Genetically Lowered Birth Weight May Cause Type 2 Diabetes

Alexander M Castellino, PhD

July 04, 2016

Observational studies have shown an association between low birth weight and type 2 diabetes. Now, based on a meta-analysis of two studies, new research published online June 23 in Diabetologia provides evidence that the link may be causal and due to genetics, at least to some extent.

Showing an association between single nucleotide polymorphisms (SNPs) linked with low birth weight and onset of type 2 diabetes in adulthood, the research indicates that for each 1-point increase in genetic risk score (with the score ranging from 1 to 10), the risk of developing type 2 diabetes increased by 6%.

"Previous studies suggested that prenatal growth retardation was associated with type 2 diabetes," senior author Lu Qi, MD, from the department of epidemiology at the Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, told Medscape Medical News.

"Based on analysis on genetic associations, our data suggest that the association is causal," he added.

"This study builds on observational data analyses that showed an association between low birth weight and diabetes. Results indicate that individuals with a higher genetic risk score for low birth weight have a higher odds of developing diabetes," noted Mary Beth Weber, PhD, assistant professor at the Global Diabetes Research Center at Emory University, Atlanta, Georgia, who was not involved with the study but was asked to comment for Medscape Medical News.

She pointed out that with diabetes being a major public-health problem, significantly affecting morbidity, mortality, and health costs worldwide, this new work adds to the body of knowledge on factors that might contribute to the high and growing diabetes incidence.

Dr Weber was, however, less emphatic about the causality of the relationship.

"This study does add strong evidence for causality...but is not sufficient for establishing causality 100%," she said, noting "future studies are needed to support these findings."

Nevertheless, "Since this study adds strong data to support low birth weight as a diabetes risk factor, physicians should collect data on patient birth weight and counsel patients with low birth weight on ways to reduce diabetes risk, for example, maintaining a healthy weight and being physically active," Dr Weber told Medscape Medical News.

"And pediatricians should work with parents of low-birth-weight children to establish healthy habits early on," she added.

Nurses and Doctors Used as Participants

For their study, lead author Tiange Wang, MD, also of Tulane University School of Public Health and Tropical Medicine Department, and colleagues looked at 3627 participants with type 2 diabetes and 12,974 controls of European ancestry from the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS).

The NHS, started in 1976, is a prospective cohort study of 121,700 US female registered nurses. The HPFS, started in 1987, is a prospective cohort of 51,529 male health professionals.

For this analysis, Dr Wang and colleagues used 1986 as the baseline date for both cohorts and included participants (5928 men and 10,673 women) of European ancestry with available genotype data.

Those diagnosed with type 2 diabetes from baseline until follow-up (2012 for the NHS and 2010 for HPFS) were included as cases; controls were those free of diabetes through follow-up.

Participants in the studies were required to provide their birth weight, which was highly correlated with recorded birth weight.

In genotyping individuals, seven SNPs identified from genomewide-association studies linked with low birth weight were identified from the genotypes. Of these, two were not considered as they were independently associated with type 2 diabetes.

A genetic risk score was calculated based on the five SNPs. Dr Qi explained that the highest genetic risk score (GRS) possible was 10 because each SNP had a score of 0, 1, or 2 based on the absence of any allele, presence of one allele, or presence of both alleles.

"The higher the GRS, the lower the birth weight," he explained.

GRS for Birth Weight Associated With Diabetes Risk

The researchers assessed the evidence for causality first by examining the association of the GRS and individual SNPs with type 2 diabetes, and second by performing a Mendelian randomization analysis to estimate the potentially causal effect size of low birth weight on type 2 diabetes.

Each 1-point increment in GRS associated with a 6% higher risk of type 2 diabetes was determined from a meta-analysis of the NHS and HPFS (odds ratio [OR], 1.06).

The Mendelian approach suggested that the association between genetically determined birth weight and type 2 diabetes was driven specifically by two of the five SNPs considered in the analysis, which both showed dose–response associations with risk of diabetes (both OR, 1.09).

Furthermore, the researchers observed an overall OR of 2.94 for type 2 diabetes per one standard deviation lower genetically determined birth weight.

"Genetic associations are less likely to be affected by confounding factors and have been increasingly used in causal inference," Dr Qi and researchers note in their discussion. The confounding factors such as socioeconomic status and lifestyle are inherent limitations in observational studies, which show an association but cannot conclusively infer causality.

The authors and Dr Weber agree that there is a need to look at these associations in other populations, for example, African Americans or Asian Indians — populations with high risk for both low birth weight and type 2 diabetes.

Intrauterine Exposure May Inform Diabetes Risk

Although these data do not have immediate implications for clinical practice, they suggest some things that can be done in the clinical management of patients. As well as informing parents of low-birth-weight babies of the potential increased risk of diabetes in adulthood, Dr Qi also stressed the importance of improving the mother's health before and during pregnancy.

"Notably, birth weight itself may not be an exposure relevant to type 2 diabetes; instead, the exposures influencing intrauterine growth are more likely to play a causal role in the development of the disease," he and his colleagues write in their discussion.

Risk factors for restricted intrauterine growth include malnutrition, anemia, infections, and placental insufficiency, Dr Qi indicated.

In addition, Dr Weber pointed out that there are many established risk factors for low birth weight such as race of the mother, low weight gain during pregnancy, and some health conditions. "Physicians should work with patients at risk to promote healthy birth weights," she said.

Dr Weber also noted that randomized, controlled trials like the US Diabetes Prevention Program have shown that diabetes can be prevented or delayed in high-risk individuals through lifestyle interventions promoting weight loss, increased physical activity, and healthy diets, or metformin.

"To my knowledge, there are no studies specifically looking at efforts for diabetes prevention among individuals with low birth weight," she said. But she explained that for many individuals, these proven interventions might be sufficient for preventing diabetes.

"Further research is needed, however, to determine whether low-birth-weight individuals are more prone to developing diabetes via insulin resistance or beta-cell dysfunction, as currently recommended prevention tools — metformin or lifestyle changes — may not be as effective in those with beta-cell dysfunction," she concluded.

For Dr Qi and researchers, their findings "validate the epidemiological observation of an inverse association between birth weight and type 2 diabetes and provide new evidence for intrauterine exposures in the pathogenesis of type 2 diabetes."

The authors and Dr Weber have reported no relevant financial relationships.

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Diabetologia. Published online June 23, 2016. Abstract

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