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"type": "journal article", "published": "2017-09-00", "journal": {"title": "PLoS Med.", "issn": "1549-1676", "volume": "14", "issue": "9", "pages": "e1002383", "issn-l": "1549-1277"}, "abstract": "Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.\n\nUsing genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 \u00d7 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.\n\nAs G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.", "doi": "10.1371/journal.pmed.1002383", "pmid": "28898252", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC5595282"}, {"db": "pii", "key": "PMEDICINE-D-17-00599"}], "notes": [], "created": "2018-12-05T11:25:19.021Z", "modified": "2026-09-23T06:33:43.552Z"}, {"entity": "publication", "iuid": "3319ed3faaa04b37904ac096febd0936", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/3319ed3faaa04b37904ac096febd0936.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/3319ed3faaa04b37904ac096febd0936"}}, "title": "Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits.", "authors": [{"family": "Justice", "given": "Anne E", "initials": "AE", "orcid": "0000-0002-8903-8712", 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"initials": "PW"}, {"family": "Froguel", "given": "Philippe", "initials": "P"}, {"family": "Gordon-Larsen", "given": "Penny", "initials": "P", "orcid": "0000-0001-5322-4188", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/480fa70683fb44a0bda6b322a1d36439.json"}}, {"family": "Grabe", "given": "Hans-J\u00f6rgen", "initials": "HJ"}, {"family": "Gudnason", "given": "Vilmundur", "initials": "V"}, {"family": "Haiman", "given": "Christopher A", "initials": "CA"}, {"family": "Hayward", "given": "Caroline", "initials": "C"}, {"family": "Hveem", "given": "Kristian", "initials": "K"}, {"family": "Johnson", "given": "Andrew D", "initials": "AD"}, {"family": "Wouter Jukema", "given": "J", "initials": "J", "orcid": "0000-0002-3246-8359", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/51be7e89ccfd4bbe93b216028c57a376.json"}}, {"family": "Kardia", "given": "Sharon L R", "initials": "SLR"}, {"family": "Kivimaki", "given": "Mika", "initials": "M", "orcid": "0000-0002-4699-5627", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/59d7f4b1a8f8464eba40b0abe733aae9.json"}}, {"family": "Kooner", "given": "Jaspal S", "initials": "JS"}, {"family": "Kuh", "given": "Diana", "initials": "D"}, {"family": "Laakso", "given": "Markku", "initials": "M"}, {"family": "Lehtim\u00e4ki", "given": "Terho", "initials": "T"}, {"family": "Marchand", "given": "Loic Le", "initials": "LL"}, {"family": "M\u00e4rz", "given": "Winfried", "initials": "W"}, {"family": "McCarthy", "given": "Mark I", "initials": "MI"}, {"family": "Metspalu", "given": "Andres", "initials": "A"}, {"family": "Morris", "given": "Andrew P", "initials": "AP"}, {"family": "Ohlsson", "given": "Claes", "initials": "C"}, {"family": "Palmer", "given": "Lyle J", "initials": "LJ"}, {"family": "Pasterkamp", "given": "Gerard", "initials": "G"}, {"family": "Pedersen", "given": "Oluf", "initials": "O"}, {"family": "Peters", "given": "Annette", "initials": "A"}, {"family": "Peters", "given": "Ulrike", "initials": "U"}, {"family": "Polasek", "given": "Ozren", "initials": "O"}, {"family": "Psaty", "given": "Bruce M", "initials": "BM"}, {"family": "Qi", "given": "Lu", "initials": "L"}, {"family": "Rauramaa", "given": "Rainer", "initials": "R"}, {"family": "Smith", "given": "Blair H", "initials": "BH", "orcid": "0000-0002-5362-9430", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5f30912f5a8e443eac572814f3990d7f.json"}}, {"family": "S\u00f8rensen", "given": "Thorkild I A", "initials": "TIA"}, {"family": "Strauch", "given": "Konstantin", "initials": "K"}, {"family": "Tiemeier", "given": "Henning", "initials": "H", "orcid": "0000-0002-4395-1397", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/bed764abb33d4d9e8bcd05dd64379a7c.json"}}, {"family": "Tremoli", "given": "Elena", "initials": "E"}, {"family": "van der Harst", "given": "Pim", "initials": "P"}, {"family": "Vestergaard", "given": "Henrik", "initials": "H", "orcid": "0000-0003-3090-269X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e2fa5c4f74894d6a833afd105ec72848.json"}}, {"family": "Vollenweider", "given": "Peter", "initials": "P"}, {"family": "Wareham", "given": "Nicholas J", "initials": "NJ"}, {"family": "Weir", "given": "David R", "initials": "DR"}, {"family": "Whitfield", "given": "John B", "initials": "JB"}, {"family": "Wilson", "given": "James F", "initials": "JF", "orcid": "0000-0001-5751-9178", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/513b6983cc9d478ab9d81c2f21579961.json"}}, {"family": "Tyrrell", "given": "Jessica", "initials": "J"}, {"family": "Frayling", "given": "Timothy M", "initials": "TM"}, {"family": "Barroso", "given": "In\u00eas", "initials": "I"}, {"family": "Boehnke", "given": "Michael", "initials": "M"}, {"family": "Deloukas", "given": "Panagiotis", "initials": "P"}, {"family": "Fox", "given": "Caroline S", "initials": "CS"}, {"family": "Hirschhorn", "given": "Joel N", "initials": "JN"}, {"family": "Hunter", "given": "David J", "initials": "DJ"}, {"family": "Spector", "given": "Tim D", "initials": "TD"}, {"family": "Strachan", "given": "David P", "initials": "DP", "orcid": "0000-0001-7854-1366", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d43385a350914b0a843fb49008d108b0.json"}}, {"family": "van Duijn", "given": "Cornelia M", "initials": "CM"}, {"family": "Heid", "given": "Iris M", "initials": "IM"}, {"family": "Mohlke", "given": "Karen L", "initials": "KL", "orcid": "0000-0001-6721-153X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/fac0e041c56347fe98cef9ae8f004b67.json"}}, {"family": "Marchini", "given": "Jonathan", "initials": "J", "orcid": "0000-0003-0610-8322", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a7d0d3e23a76434098fa7731ac294cd1.json"}}, {"family": "Loos", "given": "Ruth J F", "initials": "RJF"}, {"family": "Kilpel\u00e4inen", "given": "Tuomas O", "initials": "TO"}, {"family": "Liu", "given": "Ching-Ti", "initials": "CT", "orcid": "0000-0002-0703-0742", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/0df836bc876845a6af66828561f24a27.json"}}, {"family": "Borecki", "given": "Ingrid B", "initials": "IB"}, {"family": "North", "given": "Kari E", "initials": "KE"}, {"family": "Cupples", "given": "L Adrienne", "initials": "LA"}], "type": "journal article", "published": "2017-04-26", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "8", "issue": null, "pages": "14977", "issn-l": "2041-1723"}, "abstract": "Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.", "doi": "10.1038/ncomms14977", "pmid": "28443625", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC5414044"}, {"db": "pii", "key": "ncomms14977"}], "notes": [], "created": "2018-12-05T09:47:57.139Z", "modified": "2026-09-23T06:42:25.568Z"}]}