Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus
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Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus. / Antikainen, Anni A.V.; Sandholm, Niina; Trégouët, David Alexandre; Charmet, Romain; McKnight, Amy Jayne; Ahluwalia, Tarunveer S.; Syreeni, Anna; Valo, Erkka; Forsblom, Carol; Gordin, Daniel; Harjutsalo, Valma; Hadjadj, Samy; Maxwell, Alexander P.; Rossing, Peter; Groop, Per Henrik.
I: Cardiovascular Research, Bind 117, Nr. 2, 2021, s. 600-612.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus
AU - Antikainen, Anni A.V.
AU - Sandholm, Niina
AU - Trégouët, David Alexandre
AU - Charmet, Romain
AU - McKnight, Amy Jayne
AU - Ahluwalia, Tarunveer S.
AU - Syreeni, Anna
AU - Valo, Erkka
AU - Forsblom, Carol
AU - Gordin, Daniel
AU - Harjutsalo, Valma
AU - Hadjadj, Samy
AU - Maxwell, Alexander P.
AU - Rossing, Peter
AU - Groop, Per Henrik
PY - 2021
Y1 - 2021
N2 - Aims: Diabetes is a known risk factor for coronary artery disease (CAD). There is accumulating evidence that CAD pathogenesis differs for individuals with type 1 diabetes (T1D). However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing CAD susceptibility, especially in T1D, to examine the function of these discoveries and to study the role of the known risk loci in T1D. Methods and results: We performed the largest genome-wide association study to date for CAD in T1D, comprising 4869 individuals with T1D (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 [odds ratio (OR) = 1.32, P = 1.50 × 10-8], and rs6055069 on DEFB127 promoter (OR = 4.17, P = 2.35 × 10-9), with consistent results in survival analysis. The CDKN2B-AS1 variant replicated (P = 0.04) when adjusted for diabetic kidney disease in three additional T1D cohorts (cases/controls: 434/3123). Furthermore, we explored the function of the lead discoveries with a cardio-phenome-wide analysis. Among the eight suggestive loci (P < 1 × 10-6), rs70962766 near B3GNT2 associated with central blood pressure, rs1344228 near CNTNAP5 with intima media thickness, and rs2112481 on GRAMD2B promoter with serum leucocyte concentration. Finally, we calculated genetic risk scores for individuals with T1D with the known susceptibility loci. General population risk variants were modestly but significantly associated with CAD also in T1D (P = 4.21 × 10-7). Conclusion: While general population CAD risk loci had limited effect on the risk in T1D, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with CAD in individuals with T1D. The novel finding on β-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility, and CAD, although pending on future confirmation.
AB - Aims: Diabetes is a known risk factor for coronary artery disease (CAD). There is accumulating evidence that CAD pathogenesis differs for individuals with type 1 diabetes (T1D). However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing CAD susceptibility, especially in T1D, to examine the function of these discoveries and to study the role of the known risk loci in T1D. Methods and results: We performed the largest genome-wide association study to date for CAD in T1D, comprising 4869 individuals with T1D (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 [odds ratio (OR) = 1.32, P = 1.50 × 10-8], and rs6055069 on DEFB127 promoter (OR = 4.17, P = 2.35 × 10-9), with consistent results in survival analysis. The CDKN2B-AS1 variant replicated (P = 0.04) when adjusted for diabetic kidney disease in three additional T1D cohorts (cases/controls: 434/3123). Furthermore, we explored the function of the lead discoveries with a cardio-phenome-wide analysis. Among the eight suggestive loci (P < 1 × 10-6), rs70962766 near B3GNT2 associated with central blood pressure, rs1344228 near CNTNAP5 with intima media thickness, and rs2112481 on GRAMD2B promoter with serum leucocyte concentration. Finally, we calculated genetic risk scores for individuals with T1D with the known susceptibility loci. General population risk variants were modestly but significantly associated with CAD also in T1D (P = 4.21 × 10-7). Conclusion: While general population CAD risk loci had limited effect on the risk in T1D, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with CAD in individuals with T1D. The novel finding on β-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility, and CAD, although pending on future confirmation.
KW - Cardiovascular disease
KW - Coronary artery disease
KW - Genetics
KW - Genome-wide association study
KW - Type 1 diabetes
U2 - 10.1093/cvr/cvaa045
DO - 10.1093/cvr/cvaa045
M3 - Journal article
C2 - 32077919
AN - SCOPUS:85100279849
VL - 117
SP - 600
EP - 612
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 2
ER -
ID: 257053556