In:
PLOS Medicine, Public Library of Science (PLoS), Vol. 19, No. 5 ( 2022-5-19), p. e1003981-
Kurzfassung:
Type 2 diabetes (T2D) is highly prevalent in British South Asians, yet they are underrepresented in research. Genes & Health (G & H) is a large, population study of British Pakistanis and Bangladeshis (BPB) comprising genomic and routine health data. We assessed the extent to which genetic risk for T2D is shared between BPB and European populations (EUR). We then investigated whether the integration of a polygenic risk score (PRS) for T2D with an existing risk tool (QDiabetes) could improve prediction of incident disease and the characterisation of disease subtypes. Methods and findings In this observational cohort study, we assessed whether common genetic loci associated with T2D in EUR individuals were replicated in 22,490 BPB individuals in G & H. We replicated fewer loci in G & H ( n = 76/338, 22%) than would be expected given power if all EUR-ascertained loci were transferable ( n = 101, 30%; p = 0.001). Of the 27 transferable loci that were powered to interrogate this, only 9 showed evidence of shared causal variants. We constructed a T2D PRS and combined it with a clinical risk instrument (QDiabetes) in a novel, integrated risk tool (IRT) to assess risk of incident diabetes. To assess model performance, we compared categorical net reclassification index (NRI) versus QDiabetes alone. In 13,648 patients free from T2D followed up for 10 years, NRI was 3.2% for IRT versus QDiabetes (95% confidence interval (CI): 2.0% to 4.4%). IRT performed best in reclassification of individuals aged less than 40 years deemed low risk by QDiabetes alone (NRI 5.6%, 95% CI 3.6% to 7.6%), who tended to be free from comorbidities and slim. After adjustment for QDiabetes score, PRS was independently associated with progression to T2D after gestational diabetes (hazard ratio (HR) per SD of PRS 1.23, 95% CI 1.05 to 1.42, p = 0.028). Using cluster analysis of clinical features at diabetes diagnosis, we replicated previously reported disease subgroups, including Mild Age-Related, Mild Obesity-related, and Insulin-Resistant Diabetes, and showed that PRS distribution differs between subgroups ( p = 0.002). Integrating PRS in this cluster analysis revealed a Probable Severe Insulin Deficient Diabetes (pSIDD) subgroup, despite the absence of clinical measures of insulin secretion or resistance. We also observed differences in rates of progression to micro- and macrovascular complications between subgroups after adjustment for confounders. Study limitations include the absence of an external replication cohort and the potential biases arising from missing or incorrect routine health data. Conclusions Our analysis of the transferability of T2D loci between EUR and BPB indicates the need for larger, multiancestry studies to better characterise the genetic contribution to disease and its varied aetiology. We show that a T2D PRS optimised for this high-risk BPB population has potential clinical application in BPB, improving the identification of T2D risk (especially in the young) on top of an established clinical risk algorithm and aiding identification of subgroups at diagnosis, which may help future efforts to stratify care and treatment of the disease.
Materialart:
Online-Ressource
ISSN:
1549-1676
DOI:
10.1371/journal.pmed.1003981
DOI:
10.1371/journal.pmed.1003981.g001
DOI:
10.1371/journal.pmed.1003981.g002
DOI:
10.1371/journal.pmed.1003981.g003
DOI:
10.1371/journal.pmed.1003981.g004
DOI:
10.1371/journal.pmed.1003981.g005
DOI:
10.1371/journal.pmed.1003981.t001
DOI:
10.1371/journal.pmed.1003981.t002
DOI:
10.1371/journal.pmed.1003981.s001
DOI:
10.1371/journal.pmed.1003981.s002
DOI:
10.1371/journal.pmed.1003981.s003
DOI:
10.1371/journal.pmed.1003981.s004
DOI:
10.1371/journal.pmed.1003981.s005
DOI:
10.1371/journal.pmed.1003981.s006
DOI:
10.1371/journal.pmed.1003981.s007
DOI:
10.1371/journal.pmed.1003981.s008
DOI:
10.1371/journal.pmed.1003981.s009
DOI:
10.1371/journal.pmed.1003981.s010
DOI:
10.1371/journal.pmed.1003981.s011
DOI:
10.1371/journal.pmed.1003981.s012
DOI:
10.1371/journal.pmed.1003981.s013
DOI:
10.1371/journal.pmed.1003981.s014
DOI:
10.1371/journal.pmed.1003981.s015
DOI:
10.1371/journal.pmed.1003981.s016
DOI:
10.1371/journal.pmed.1003981.s017
DOI:
10.1371/journal.pmed.1003981.s018
DOI:
10.1371/journal.pmed.1003981.s019
DOI:
10.1371/journal.pmed.1003981.s020
DOI:
10.1371/journal.pmed.1003981.s021
DOI:
10.1371/journal.pmed.1003981.s022
DOI:
10.1371/journal.pmed.1003981.s023
DOI:
10.1371/journal.pmed.1003981.s024
DOI:
10.1371/journal.pmed.1003981.r001
DOI:
10.1371/journal.pmed.1003981.r002
DOI:
10.1371/journal.pmed.1003981.r003
DOI:
10.1371/journal.pmed.1003981.r004
DOI:
10.1371/journal.pmed.1003981.r005
DOI:
10.1371/journal.pmed.1003981.r006
DOI:
10.1371/journal.pmed.1003981.r007
Sprache:
Englisch
Verlag:
Public Library of Science (PLoS)
Publikationsdatum:
2022
ZDB Id:
2164823-2
