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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 12 4650-4655
Copyright © 2007 by The Endocrine Society

Familial Risk Factors for Microvascular Complications and Differential Male-Female Risk in a Large Cohort of American Families with Type 1 Diabetes

Maria C. Monti, John T. Lonsdale, Cristina Montomoli, Rebecca Montross, Erin Schlag and David A. Greenberg

Division of Statistical Genetics (M.C.M., D.A.G.), Departments of Biostatistics (M.C.M., D.A.G.) and Psychiatry (D.A.G.), Columbia University, New York, New York 10032; National Disease Research Interchange (J.T.L., R.M., E.S.), Philadelphia, Pennsylvania 19103; Section of Medical Statistics and Epidemiology (M.C.M., C.M.), Department of Health Sciences, University of Pavia, 27100 Pavia, Italy; and New York State Psychiatric Institute (D.A.G.), New York, New York 10032

Address all correspondence and requests for reprints to: David A. Greenberg, 722 West 168th Street, Room 623, New York, New York 10032. E-mail: dag2005{at}columbia.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Type 1 diabetes (T1D) complications are responsible for much of the disease morbidity. Evidence suggests that familial factors exert an influence on susceptibility to complications.

Objectives: We investigated familial risk factors and gender differences for retinopathy, nephropathy, and neuropathy.

Design and Setting: This study was a case-control design nested on a cohort of T1D families. We collected data (questionnaire, medical records) starting in 1988. Follow-up has been ongoing since 2004.

Patients: There were 8114 T1D patients among 6707 families. All patients had T1D onset age younger than 30 yr and required insulin treatment. Patients who remained without a complication after more than 15 yr of diabetes were considered to be without that complication for our analyses.

Results: A complication in a sibling increased the risk for that complication among probands: odds ratio 9.9 (P < 0.001) for retinopathy, 6.2 for nephropathy (P < 0.001), and 2.2 for neuropathy (P < 0.05). Compared with male probands, a female T1D proband had 1.7-fold higher retinopathy risk (P < 0.001) and 2-fold higher neuropathy risk (P < 0.001). T1D cases with onset between ages 5 and 14 yr had an increased complications risk compared with subjects diagnosed either at a very young age or after puberty. The presence of one complication significantly increased the risk for others. If a parent had type 2 diabetes, the risk for nephropathy increased (odds ratio 1.9, P < 0.01, but T1D in a parent did not increase the risk).

Conclusions: We confirmed that familial factors influence T1D microvascular pathologies, suggesting a shared genetic basis for complications, perhaps independent of T1D susceptibility. We also found an unexpected increased female risk for complications.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
RETINOPATHY, NEPHROPATHY, and neuropathy are long-term microvascular complications responsible for much of the morbidity in type 1 diabetes and type 2 diabetes. Retinopathy, a major cause of blindness (1), occurs in up to 50% of type 1 diabetes patients and in about 10% of patients with type 2 diabetes who have had the disease for 15 or more years (2). Ten to 20% (cumulative prevalence) of type 1 diabetes patients have established nephropathy (3, 4, 5, 6, 7), a leading cause of end-stage renal failure and the primary cause of excess mortality in type 1 diabetes patients (8). Diabetic neuropathies affect different parts of the nervous system and present with diverse clinical manifestations. Evidence suggests that familial factors exert a strong influence on susceptibility to complications (8, 9, 10, 11); and a family history of type 2 diabetes has been reported to be a risk factor for diabetic nephropathy in type 1 diabetes patients (12).

Our goals were to identify familial risk factors for diabetic microvascular complications and to examine how these risk factors influence retinopathy, nephropathy, and neuropathy onset. We analyzed data from the large cohort of type 1 diabetes patients and families assembled over 25 yr by the Human Biological Data Interchange (HBDI), a program of the nonprofit National Disease Research Interchange (NDRI).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Type 1 diabetes subjects

A total of 8114 subjects in the HBDI sample had type 1 diabetes diagnosed before age 30 yr (Table 1Go), of whom 4935 were probands and 921 were affected siblings. Of those, 1225 had at least one diabetic complication; 695 subjects were parents and 1563 were third- or fourth-degree relatives of probands. There were 740 multiplex families (i.e. families with more than one type 1 diabetes sibling diagnosed before age of 30 yr). Ninety-four percent of type 1 diabetes patients were Caucasian, 1.8% Hispanic, 1.1% black, 0.8% American Indian, 0.2% Asian, 0.2% African-American, 0.2% biracial, and 1.7% unknown. The prevalence of type 1 diabetes in the United States is 0.5–2 per 1000 and affects 120,000–500,000 people (13, 14, 15). Considering only the probands and siblings, 20% of the subjects have follow-up information about complications. Considering only multiplex families with two affected siblings, type 1 diabetes duration averages 28 ± 10 yr among probands and 25 ± 10 yr among siblings, and follow-up information was present for 39.4% of the probands and siblings.


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  		TABLE 1. Characteristics of type 1 diabetes patients by total number of type 1 diabetes subjects in the database (n = probands + siblings + parents + third- or fourth-degree relatives) and numbers of probands, siblings, and parents only (data on, including data on complications in the 1563 third- or fourth-degree relatives of probands are not included)

 
About 10% of type 1 diabetes cases are "familial" (i.e. type 1 diabetes is seen in the first or second degree relatives) and do not appear to be etiologically different from "sporadic" cases (16). Thus, the HBDI registry represents a notable proportion of all type 1 diabetes cases in the United States: approximately 1–5% of all cases and perhaps 10–30% of familial cases.

HBDI data

The subjects included in this study were drawn from the 6707 extended families (81,810 individuals) present in the HBDI database at the end of 2004. A total of 49.5% of all subjects were females. Including third- and fourth-degree relatives (subjects not used in any analysis), there were 8,114 with type 1 diabetes, 63,951 subjects in the database without diabetes, and 4,566 individuals reporting type 2 diabetes. Fifty patients had maturity-onset diabetes of the young (MODY), two patients had gestational diabetes, and 5127 had diabetes type unknown or unclassified (e.g. type 1 diabetes diagnosed after age 30 yr).

Family identification and data collection

Data were collected from American families ascertained through the presence of at least one type 1 diabetes subject (the proband). Families were invited to be part of the HBDI data collection through a series of advertisements sent to the entire mailing list of the Juvenile Diabetes Foundation International (JDFI) during the period 1988–1990 (17). All JDFI member families were asked to complete a standardized confidential questionnaire sent by mail, data from which were added to the HBDI database. The questionnaire was administered to the proband (or parents if the proband was a child) and also to additional family informants. Inquiries included demographic, medical, genealogical, and familial information about complications. One hundred seventy-nine type 1 diabetes patients (2.2%) sent medical records with the original questionnaire.

Starting in 2004, follow-up questionnaires have been periodically sent to a subset of families to obtain updated information about development of complications, new cases of diabetes, and related medical history data, with 1000–2000 families targeted each year. The follow-up protocol requests a copy of all medical records of relevance to the diabetes and complications history.

Follow-up is sent to the primary contact person (typically the mother or father) for each family. If no address is available for the primary contact, follow-up questionnaires are sent to the next highest priority family member.

The follow-up study is ongoing. By the end of 2006, we received updated information from 1867 (23.0%) of the type 1 diabetics in the HBDI database. Whereas only 10% of subjects sent back medical records with the follow-up questionnaire, our experience is that the questions in the follow-up questionnaire reliably reflect the individual medical record information (per an ongoing validation study at HBDI), giving us some confidence in the follow-up material. Written informed consent was obtained from all individuals; the University of Pennsylvania Institutional Review Board approved the study.

Assessment and definition of diabetes and diabetic complications

We included patients with type 1 diabetes diagnosed before age 30 yr who required insulin treatment. The age of onset of microvascular complications was available for only 1.7% of the type 1 diabetes patients in the data set.

The accuracy of the self-reported information with respect to presence/absence of complications (e.g. presence of retinopathy, yes or no) was evaluated by:

1) Including extra questions about related conditions in the questionnaire. The presence of macular edema or complete or partial blindness were considered indicators of retinopathy; the presence of end-stage renal failure, kidney failure, or repeated high urinary albumin levels were considered indicators of nephropathy. In cases of inconsistencies (e.g. presence of macular edema but not retinopathy), further investigations were carried out through phone interviews.

2) The data available from follow-up were used to confirm or update the presence/absence and progression of complications.

3) Collecting medical records. For the subset of patients with medical records available, we verified the presence of type 1 diabetes and complications according to American Diabetes Association guidelines (18, 19, 20, 21).

4) Information indicating absence of a complication in a subject and was considered reliable only if the subject was without that complication for at least 15 yr after type 1 diabetes onset.

Examination of target variables for this study suggests that there is no consistent difference between the follow-up sample of probands and siblings and those without follow-up. For example, age is similar in both groups (34.2 ± 11.6 vs. 32.8 ± 11.5 yr) as is duration of diabetes (25.1 ± 9.8 vs. 23.7 ± 9.3 yr) and age of onset of diabetes (8.6 ± 5.7 vs. 8.5 ± 6.0 yr). As expected, the follow-up group shows an increase in the percent of patients with complications. The proportion of diabetic subjects with retinopathy is 21.7% in the follow-up sample vs. 8.3% in the subjects without follow-up, and nephropathy, 10.1% of follow-ups vs. 4.3% without. For neuropathy the figures are 6.7 vs. 3.2%.

Research design

We used a case-control design nested on the cohort of the HBDI type 1 diabetes patients and their families. The probands with a target complication (e.g. retinopathy) were considered the "cases." "Controls" were probands without that complication.

To identify risk factors for type 1 diabetes complications, the presence of the risk predictor(s) in the probands was considered the "exposure." We especially tested three familial risk factors: the presence of types 1 and 2 diabetes in the parents and the presence of the same complication in siblings of the proband. To control for bias related to family structure (e.g. family size, number of affected offspring) when testing for a history of a complication in a sibling, we used only nuclear families with two type 1 diabetes-affected siblings (sib-pairs).

We also examined the association among complications (risk for developing more than one complication), using the cooccurrence of other complications (e.g. nephropathy or neuropathy) as the exposure.

Statistical analysis

We used unconditional logistic regression analyses to determine associations with diabetic complications. We calculated odds ratios (ORs) and 95% confidence intervals (CIs). We adjusted for the potential confounders of age (using 5-yr intervals), and duration of diabetes (using 5-yr intervals). We examined interaction among complications. Each interaction was estimated as the ratio of the ORs among subjects who have both exposure covariates and among subjects who have only one exposure (e.g. one complication). We used nested likelihood ratio {chi}2 tests (LRTs) to determine the significance of the interaction term by comparing a model with the interaction term vs. a model with main covariate effects only (22, 23). We tested for a linear trend of the log odds for developing complications using the score test against the categories of duration of diabetes (23). A two-tailed P < 0.05 was considered statistically significant. All of the analyses were performed using the statistical package Stata 8.0 (Stata Corp., College Station, TX, 2003).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Using a total of 4389 probands with duration of type 1 diabetes longer than 15 yr and information about complications’ presence/absence available, Table 2Go gives unadjusted and adjusted ORs for microvascular complications according to parental history of type 2 diabetes or type 1 diabetes, gender, duration of diabetes, age of onset of type 1 diabetes, and age class. We will primarily interpret the adjusted analyses.


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  		TABLE 2. Unadjusted OR and adjusted OR and 95% CI for association between the presence of retinopathy, nephropathy, and neuropathy in the probands and key risk factors for type 1 diabetes

 
The presence of type 2 diabetes in a parent is a significant familial risk factor for nephropathy (OR 1.9, CI 1.2–2.9) (using unadjusted logistic regression models, the presence of type 2 diabetes in a parent is significantly associated with the development of all three microvascular complications).

We found no significant effects on the risk for developing complications related to presence of type 1 diabetes in a parent. In fact, we observed no significant difference between the proportion of diabetic offspring with complications in 188 families in which at least one parent had type 1 diabetes and the 3400 families in which both parents were healthy (27 families had missing information about diabetes in the proband’s parents).

The effect of gender on complications was statistically significant. If the type 1 diabetes proband is a female, the risk for developing retinopathy is 1.7-fold higher (CI 1.3–2.1) than the risk for a male proband, and the risk for developing neuropathy is 2-fold higher (CI 1.4–2.8) than the risk for a male. The risk for developing nephropathy tends to be higher in females, but the difference is not statistically significant. This result is not significantly influenced by the presence or absence of other complications in the probands.

The duration of diabetes was a modifier of complications risk. There is a statistically significant increasing trend for developing each complication as a function of the number of years with type 1 diabetes (retinopathy: {chi}2trend = 961.2, P < 0.001; nephropathy: {chi}2trend = 411.5 P < 0.001; and neuropathy: {chi}2trend = 379.5, P < 0.001). The OR for retinopathy was 2.7-fold higher (CI 2.4–3.0) for each increment of 5 yr of life with type 1 diabetes; the OR for nephropathy was 2.2 (CI 1.9–2.5) and was 2.3 (CI 1.9–2.7) for neuropathy.

The age of onset of diabetes (defined in categories 0–4 yr, 5–9 yr, 10–14 yr, and more than 15 yr of age) affected the risk for complications (ORs and CIs in Table 2Go). Subjects diagnosed at a very young age (<5 yr) or past puberty (>14 yr) were significantly less likely to develop complications (retinopathy, nephropathy, and neuropathy) than subjects diagnosed as older children (5–9 and 9–14 yr). This may suggest an increased vulnerability to complications during ages of rapid development.

Using 637 type 1 diabetes probands with a type 1 diabetes sibling (sib-pairs), we tested the association between observing a complication in the type 1 diabetes proband and having a history of a complication in the sibling (adjusted by gender, presence of a type 2 diabetes parent, duration of diabetes, age of onset of type 1 diabetes, and age class). The ORs for retinopathy in the proband were 9.9 (CI 5.6–17.7, P < 0.001) if the sibling had retinopathy (57 siblings had retinopathy in 125 families of probands with retinopathy vs. 26 siblings who had retinopathy in 512 families of probands without retinopathy). The corresponding OR for nephropathy was 6.18 (CI 2.9–13.2, P < 0.001) (16 siblings had nephropathy in families of 50 probands with nephropathy vs. 25 siblings who had nephropathy in 587 families of probands without nephropathy). The OR for neuropathy was 2.2 (CI 1.0–5.2; P < 0.05) (nine siblings had neuropathy in 40 families in which the proband had neuropathy vs. 32 siblings who had neuropathy in 597 families in which the proband was without neuropathy).

The genetic influence on nephropathy is well established, whereas little is known about genetic influences on retinopathy. To correct for the possibility that nephropathy is a modifier of effect, we tested sib-pairs in which neither the sibling nor the proband had neuropathy or nephropathy. If nephropathy or neuropathy were modifiers of effect, then the risk for retinopathy would be lower than for the whole sample. In fact, the adjusted OR of retinopathy in the proband was 12.2 (CI 5.5–27.4, P < 0.001) if the sibling had retinopathy (20 siblings had retinopathy in 59 families of probands with retinopathy vs. 17 siblings who had retinopathy in 483 families of probands without retinopathy), confirming a possible familial risk for retinopathy independent of the presence of the other complications.

The presence of any diabetic complication is a good predictor for the risk of the other complications, and the interaction terms between exposures (e.g. presence of nephropathy and neuropathy as risk predictors for retinopathy) presented suggestive evidence for an interaction (Table 3Go).


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  		TABLE 3. OR and 95% CI for association between the incidence of the single complication of retinopathy, nephropathy, and neuropathy and the occurrence of the other microvascular complications (covariates)

 
We also found that the percentage of females exhibiting a second complication is greater than the percentage of males with a second complication: 4.5% of females and 3.2% of males exhibited retinopathy together with nephropathy (Z = –2.62, P = 0.008); 3.4% of females exhibited retinopathy with neuropathy, compared with 2.3% of males (Z = –2.2, P = 0.02); 2.3% of females and 1.5% of males exhibited nephropathy and neuropathy (Z = –1.83, P = 0.06).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This work represents the first family-based case-control study that explores the risk for developing the three major type 1 diabetes microvascular complications. It is also the first study using a single set of data ascertained through a broad outreach program to type 1 diabetes families and a data set representing a notable proportion of familial type 1 diabetes cases in United States.

This study: 1) confirms that familial risk factors are associated with not only presence of type 1 diabetes but also the complications of nephropathy (8, 9, 10, 11, 24) and retinopathy (11, 25, 26); 2) finds new evidence that neuropathy is also familial; 3) demonstrates a female preponderance for complications; and 4) supports the idea that complications share underlying, possibly genetic, risk factors.

We observed a significant increase in frequency of complications in probands with a parental history of type 2 diabetes. For nephropathy, this association was unaffected by potential confounders, but for retinopathy and neuropathy, it was influenced by type 1 diabetes duration. The prevalence of type 2 diabetes increases with age (27), and an apparent difference in prevalence could be the result of a difference in age between the parents with type 2 diabetes and the parents without diabetes (12). However, in our study, the parents with type 2 diabetes (mean age 62 ± 12 yr) were actually younger than parents reporting no type 2 diabetes (mean age 72 ± 15 yr), a fact supporting the idea that this observation is related to the presence of type 2 diabetes in the parents and is not an age-related cohort effect. In the study by Roglic et al. (28), there is evidence of an association of parental diabetes and albuminuria in type 1 diabetes offspring, a finding that was strongest in female type 1 diabetes patients. Interestingly, in examining families in which parents had type 1 diabetes, we did not find evidence of increased risk for any complication in the type 1 diabetes offspring. However, the parents in our sample with type 1 diabetes (mean age 57 ± 12 yr) might have been too young to have offspring old enough to develop complications.

According to the literature, 15 yr with diabetes is enough time for at least 50% of patients to exhibit complications (29). Retinopathy risk increases after 20 yr duration of type 1 diabetes (7). A young cohort (in terms of duration of diabetes) could lead to an overestimation of the subjects without complications. However, the mean duration of diabetes in the subjects (probands and siblings) without retinopathy in our analyses is 24.0 ± 7.9 yr, without nephropathy, 25.0 ± 8.6 yr, and without neuropathy, 24.9 ± 8.4 yr.

We also observed that onset in the peripubertal years had an increased risk for complications, compared with both younger and older ages. This could be because of greater reluctance to acknowledge disease status due to self-image issues among teens (a well-known fact for diabetologists) or some developmental phenomenon. For example, Harjutsalo et al. (8) observed the same trend, which is also seen in older studies that stratified risk by life periods marked by hormonal level lability (4, 27, 30).

Type 1 diabetes is one of the few autoimmune diseases without female preponderance, and our analysis also showed no distortion in the type 1 diabetes male to female ratio. However, we showed that there is a female preponderance for diabetic complications in our sample. The percentage of females exhibiting a second complication was also higher than that for males. Such observations suggest that the risk of developing complications is higher in female patients. A differential effect of sex hormones may, in part, explain this difference (30). However, we lack the data to test sex-specific differences in age of onset of complications or diabetes duration before complication onset. A self-selection bias (i.e. higher likelihood of female than male questionnaire response) is unlikely to account for the increased female risk: responses to follow-up requests were 53.1% male and 46.1% female.

We found a significant association between the presence of a complication in the type 1 diabetes proband and having a history of that complication in the sibling. However, we do not have information about the age of onset of complications or their progression. This limits the interpretation of the computed risk magnitude (because we may be observing, for example, the correlation of the age of onset in siblings rather than the presence of the complication) but still clearly indicates evidence of familiality. A follow-up related study designed to test the accuracy of the computed risk magnitudes is ongoing.

Familiality of complications could reflect nongenetic factors, e.g. age, diabetes duration, and sex, but these were taken into account in our analyses. Stringent control of glucose, as reflected in glycosylated hemoglobin (HbA1c) level, is associated with a reduced risk of complications (31, 32). We could not test the question of control because HbA1c data were unavailable for the majority of the subjects in our study. However, even if glycemic control, as reflected in HbA1c levels, is responsible for susceptibility to complications [a hypothesis that has been disputed (33)], it does not rule out a separate genetic component for complication susceptibility or the possibility that the HbA1c phenomenon itself is, at least partly, under genetic control. Although glycemic control is thought to be a nongenetic risk factor for microvascular complications (8), a twin study by Snieder et al. (34) suggested that HbA1c levels are themselves genetically determined. Familial clustering of complications has been reported in studies that were able to adjust for HbA1c levels (11). Furthermore, work by Khoury et al. (35) showed that in the absence of genetic susceptibility, familial clustering of an environmental risk factor is unlikely to explain disease aggregation among siblings. Thus, genes associated with glycemic control may play a role in the background of a familial predisposition to microvascular pathologies. In a follow-up analysis, we will explore the effect (causality) of control of glucose levels on the apparent familiality of complications.

The risk for developing one complication was not independent of the risk for developing another one. Published evidence supports an association between neuropathy and other complications (36, 37). The Diabetes Control and Complication Trial (DCCT) (31) and European Diabetes Epidemiology Group (EURODIAB) (29) groups established that hyperglycemia is the initiating cause of the diabetic tissue damage, leading to evidence of microvascular complications (38).

These new findings tell us that the explanation for what causes complications must involve shared pathogenic mechanisms in the family (mechanisms that may be independent of the susceptibility to type 1 diabetes). The severity of the process could be modified by genetic determinants of individual and familial susceptibility and independent accelerating factors (such as hypertension, age, and poor glycemic control). There are limitations to our data: incomplete medical data such as HbA1c levels, complication onset age (which for retinopathy requires difficult-to-obtain serial fundus photographs), and incomplete follow-up. Nonetheless, it is compelling that many of our findings are replications of previous studies performed with complete data collection and assessment but with much smaller samples than HBDI, suggesting our confirmatory and newer findings represent reliable results. Furthermore, some of these questions are being addressed in our ongoing follow-up. A study of familial aggregation can provide only an initial indication of a possible genetic contribution to a phenotype and a crude measure of its strength but suggests the need for further genetic studies. As candidate genes for pathogenesis are identified, this HBDI resource should be invaluable for testing their role in complications. Such studies are possible because DNA from 500 of the families used in this study is available from the HBDI genetic repository.


   Acknowledgments
 
We thank the families who participated in the study, National Disease Research Interchange’s staff, and its president, Lee Ducat.


   Footnotes
 
This work was supported by Pennsylvania State 2004 Formula Grant, 4100026183, and National Institutes of Health Grants DK31775, NS27941, and MH48858.

Disclosure Statement: The authors have nothing to disclose.

First Published Online September 18, 2007

Abbreviations: CI, Confidence interval; HbA1c, glycosylated hemoglobin; HBDI, Human Biological Data Interchange; LRT, likelihood ratio {chi}2 test; OR, odds ratio.

Received May 30, 2007.

Accepted September 11, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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