0.03 to <0.001). Haplotype analysis with respect to these 33 SNPs revealed six haplotype blocks and 11 hap-tags within these blocks. To identify genetic features for best-predicting iris color, we selected sets of SNPs by parsing P values among possible combinations and identified four discontinuous and non-overlapping sets across the LD blocks (p-Selected SNP sets). In a second, partially overlapping sample of 1,072, samples with matching diplotypes comprised of these p-Selected OCA2 SNPs exhibited a rate of C concordance of 96.3% (n = 82), which was significantly greater than that obtained from randomly selected samples (62.6%, n = 246, P<0.0001). In contrast, the rate of C concordance using diplotypes comprised of the 11 identified hap-tags was only 83.7%, and that obtained using diplotypes comprised of all 33 SNPs organized as contiguous sets along the locus (defined by the LD block structure) was only 93.3%. These results confirm that OCA2 is the major human iris color gene and suggest that using an empirical database-driven system, genotypes from a modest number of SNPs within this gene can be used to accurately predict iris melanin content from DNA. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Genome-wide association study of bronchial asthma in the Volga-Ural region of Russia

Bronchial asthma is a chronic inflammatory respiratory disease that is caused by the complex interaction of environmental influences and genetic susceptibility. The first genome-wide association study of bronchial asthma discovered a significant association between SNPs within 17q12-21 genomic region and childhood bronchial asthma in individuals of European descent. Association with this genomic region was then replicated in a number of independent samples of European and Asian descent. Here we report results of the first genome-wide association study of bronchial asthma in the Volga-Ural region of Russia. The present study includes 358 unrelated patients with physician-diagnosed bronchial asthma and 369 disease-free control subjects of different ethnic origin (Russians, Tatars and Bashkirs). Genotyping of DNA samples was carried out using the Illumina Human610 quad array as a part of GABRIEL project (contract from the EC No LSHB-CT-2006-018996). After QC filtering procedures, a final set of 550915 SNPs genotyped in 330 cases and 348 controls was tested for association with bronchial asthma. Five markers on chromosome 17q12-21 showed statistically significant association with bronchial asthma (p < or = 4.79 x 10(-7)). SNP rs7216389 with the strongest evidence for association (p = 1.01 x 10(-7)) is located within the first intron of the GSDMB gene. Evidence for association was stronger with childhood-onset asthma (p = 1.97 x 10(-6) for SNP rs7216389) compared to late-onset asthma (p = 1.8 x 10(-4) for SNP rs7216389). Our replication study using three SNPs within GSDMB gene confirmed association with only childhood-onset asthma. In summary, these results suggest an important role for genetic variants within 17q12-q21 region in the development of bronchial asthma in the Volga-Ural region of Russia.     

Association study on chromosome 20q11.21-13.13 locus and its contribution to type 2 diabetes susceptibility in Japanese

Several linkage studies have predicted that human chromosome 20q is closely related to type 2 diabetes, but there is no clear evidence that certain variant(s) or gene(s) have strong effects on the disease within this region. To examine disease susceptibility variant in Japanese, verified SNPs from the databases, with a minor allele frequency larger than 0.15, were selected at 10-kb intervals across a 19.31-Mb region (20q11.21-13.13), which contained 291 genes, including hepatocyte nuclear factor 4α (HNF4α). As a result, a total of 1,147 SNPs were genotyped with TaqMan assay using 1,818 Japanese samples. By searching for HNF4α as a representative disease-susceptible gene, no variants of HNF4α were strongly associated with disease. To identify other genetic variant related with disease, we designed an extensive two-stage association study (725 first and 1,093 second test samples). Although SNP1146 (rs220076) was selected as a landmark within the 19.31 Mb region, the magnitude of the nominal P value (P = 0.0023) was rather weak. Subsequently, a haplotype-based association study showed that two common haplotypes were weakly associated with disease. All of these tests resulted in non-significance after adjusting for Bonferroni’s correction and the false discovery rate to control for the impact of multiple testing. Contrary to the initial expectations, we could not conclude that certain SNPs had a major effect on this promising locus within the framework presented here. As a way to extend our observations, we emphasize the importance of a subsequent association study including replication and/or meta-analysis in multiple populations.Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Identification of four SNPs and association analysis with meat quality traits in the porcine <Emphasis Type="Italic">Pitx2c</Emphasis> gene

The association of the porcine Pitx2c gene with meat quality traits was investigated in the present study. A total of eight single nucleotide polymorphisms (SNPs) were found. Allele frequencies of four SNPs were further detected in four commercial breeds and eight Chinese indigenous breeds. Single SNP and meat quality associations were analyzed in a Yorkshire×Meishan F₂ population. The SNPs c.474C>T (P<0.01) and c.636C>T (P<0.05) showed a significant association with meat color (MCV1). The SNPs c.*37G>A and c.*47G>A were significantly associated with drip loss rate (DLR), water holding capacity (WHC) and meat color value (MCV1) consistently (P<0.05). Linkage disequilibrium (LD) analysis revealed that the adjacent SNPs were in LD. Two major haplotypes were identified, and association analysis between haplotype combinations and meat quality indicated that the presence of two copies of haplotype 1 -CCGG- may improve meat quality.     

Association of Gasdermin B Gene GSDMB Polymorphisms with Risk of Allergic Diseases

The GSDMB gene encodes gasdermin B from the family of gasdermin domain-containing proteins involved in various cellular processes related to tumor development and progression, such as differentiation, cell cycle control and apoptosis. Previously, we conducted GWAS on asthma in the Volga-Ural region of Russia and found SNPs associated with asthma with genome-wide significance (rs9303277, rs8067378, rs2290400, rs7216389, rs4795405) and located in the chromosomal region 17q12-q21, which contains IKZF3 (IKAROS family zinc finger 3), ZPBP2 (zona pellucida binding protein-like), GSDMB (gasdermin B), ORMDL3 (orosomucoid 1-like 3) and LRRC3C (leucine-rich repeat-containing 3C) genes. In the present study, we investigated the association of SNPs of the GSDMB gene with the development of various allergic diseases and their combined manifestations in individuals of Russian, Tatar and Bashkir ethnic origin. Our results revealed that polymorphic variants rs7216389, rs2290400 and rs2305480 are associated with the development of allergic diseases as well as with asthma and asthma combined with allergic rhinitis. We did not reveal the association of rs7216389 and rs2290400 with the development of allergic rhinitis and atopic dermatitis in the groups of patients without asthma symptoms. This may reflect a more important role of these SNPs in the development of asthma.

     

Mouse to human comparative genetics reveals a novel immunoglobulin E-controlling locus on Hsa8q12

Atopy is a predisposition to hyperproduction of immunoglobulin E (IgE) against common environmental allergens. It is often associated with development of allergic diseases such as asthma, rhinitis, and dermatitis. Production of IgE is influenced by genetic and environmental factors. In spite of progress in the study of heredity of atopy, the genetic mechanisms of IgE regulation have not yet been completely elucidated. The analysis of complex traits can benefit considerably from integration of human and mouse genetics. Previously, we mapped a mouse IgE-controlling locus Lmr9 on chromosome 4 to a segment of <9 Mb. In this study, we tested levels of total IgE and 25 specific IgEs against inhalant and food allergens in 67 Czech atopic families. In the position homologous to Lmr9 on chromosome 8q12 marked by D8S285, we demonstrated a novel human IgE-controlling locus exhibiting suggestive linkage to composite inhalant allergic sensitization (limit of detection, LOD = 2.11, P = 0.0009) and to nine specific IgEs, with maximum LOD (LOD = 2.42, P = 0.0004) to plantain. We also tested 16 markers at previously reported chromosomal regions of atopy. Linkage to plant allergens exceeding the LOD > 2.0 was detected at 5q33 (D5S1507, LOD = 2.11, P = 0.0009) and 13q14 (D13S165, LOD = 2.74, P = 0.0002). The significant association with plant allergens (quantitative and discrete traits) was found at 7p14 (D7S2250, corrected P = 0.026) and 12q13 (D12S1298, corrected P = 0.043). Thus, the finding of linkage on chromosome 8q12 shows precision and predictive power of mouse models in the investigation of complex traits in humans. Our results also confirm the role of loci at 5q33, 7p14, 12q14, and 13q13 in control of IgE. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.