A common mitchondrial DNA variant is associated with thinness in mothers and their 20-yr-old offspring

Ellen Parker,1 D. I. W. Phillips,2 Richard A. Cockington,3 Carole Cull,4 and Jo Poulton1

1Nuffield Department of Obstetrics and Gynaecology, The Women’s Centre, John Radcliffe Hospital, Oxford; 2Medical Research Council Environmental Epidemiology Unit, University of Southampton, Southampton, United Kingdom; 3Department of Child and Adolescent Development and Rehabilitation, Women’s and Children’s Hospital, Adelaide, South Australia; and 4Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, United Kingdom

Submitted 21 December 2004 ; accepted in final form 27 June 2005


    ABSTRACT
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 ABSTRACT
 SUBJECTS, MATERIALS, AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
A common mitochondrial (mt)DNA variant that is maternally inherited, the 16189 variant, is associated with type 2 diabetes and thinness at birth. To elucidate the association of the variant with thinness, we studied the 16189 variant in a well-characterized Australian cohort (n = 161) who were followed up from birth to age 20 yr. PCR analysis and mtDNA haplotyping was carried out on DNA from 161 offspring from consecutive, normal, singleton pregnancies followed from birth to age 20 yr. The 16189 mtDNA variant was present in 14 of the 161 20 yr olds (8.7%). Both the mothers with the 16189 variant and their 20-yr-old offspring were thinner than those without. Median (interquartile range) BMI was 21.9 kg/m2 (20.4 to 22.9) in mothers with the variant compared with 23.5 (21.4 to 26.6) in those without (P = 0.013) and 22.2 (21.1 to 23.8) in 20 yr olds with the variant compared with 22.7 (20.8 to 25.6) in those without (P = 0.019). The 16189 variant was also associated with a high placental weight and high placental-to-birth weight ratio (P = 0.051 and P = 0.0024, respectively). Insulin sensitivity was normal in 20 yr olds with the 16189 variant. This contrasts with 20 yr olds who did not have the variant but who had been thin or small at birth and who had normal BMI and normal placental-to-birth weight ratio, but were insulin resistant. This study suggests that the 16189 mtDNA variant is associated with maternally inherited thinness in young adults. This may be mediated by effects on mtDNA replication and, thence, placental function. Further research is required to confirm these hypotheses.

mitochondrial deoxyribonucleic acid; placenta; birth weight; 16189 variant; OriB variant; 16189-16193 Poly-C tract


OBESITY AND FAT DISTRIBUTION are important determinants of type 2 diabetes and early cardiovascular mortality (18). Mitochondrial (mt) function is emerging as an important contributor to the risk of diabetes (19, 23, 25) and other diseases related to aging (24, 35). Transcription factors regulating the formation and activity of fat cells (6) are also regulators of mitochondrial function (14). Drugs used for treating AIDS that result in mtDNA depletion (due to inhibition of the mtDNA DNA polymerase) affect adipocyte differentiation both in vivo (22) and in tissue culture. Patients with mtDNA disease are often thin and may have abnormal fat (36). Furthermore, we (4) have shown that a common mitochondrial polymorphism, which we have termed the 16189 variant, is associated with a low Ponderal index in babies who are small in utero and subsequently "catch up".

Diabetes can be precipitated by exposure to mitochondrial poisons (37) and by downregulation of mitochondrial function in a mouse knockout (32), because ATP is critically important to both insulin production and release (2, 33). Hence, insulin secretion is impaired in maternally inherited diabetes and/or deafness (MIDD) (34), caused by the 3243G:C point mutation of mtDNA (29). In addition, {beta}-cell numbers may be reduced in mtDNA disorders (27). We (26) previously demonstrated that a common variant of mtDNA at bp 16189 is associated with type 2 diabetes in a case control study. We also showed that the variant was associated with decreased Ponderal index [weight/(height)2] and impaired glucose tolerance in adults who had gained weight rapidly after birth. This is biologically credible (19a) and suggests that the 16189 variant exacerbates the effect of impaired intrauterine nutrition on both thinness and on subsequent glucose tolerance (4),

The aim of this study was to see whether the 16189 variant was associated with reduced BMI in mothers and their offspring from birth to 20 yr in a well-characterized cohort (8) and to see whether this was related to placental weight or glucose tolerance.


    SUBJECTS, MATERIALS, AND METHODS
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 ABSTRACT
 SUBJECTS, MATERIALS, AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
DNA was available on 161 of a total of 764 individuals (21%) from the Adelaide Children’s Hospital Family Heart Survey (8). All 161 were offspring from singleton pregnancies who were followed and underwent measurment of BMI (21) and an intravenous glucose tolerance test (IVGTT) at age 20 yr. The BMI of the mothers had been measured when their offspring were aged 8 yr.

For the purposes of the current study, the lightest one-third of the whole population at birth (i.e., males weighing <3.32 and females <3.18 kg) were defined as low birth weight and the higher two tertiles as normal weight. DNA was analyzed using PCR of a 506-bp region of the large noncoding region, including the first hypervariable region (HV1) (26). Restriction digestion of the PCR product was used as previously (26) to identify individuals with the 16189 variant. All PCR products in which the MnlI site loss generated by the 16189 variant was detected were sequenced in both directions as previously in order to confirm the presence of the homopolymeric C tract and to determine the mtDNA haplotype (30). As previously, we defined the 16189 variant as the T16189C transition along with an uninterrupted homopolymeric C tract. This definition excludes those with both the T16189C transition and homoplasmy for the C16186T or C16192T transition (25a), and could thus be termed the mtDNA 16184-93 PolyC tract (11a).

Statistical analyses were performed using SAS v. 8.2 (SAS Institute; Cary, NC). Continuous data are reported as means (SD) if normally distributed, geometric mean (1 SD interval) if log-normally distributed, or median [interquartile range (IQR)], and categorical data as percentages. For normally and log-normally distributed continuous variables, comparison of multiple means was by t-tests, and adjusted P values were obtained from a generalized linear model (GLM). Nonnormally distributed continuous variables were log transformed before analysis. For categorical variables a {chi}2 test was used. P < 0.05 was taken as conventionally significant. To allow for multiple testing, P < 0.0038 would be required.


    RESULTS
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 SUBJECTS, MATERIALS, AND METHODS
 RESULTS
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Fourteen of the 161 individuals had the 16189 variant (prevalence 8.7%), confirmed by restriction enzyme analysis and sequencing. BMI of mothers of offspring with the 16189 variant were significantly lower (P = 0.013). As expected, there was a highly significant association between maternal weight and birth weight (rs = 0.23, P = 0.0051, partial correlation controlling for sex and length of gestation), between BMI and maternal BMI (rs = 0.27, P = 0.0006, partial correlation of BMI on maternal BMI controlling for sex, and the presence of the variant) and between maternal BMI and birth weight (rs = 0.19, P = 0.014, partial correlation controlling for sex). Maternal BMI was a major determinant of BMI at age 20 yr and had considerably more impact than did birth weight. The proportion of variance in BMI at age 20 yr accounted for by maternal BMI controlling for sex (difference in R2) was 80%, whereas the proportion accounted for by birthweight was 2%.

The presence of the 16189 variant was associated with BMI at age 20 yr, placental weight, placental-to-birth weight ratio, and length of gestation (P = 0.019, 0.051, 0.0024, and 0.033, respectively; Table 1). The associations of the presence of the variant with placental weight, placental weight-to-birth weight ratio, and maternal BMI were independent of gestational age, sex, maternal age, BMI at age 20 yr, and birth weight, whereas that with gestational age was independent of sex (Table 1). The association with BMI at age 20 yr was not independent of sex or gestational age.


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Table 1. Comparison of 14 individuals with the 16189 variant with remainder of cohort (n = 147) who are normal (WT)

 
Plasma insulin was lower in individuals with the 16189 variant than in those without at all time points during the IVGTT (Fig. 1), but because individuals with the 16189 variant were significantly thinner, this did not reach clear statistical significance. There was no clear difference in insulin sensitivity assessed from the IVGTT data or in {beta}-cell function as was assessed with the HOMA2 model [homeostatic model assessment (17)].



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Fig. 1. Plasma glucose (A) and insulin (B) levels during an intravenous glucose tolerance test (IVGTT) in subjects at 20 yr old, classified into 3 groups: variant mitochondrial (mt)DNA (16189), wild-type (WT) mtDNA with birth weight (BW) ≥3,270 g (WT normal BW), and WT mtDNA with BW <3,270 g (WT low BW). Insulin and glucose levels during IVGTT were not significantly different in 20 yr olds with the 16189 variant compared with the whole WT population. Compared with the lower one-third of BW in the WT mtDNA group there was a suggestion of lower plasma insulin during the first 20–30 min, but this reached statistical significance only at 3 min (P = 0.0101, controlling for sex and BMI). Similarly, the 3-min plasma glucose level was significantly lower (P = 0.046 controlling for sex and BMI). These results must be viewed with caution in view of multiple testing and the small number of individuals with the variant mtDNA. Error bars are ±2 SE.

 
Sequence analysis demonstrated 12 distinct mitochondrial haplotypes in individuals with the 16189 variant (Table 2) (30), implying that the 16189 variants arose independently in several different maternal lines.


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Table 2. mtDNA haplotypes identified in the 14 individuals with the 16189 variant in the mtDNA hypervariable region 1

 

    DISCUSSION
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 ABSTRACT
 SUBJECTS, MATERIALS, AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
We demonstrated a significant association between the 16189 variant and thinness (low BMI) in both mothers and their 20-yr-old offspring, associated with significantly raised placental weight, and raised placental-to-birth weight ratio, in an Australian birth cohort. Although we recognize that the power to detect differences in this study at ~5% is too small to provide any proof of an association, the study nevertheless provides support for the hypothesis and further supports a recent animal study (35) suggesting that mtDNA may be an important genetic contributor to heritable thinness (5). Because placental surface area and, hence, weight reflect placental function (21), our study also supports the suggestion that thinness in adult life may be linked to intrauterine nutrition.

Because ours was a cohort study, it gives a useful estimate of the prevalence of the 16189 variant in the Caucasian Adelaide population as 8.7%. This is similar to the prevalence found in a different Caucasian population (8.8%) (4). Recombination of mtDNA is extremely rare; hence, mtDNA haplotypes reflect maternal origins. Haplotype analysis (Table 2) (30) demonstrated that the 16189 variant had arisen several times independently in this population. Hence, the excess of individuals with the 16189 variant who were thin at age 20 yr was not due to a single mitochondrial founder. This is a strong finding because of the advantage that mtDNA haplotyping confers to this study over association studies of nuclear genes. Because recombination is not a common feature of mitochondrial inheritance (12), we are able to infer that it is probably the 16189 variant per se, and not cosegregating genetic factors, that underlies the association with large placenta and thinness in both 20 yr olds and their mothers.

A high placental-to-birth weight ratio has been observed where mothers smoke, are anemic (10), are hypoxic due to high altitude (31), or have low carbohydrate intakes early in pregnancy (9) and in babies that are small for gestational age (13). A unifying hypothesis for these observations would be that the placenta enlarges to compensate for whatever "fetal stress" results in the thinness. Individuals with the 16189 variant were thinner and had thinner mothers and higher placental-to-birth weight ratios than normal, suggesting that the 16189 variant may act as another such stress. It is not known whether such a trend is apparent in babies with mtDNA diseases. In the majority of unstressed pregnancies, maternal BMI is positively correlated with placental-to-birth weight ratio (15). Other studies have shown that mutations in maternal and fetal glucokinase genes affecting insulin release may influence the growth of both fetus (11) and placenta. Hence, genes that are important in intrauterine development may also predispose to diabetes.

Although this study was too small to investigate precisely our previous finding in a United Kingdom birth cohort (n = 545) where babies whose postnatal growth subsequently "caught up" and had the 16189 variant were thinner at birth than those without (4), it confirms that the variant is related to thinness. The marginally lower insulin levels at age 20 yr (Fig. 1) suggest that thinness may result from low levels of insulin in utero. This is consistent with the key role that mitochondria play in the differentiation of adipose tissue and the association of mitochondrial inhibitors with lipodystrophy (22). It is clear that genes relating to adipocyte metabolism may be important determinants of obesity and subsequent diabetes (1, 3, 16).

In a previous analysis of the current patient series (8), men who were lighter or shorter as babies were less insulin sensitive independently of their BMI or body fat distribution. They also had higher insulin secretion and increased glucose effectiveness. Overall glucose tolerance, however, did not correlate with birth size for the whole group. In contrast, the metabolic profiles of individuals with the 16189 variant in the current study were substantially different from individuals with the lowest birth weights. Although individuals who were small or short at birth and had normal mtDNA were insulin resistant by age 20 yr (8), those with the 16189 variant had normal insulin sensitivity (Table 1). Hence, the current data suggest that the association of the 16189 variant with type 2 diabetes is not because the variant causes low birth weight and thence insulin resistance. Mitochondrial function may also be important in insulin resistance, since there is recent evidence for a coordinated downregulation of genes involved in oxidative phosphorylation in skeletal muscle of patients with type 2 diabetes (19, 23). It is thus possible that mild mitochondrial dysfunction, conferred in part by the 16189 variant, may predispose to type 2 diabetes both at the level of the {beta}-cell and at the level of glucose disposal related to aging. The 16189 variant lies within the control region of mtDNA. A very recent paper presents evidence for a novel origin of replication centered on bp 16189 of mtDNA (38). Although previously there was no link to replication, these new data provide a molecular rationale for the associations described here. We (20) have recently demonstrated that the 16189 variant has a subtle effect on mitochondrial function, as we have observed a reproducible segregation of the variant in cell culture that is characteristic of detrimental mutants.

There is, however, an apparent difference between the effect of the 16189 variant on BMI and on fasting insulin level in the 20 yr olds and in our previous study of 64-yr-old men, where we found normal BMI and high fasting insulin levels (28). In neither of these studies were there prospective data covering the age range when type 2 diabetes normally develops. The progressive deterioration that is characteristic of mtDNA disease may underlie a change in glucose homeostasis occurring during the period when we have no data. Furthermore, a decline in mitochondrial function may contribute to the progressive insulin resistance that is a consequence of aging (24).

In conclusion, this study suggests that the 16189 variant is associated with thinness in young adults and their mothers. The association with high placental-to-birth weight ratio suggests some kind of biological compensation. In contrast with 20 yr olds who had been small at birth for other reasons, thinness associated with the 16189 variant is not accompanied by insulin resistance. As with other causes of small size in early life, the 16189 variant increases the risk of type 2 diabetes, but apparently by a distinct mechanism. Further research is required to confirm these hypotheses.


    GRANTS
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 ABSTRACT
 SUBJECTS, MATERIALS, AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Financial support for the mitochondrial studies was from The Royal Society, the Medical Research Council, the Wellcome Trust, and Diabetes UK.


    ACKNOWLEDGMENTS
 
We thank the patients and their physicians for cooperation with the study, particularly Dr. V. M. Moore. We thank Drs. A. Clark, P. Oakeshott, and T. Wallace and Prof. D. Matthews for useful comments on the manuscript, and Prof. D. Barlow for support. J. Poulton is a Royal Society University Research Fellow.


    FOOTNOTES
 

Address for reprint requests and other correspondence: J. Poulton, Nuffield Dept. of Obstetrics and Gynaecology, The Women’s Centre, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom (e-mail: Joanna.poulton{at}obs-gyn.ox.ac.uk)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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 DISCUSSION
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