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. 2022 Oct 21;17(10):e0275934.
doi: 10.1371/journal.pone.0275934. eCollection 2022.

Genome-wide discovery for diabetes-dependent triglycerides-associated loci

Margaret Sunitha Selvaraj  1   2   3 , Kaavya Paruchuri  1   2 , Sara Haidermota  1   2 , Rachel Bernardo  1   2 , Stephen S Rich  4 , Gina M Peloso  5 , Pradeep Natarajan  1   2   3
Affiliations

Genome-wide discovery for diabetes-dependent triglycerides-associated loci

Margaret Sunitha Selvaraj et al. PLoS One. .

Abstract

Purpose: We aimed to discover loci associated with triglyceride (TG) levels in the context of type 2 diabetes (T2D). We conducted a genome-wide association study (GWAS) in 424,120 genotyped participants of the UK Biobank (UKB) with T2D status and TG levels.

Methods: We stratified the cohort based on T2D status and conducted association analyses of TG levels for genetic variants with minor allele count (MAC) at least 20 in each stratum. Effect differences of genetic variants by T2D status were determined by Cochran's Q-test and we validated the significantly associated variants in the Mass General Brigham Biobank (MGBB).

Results: Among 21,176 T2D and 402,944 non-T2D samples from UKB, stratified GWAS identified 19 and 315 genomic risk loci significantly associated with TG levels, respectively. Only chr6p21.32 exhibited genome-wide significant heterogeneity (I2 = 98.4%; pheterogeneity = 2.1x10-15), with log(TG) effect estimates of -0.066 (95%CI: -0.082, -0.050) and 0.002 (95%CI: -0.002, 0.006) for T2D and non-T2D, respectively. The lead variant rs9274619:A (allele frequency 0.095) is located 2Kb upstream of the HLA-DQB1 gene, between HLA-DQB1 and HLA-DQA2 genes. We replicated this finding among 25,137 participants (6,951 T2D cases) of MGBB (pheterogeneity = 9.5x10-3). Phenome-wide interaction association analyses showed that the lead variant was strongly associated with a concomitant diagnosis of type 1 diabetes (T1D) as well as diabetes-associated complications.

Conclusion: In conclusion, we identified an intergenic variant near HLA-DQB1/DQA2 significantly associates with decreased triglycerides only among those with T2D and highlights an immune overlap with T1D.

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Conflict of interest statement

P.N. reports grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech / Roche, Novartis, and TenSixteen Bio, equity in geneXwell, and TenSixteen Bio, co-founder of TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Genome-wide heterogeneity between T2D strata.
Manhattan plot for heterogeneity p-values comparing T2D and non-T2D groups. Only one locus achieved genome-wide significance and the corresponding variants are colored in green. Lambda GC values from GWAS stratified by T2D status is shown in the figure. Red line: Genome-wide significance (p-value = 5x10-8), Blue line: Suggestive significance (p-value = 1x10-5). GWAS–Genome wide association studies; T2D –Type 2 Diabetes.
Fig 2
Fig 2. HLA-DQB1/DQA2 rs9274619:A significantly interacts with T2D on triglycerides.
A) Allele frequency of rs9274619:A in T2D and non-T2D samples grouped by raw TG values. Significance of samples proportions between the groups was assessed using Fisher’s exact test for the lower and higher TG bins. B) GWAS and heterogeneity statistics of the lead variant rs9274619:A at the HLA-DQB1/DQA2 locus from discovery (UKB) and replication (MGBB) cohorts based on T2D stratification. CI–Confidence Intervals; GWAS–Genome wide association studies; HLA–Human Leukocyte Antigens; MGBB–Mass General Brigham Biobank; NS–Non Significant; T2D –Type 2 Diabetes; TG–Triglycerides; UKB–UK Biobank.
Fig 3
Fig 3. Phenome wide association (PheWAS) of disease conditions stratified by T2D status.
Interaction between the rs9274619:A and T2D with multiple disease conditions as outcomes (combination of incidence and prevalence) was modeled while adjusting for all covariates (sex, age, age2, race, PC1-10). Bonferroni corrected 45 significant phenotypes were stratified by T2D status and analyzed using logistic regression. The T2D effect estimates for rs9274619:A and the interaction p-value are documented, the disease conditions are ordered based on T2D beta. From the 45 disease conditions tested, highly correlated Type1 diabetic conditions were removed while plotting the figure. PC–Principal Components; PheWAS–Phenome Wide Association Studies; T2D –Type 2 Diabetes.
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