Elsevier

Diabetes & Metabolism

Volume 43, Issue 6, December 2017, Pages 536-542
Diabetes & Metabolism

Original article
Family history of type 1 and type 2 diabetes and risk of latent autoimmune diabetes in adults (LADA)

https://doi.org/10.1016/j.diabet.2017.05.010Get rights and content

Abstract

Background

A family history of diabetes (FHD) is a strong predictor of diabetes risk, yet has rarely been investigated in latent autoimmune diabetes in adults (LADA). This study therefore investigated the risk of LADA and type 2 diabetes (T2D) in relation to FHD, taking into account the type of diabetes in relatives.

Methods

Data from a population-based study were used, including incident cases of LADA [glutamic acid decarboxylase antibody (GADA)-positive, n = 378] and T2D (GADA-negative, n = 1199), and their matched controls (n = 1484). First-degree relatives with disease onset at age < 40 years and taking insulin treatment were classified as type 1 diabetes (T1D) or, if otherwise, as T2D. Odds ratios (ORs) were adjusted for age, gender, BMI, education and smoking. Cases were genotyped for high- and low-risk HLA genotypes.

Results

Both FHD–T1D (OR: 5.8; 95% CI: 3.2–10.3) and FHD–T2D (OR: 1.9; 95% CI: 1.5–2.5) were associated with an increased risk of LADA, whereas the risk of T2D was associated with FHD–T2D (OR: 2.7; 95% CI: 2.2–3.3), but not FHD–T1D. In LADA patients, FHD–T1D vs FHD–T2D was associated with higher GADA but lower C-peptide levels, lower prevalence of low-risk HLA genotypes (5.0% vs 28.6%, respectively; P = 0.038) and a tendency for higher prevalence of high-risk genotypes (90.0% vs 69.1%, respectively; P = 0.0576).

Conclusion

The risk of LADA is substantially increased with FHD–T1D but also, albeit significantly less so, with FHD–T2D. This supports the idea of LADA as a mix of both T1D and T2D, but suggests that the genes related to T1D have greater impact. LADA patients with FHD–T1D had more T1D-like features, emphasizing the heterogeneity of LADA.

Introduction

A family history of diabetes (FHD) encompasses both genetic and shared environmental factors, and is a strong predictor of diabetes risk. Previous studies have indicated that diabetes in first-degree relatives confers a ninefold greater risk of type 1 diabetes (T1D) [1] and a threefold greater risk of type 2 diabetes (T2D) [2]. The genetic risk of T1D is mainly attributed to genes in the human leucocyte antigen (HLA) region, which are estimated to explain around 30–50% of familial clusterings [3]. Recent studies have identified several genes related to T2D, of which variants within the TCF7L2 gene have the strongest effect [4]. The currently identified genes, however, can only explain about 20% of the genetic heritability of T2D [5] and only a fraction of its familial aggregation [2]. Therefore, FHD remains an important, easily obtained predictor of diabetes risk [2].

Latent autoimmune diabetes in adults (LADA) is thought to be a genetic mix of both T1D and T2D [6], and linked to HLA DQB1 risk genotypes associated with autoimmunity [7], [8] as well as genes associated with T2D, including TCF7L2 [9], [10], [11]. Consequently, a family history of both type 1 diabetes (FHD–T1D) and type 2 diabetes (FHD–T2D) may promote LADA. Findings from prospective data indicate that FHD increases LADA risk two- to fourfold [12], [13], while cross-sectional studies also reveal a high prevalence of FHD [14], [15]. While studies of the relative importance of FHD–T1D vs FHD–T2D are scarce, data from a few small-scale studies support links to both T1D and T2D [16], [17], [18], [19], [20]. Also, in a prospective follow-up study of a non-diabetic population, FHD–T1D conferred a twofold greater risk of developing non-insulin-dependent diabetes [13].

Our aim was to clarify the role of FHD–T1D and FHD–T2D in relation to LADA and T2D. To this end, data were taken from a novel Swedish population-based study to create the largest study to date of FHD and LADA.

Section snippets

Study population and design

The present study used data from the Epidemiological Study of Risk Factors for LADA and Type 2 Diabetes (ESTRID), a population-based study including incident cases. A detailed description of the study design has been previously reported [21]. Briefly, ESTRID is a substudy of ANDIS (All New Diabetics in Scania) [22], a detailed study aiming to characterize all new cases of diabetes in the Swedish county of Scania. For ESTRID, all newly diagnosed LADA patients and a random sample of newly

Characteristics

As expected, patients with LADA were younger at onset, leaner, had lower levels of C-peptide and HOMA-β, and were more often treated with insulin than patients with T2D (43.5% vs 5.9%, P < 0.0001; Table 1). FHD–T1D was reported by 10.1% and FHD–T2D by 35.5% of patients with LADA. Corresponding frequencies in those with T2D were 4.8% and 46.2%, respectively. Of the genotype combinations investigated, the most common were high-risk DR4-DQ8 and low-risk DRX/X (Table SI; see supplementary materials

Discussion

Our present study is, to our knowledge, the first to explore the relative contributions of FHD–T1D and FHD–T2D to the risk of LADA. Indeed, our findings indicate that the risk of LADA is, by far, more pronounced in individuals with T1D in the family: a sixfold greater risk was associated with FHD–T1D in first-degree relatives compared with a twofold increased risk with FHD–T2D. Associations with both FHD–T1D and FHD–T2D lend support to the hypothesis of LADA as a genetic mix of T1D and T2D [10]

Strengths and limitations

Our study strengths include the large number of LADA cases, with detailed information on FHD and potential confounders, as well as the population-based nature of the study. The main limitation was that the information on FHD was self-reported. Also, patients with diabetes may be more likely to remember or enquire about their relatives with diabetes, and relatives may also be more inclined to seek medical care for symptoms, which may have led to overestimation of the association between FHD and

Author contributions

S.C., P.-O.C., L.G., M.M., B.R. and P.S. contributed to the collection of data, interpretation of the results and writing of the manuscript. L.A., V.G. and T.T. interpreted the results and participated in the writing and editing of the manuscript. T.A. contributed with statistical considerations, analysing the data and writing of the manuscript. S.C. conceptualized the research objectives and designed the study. R.H. contributed to the conduct of the study and was responsible for analysing the

Funding

The ESTRID study was funded by grants from the Swedish Medical Research Council, the Swedish Research Council for Health, Working life and Welfare, AFA Insurance Company, the Swedish Diabetes Association and the Novo Nordisk Foundation. ANDIS was funded by grants from the Swedish Medical Research Council and ERC Advanced Researcher grant (GA 269045) to LG and ALF- Swedish Research Council funding for Clinical research. Funding for ANDIU was provided by the Swedish Medical Research Council, a

Disclosure of interest

The authors declare that they have no competing interest.

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