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. 2022 Sep 14;28(1):113.
doi: 10.1186/s10020-022-00542-0.

Variants influencing age at diagnosis of HNF1A-MODY

Agnieszka H Ludwig-Słomczyńska  1 , Michał T Seweryn  1   2 , Piotr Radkowski  1 , Przemysław Kapusta  1 , Julita Machlowska  1 , Stepanka Pruhova  3 , Daniela Gasperikova  4 , Christine Bellanne-Chantelot  5 , Andrew Hattersley  6 , Balamurugan Kandasamy  7 , Lisa Letourneau-Freiberg  7 , Louis Philipson  7 , Alessandro Doria  8 , Paweł P Wołkow  1 , Maciej T Małecki  9 , Tomasz Klupa  10
Affiliations

Variants influencing age at diagnosis of HNF1A-MODY

Agnieszka H Ludwig-Słomczyńska et al. Mol Med. .

Abstract

Background: HNF1A-MODY is a monogenic form of diabetes caused by variants in the HNF1A gene. Different HNF1A variants are associated with differences in age of disease onset, but other factors are postulated to influence this trait. Here, we searched for genetic variants influencing age of HNF1A-MODY onset.

Methods: Blood samples from 843 HNF1A-MODY patients from Czech Republic, France, Poland, Slovakia, the UK and the US were collected. A validation set consisted of 121 patients from the US. We conducted a genome-wide association study in 843 HNF1A-MODY patients. Samples were genotyped using Illumina Human Core arrays. The core analysis was performed using the GENESIS package in R statistical software. Kinship coefficients were estimated with the KING and PC-Relate algorithms. In the linear mixed model, we accounted for year of birth, sex, and location of the HNF1A causative variant.

Results: A suggestive association with age of disease onset was observed for rs2305198 (p = 2.09E-07) and rs7079157 (p = 3.96E-06) in the HK1 gene, rs2637248 in the LRMDA gene (p = 2.44E-05), and intergenic variant rs2825115 (p = 2.04E-05). Variant rs2637248 reached nominal significance (p = 0.019), while rs7079157 (p = 0.058) and rs2825115 (p = 0.068) showed suggestive association with age at diabetes onset in the validation set.

Conclusions: rs2637248 in the LRMDA gene is associated with age at diabetes onset in HNF1A-MODY patients.

Keywords: Age at disease onset; Diabetes; GWAS; HNF1A-MODY.

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Conflict of interest statement

The authors declare they have no competing interests.

Figures

Fig. 1
Fig. 1
Dependence of age at disease diagnosis on date of birth
Fig. 2
Fig. 2
Location of HNF1A variant and age at diagnosis in patients with variants in the DNA-binding (B), dimerization (D) or transactivation (T) domains of HNF1A
Fig. 3
Fig. 3
eQTL analysis for HK1 SNP rs2305198 A and STON1-GTF2A1L SNP rs10865231 B and LRMDA SNP rs2637248 (C); CI confidence interval, eQTL expression quantitative trait locus, NES normalized effect size, SNP singlE−nucleotide polymorphism
Fig. 3
Fig. 3
eQTL analysis for HK1 SNP rs2305198 A and STON1-GTF2A1L SNP rs10865231 B and LRMDA SNP rs2637248 (C); CI confidence interval, eQTL expression quantitative trait locus, NES normalized effect size, SNP singlE−nucleotide polymorphism
Fig. 3
Fig. 3
eQTL analysis for HK1 SNP rs2305198 A and STON1-GTF2A1L SNP rs10865231 B and LRMDA SNP rs2637248 (C); CI confidence interval, eQTL expression quantitative trait locus, NES normalized effect size, SNP singlE−nucleotide polymorphism
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