PMC:4572492 / 13306-16889 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4572492","sourcedb":"PMC","sourceid":"4572492","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4572492","text":"Application Data: HbA1c Levels in Type 1 Diabetes and Cystic Fibrosis Lung Disease\nWe tested the proposed JLS approach with applications to genetic association studies of HbA1c levels in type 1 diabetes and lung disease in cystic fibrosis.\nThe T1D application used the Diabetes Control and Complications Trial (DCCT) sample in which 667 individuals were conventionally treated and 637 intensively treated.18 In this sample, an earlier GWAS of HbA1c levels in type 1 diabetes18 showed that rs1358030 near SORCS1 (10q25.1 [MIM: 606283]) interacts with treatment type (conventional versus intensive) on HbA1c levels (quarterly measured values spanning 6.5 years). To demonstrate that the JLS testing framework could leverage the interaction effect without knowledge of the interacting variable, we analyzed the association of rs1358030 with the average, inverse normal transformed HbA1c value, assuming the treatment variable was not available.\nThe CF application involves association studies of an averaged lung function measure, forced expiratory volume in 1 s, adjusted for sex, age, height, and mortality, and normalized (SaKnorm),24 using data from the Canadian Cystic Fibrosis Gene Modifier Study (CGS).25 To reduce the duration of heterogeneous environmental exposures that were not measured, and recognizing that age can serve as a surrogate for these exposures, we19 previously restricted our (location-only) analysis to lung function measures from pediatric ages (\u003c18 years, n = 815 subjects from 753 unique families), analyzing eight SNPs in three genes, SLC9A3 (MIM: 182307), SLC6A14 (MIM: 300444), and SLC26A9 (MIM: 608481), previously identified as associated with meconium ileus in a hypothesis-driven GWAS (GWAS-HD).5 This approach involved a 46% reduction in sample size, and that the age restriction be fixed for all variants, despite the possibility that the optimal exposure (here, age) is gene specific. Here we re-analyzed the SNPs with the individual location-only and scale-only tests, as well as the joint JLS-Fisher, JLS-minP, LRT,17 and distribution16 tests, removing the age restriction and using the full CGS sample (n = 1,409 unrelated subjects). For comparison, the location-only analyses restricted to the pediatric population using different age cut-off points were also investigated.\nWith the full CGS sample, we further tested the hypothesis that multiple proteins present on the apical plasma membrane contribute to lung disease severity as measured by SakNorm; the hypothesis was considered previously for meconium ileus susceptibility in CF.5 In total, 3,814 GWAS SNPs (MAF \u003e 0.02) were annotated to within ±10 kb of 155 apical genes obtained from the Gene Ontology project.5 The JLS-Fisher test was first applied to each SNP, and the SNP-specific test statistic was then aggregated across all SNPs to perform the multivariate apical gene-set analysis. We then used an independent French sample (n = 1,232) for replication. Imputation based on 1000 Genomes26,27 (as outlined in the Online Methods of Sun et al.5) was used to assess regional association within the SLC9A3R1, SLC9A3R2, and EZR binding sites of SLC9A3.\nInstitutional review committees at all participating institutions for the DCCT T1D study as well as all Canadian CF clinics approved this study. Consent was also obtained for participants from France with procedural approval (CPP 2004/15) and information collection approval by CNIL (04.404). Data collection, genotyping, and quality-control procedures are reported elsewhere for the T1D18 and CF (Canadian and French) studies.5,25","divisions":[{"label":"title","span":{"begin":0,"end":82}},{"label":"p","span":{"begin":83,"end":239}},{"label":"p","span":{"begin":240,"end":941}},{"label":"p","span":{"begin":942,"end":2314}},{"label":"p","span":{"begin":2315,"end":3151}}],"tracks":[{"project":"2_test","denotations":[{"id":"26140448-19875614-2053695","span":{"begin":405,"end":407},"obj":"19875614"},{"id":"26140448-19875614-2053696","span":{"begin":474,"end":476},"obj":"19875614"},{"id":"26140448-21462361-2053697","span":{"begin":1132,"end":1134},"obj":"21462361"},{"id":"26140448-21602797-2053698","span":{"begin":1206,"end":1208},"obj":"21602797"},{"id":"26140448-24057835-2053699","span":{"begin":1370,"end":1372},"obj":"24057835"},{"id":"26140448-22466613-2053700","span":{"begin":1729,"end":1730},"obj":"22466613"},{"id":"26140448-24482837-2053701","span":{"begin":2054,"end":2056},"obj":"24482837"},{"id":"26140448-23512279-2053702","span":{"begin":2073,"end":2075},"obj":"23512279"},{"id":"26140448-22466613-2053703","span":{"begin":2576,"end":2577},"obj":"22466613"},{"id":"26140448-22466613-2053704","span":{"begin":2709,"end":2710},"obj":"22466613"},{"id":"26140448-19715440-2053705","span":{"begin":2994,"end":2996},"obj":"19715440"},{"id":"26140448-21058334-2053705","span":{"begin":2994,"end":2996},"obj":"21058334"},{"id":"26140448-22466613-2053706","span":{"begin":3045,"end":3046},"obj":"22466613"},{"id":"26140448-19875614-2053707","span":{"begin":3539,"end":3541},"obj":"19875614"},{"id":"26140448-22466613-2053708","span":{"begin":3581,"end":3583},"obj":"22466613"},{"id":"26140448-21602797-2053708","span":{"begin":3581,"end":3583},"obj":"21602797"}],"attributes":[{"subj":"26140448-19875614-2053695","pred":"source","obj":"2_test"},{"subj":"26140448-19875614-2053696","pred":"source","obj":"2_test"},{"subj":"26140448-21462361-2053697","pred":"source","obj":"2_test"},{"subj":"26140448-21602797-2053698","pred":"source","obj":"2_test"},{"subj":"26140448-24057835-2053699","pred":"source","obj":"2_test"},{"subj":"26140448-22466613-2053700","pred":"source","obj":"2_test"},{"subj":"26140448-24482837-2053701","pred":"source","obj":"2_test"},{"subj":"26140448-23512279-2053702","pred":"source","obj":"2_test"},{"subj":"26140448-22466613-2053703","pred":"source","obj":"2_test"},{"subj":"26140448-22466613-2053704","pred":"source","obj":"2_test"},{"subj":"26140448-19715440-2053705","pred":"source","obj":"2_test"},{"subj":"26140448-21058334-2053705","pred":"source","obj":"2_test"},{"subj":"26140448-22466613-2053706","pred":"source","obj":"2_test"},{"subj":"26140448-19875614-2053707","pred":"source","obj":"2_test"},{"subj":"26140448-22466613-2053708","pred":"source","obj":"2_test"},{"subj":"26140448-21602797-2053708","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#93ecea","default":true}]}]}}