̽��ֱ�� of Cambridge - Joanna Howson

Mothers can influence offspring’s height, lifespan and disease risk in unexpected ways – through their mitochondria

cjb250 — Mon, 17 May 2021 15:00:18 +0000

̽��ֱ��study, published today in Nature Genetics, found that genetic variants in the DNA of mitochondria could increase the risk of developing these conditions, as well influencing characteristics such as height and lifespan.

There was also evidence that some changes in mitochondrial DNA were more common in people with Scottish, Welsh or Northumbrian genetic ancestry, implying that mitochondrial DNA and nuclear DNA (which accounts for 99.9% of our genetic make-up) interact with each other.

Almost all of the DNA that makes up the human genome – the body’s ‘blueprint’ – is contained within the nuclei of our cells. Among other functions, nuclear DNA codes for the characteristics that make us individual as well as for the proteins that do most of the work in our bodies.

Our cells also contain mitochondria, often referred to as ‘batteries’, which provide the energy for our cells to function. They do this by converting the food that we eat into ATP, a molecule capable of releasing energy very quickly. Each of these mitochondria is coded for by a tiny amount of ‘mitochondrial DNA’. Mitochondrial DNA makes up only 0.1% of the overall human genome and is passed down exclusively from mother to child.

While errors in mitochondrial DNA can lead to so-called mitochondrial diseases, which can be severely disabling, until now there had been little evidence that these variants can influence more common diseases. Several small-scale studies have hinted at this possibility, but scientists have been unable to replicate their findings.

Now, a team at the ̽��ֱ�� of Cambridge has developed a new technique to study mitochondrial DNA and its relation to human diseases and characteristics in samples taken from 358,000 volunteers as part of UK Biobank, a large-scale biomedical database and research resource.

Dr Joanna Howson, who carried out the work while at the Department of Public Health and Primary Care at the ̽��ֱ�� of Cambridge, said: “Using this new method, we've been able to look for associations between the numerous features that have been recorded for participants of UK Biobank and see whether any correlate with mitochondrial DNA.

“Aside from mitochondrial diseases, we don’t generally associate mitochondrial DNA variants with common diseases. But what we’ve shown is that mitochondrial DNA – which we inherit from our mother – influences the risk of some diseases such as type 2 diabetes and MS as well as a number of common characteristics.”

Among those factors found to be influenced by mitochondrial DNA are: type 2 diabetes, multiple sclerosis, liver and kidney function, blood count parameters, life span and height. While some of the effects are seen more extremely in patients with rare inherited mitochondrial diseases – for example, patients with severe disease are often shorter than average – the effect in healthy individuals tends to be much subtler, likely accounting for just a few millimetres’ height difference, for example.

There are several possible explanations for how mitochondrial DNA exerts its influence. One is that changes to mitochondrial DNA lead to subtle differences in our ability to produce energy. However, it is likely to be more complicated, affecting complex biological pathways inside our bodies – the signals that allow our cells to operate in a coordinated fashion.

Professor Patrick Chinnery from the MRC Mitochondrial Biology Unit at Cambridge said: “If you want a complete picture of common diseases, then clearly you’re going to need to factor in the influence of mitochondrial DNA. ̽��ֱ��ultimate aim of studies of our DNA is to understand the mechanisms that underlie these diseases and find new ways to treat them. Our work could help identify potential new drug targets.”

Regional variations in mitochondrial DNA suggest complex interaction with nuclear DNA

Unlike nuclear DNA, which is passed down from both the mother and the father, mitochondria DNA is inherited exclusively from the mother. This suggests that the two systems are inherited independently and hence there should be no association between an individual’s nuclear and mitochondrial DNA – however, this was not what the team found.

̽��ֱ��researchers showed that certain nuclear genetic backgrounds are associated preferentially with certain mitochondrial genetic backgrounds, particularly in Scotland, Wales and Northumbria. This suggests that our nuclear and mitochondrial genomes have evolved – and continue to evolve – side-by-side and interact with each other.

One reason that may explain this is the need for compatibility. ATP is produced by a group of proteins inside the mitochondria, called the respiratory chain. There are over 100 components of the respiratory chain, 13 of which are coded for by mitochondrial DNA; the remainder are coded for by nuclear DNA. Even though proteins in the respiratory chain are being produced by two different genomes, the proteins need to physically interlock like pieces of a jigsaw.

If the mitochondrial DNA inherited by a child was not compatible with the nuclear DNA inherited from the father, the jigsaw would not fit together properly, thereby affecting the respiratory chain and, consequently, energy production. This might subtly influence an individual’s health or physiology, which over time could be disadvantageous from an evolutionary perspective. Conversely, matches would be encouraged by evolution and therefore become more common.

This could have implications for the success of mitochondrial transfer therapy – a new technique that enables scientists to replace a mother’s defective mitochondria with those from a donor, thereby preventing her child from having a potentially life-threatening mitochondrial disease.

“It looks like our mitochondrial DNA is matched to our nuclear DNA to some extent – in other words, you can’t just swap the mitochondria with any donor, just as you can’t take a blood transfusion from anyone,” explained Professor Chinnery. “Fortunately, this possibility has already been factored into the approach taken by the team at Newcastle who have pioneered this therapy.”

̽��ֱ��study was funded by Wellcome and the British Heart Foundation. Additional support was provided by the NIHR Cambridge Biomedical Research Centre.

Reference
Yonova-Doing, E et al. An atlas of mitochondrial DNA genotype-phenotype associations in the UK Biobank. Nature Genetics; 17 May 2021; DOI: 10.1038/s41588-021-00868-1

Mitochondria - the ‘batteries’ that power our cells – play an unexpected role in common diseases such as type 2 diabetes and multiple sclerosis, concludes a study of over 350,000 people conducted by the ̽��ֱ�� of Cambridge.

If you want a complete picture of common diseases, then clearly you’re going to need to factor in the influence of mitochondrial DNA

Patrick Chinnery

Bruno Nascimento

Mother and child

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Major global study reveals new hypertension and blood pressure genes

sc604 — Mon, 12 Sep 2016 15:00:00 +0000

̽��ֱ��discoveries include DNA changes in three genes that have much larger effects on blood pressure in the population than previously seen, providing new insights into the physiology of hypertension and suggesting new targets for treatment.

High blood pressure or hypertension is a major risk factor for cardiovascular disease and premature death. It is estimated to be responsible for a larger proportion of global disease burden and premature mortality than any other disease risk factor. However, there is limited knowledge on the genetics of blood pressure.

̽��ֱ��teams investigated the genotypes of around 347,000 people and their health records to find links between their genetic make-up and cardiovascular health. ̽��ֱ��participants included healthy individuals and those with diabetes, coronary artery disease and hypertension, from across Europe, (including the UK, Denmark, Sweden, Norway, Finland and Estonia), the USA, Pakistan and Bangladesh. ̽��ֱ��study brought together around 200 investigators from across 15 countries.

Study author Professor Patricia Munroe from QMUL said: “We already know from earlier studies that high blood pressure is a major risk factor for cardiovascular disease. Finding more genetic regions associated with the condition allows us to map and understand new biological pathways through which the disease develops, and also highlight potential new therapeutic targets. This could even reveal drugs that are already out there but may now potentially be used to treat hypertension.”

Most genetic blood pressure discoveries until now have been of common genetic variants that have small effects on blood pressure. ̽��ֱ��study, published in Nature Genetics, has found variants in three genes that appear to be rare in the population, but have up to twice the effect on blood pressure.

“ ̽��ֱ��sheer scale of our study has enabled us to identify genetic variants carried by less than one in a hundred people that affect blood pressure regulation,” said study author, Dr Joanna Howson from Cambridge’s Department of Public Health and Primary Care. “While we have known for a long time that blood pressure is a risk factor for coronary heart disease and stroke, our study has shown that there are common genetic risk factors underlying these conditions.”

RBM47 is a gene that encodes for a protein responsible for modifying RNA. RRAS is involved in cell cycle processes and has already been implicated in a syndrome related to ‘Noonan syndrome’ which is characterised by heart abnormalities. COL21A1 is involved in collagen formation in many tissues, including the heart and aorta. COL21A1 and RRAS warrant particular interest since both are involved in blood vessel remodelling, with relevance to hypertension.

̽��ֱ��team also found a mutation in a key molecule ENPEP that affects blood pressure. This gene codes for an enzyme that is a key molecule involved in regulating blood pressure through the dilation and constriction of blood vessels, and is currently a therapeutic target.

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation which part-funded the research, said: “Large scale genetic studies continue to expand the number of genes that may contribute to the development of heart disease, or risk factors such as high blood pressure. But so far most of the genes discovered in these studies individually have only very small effects on risk – though they may still provide valuable clues for new drug targets.

“This study has increased the number of genes implicated in control of blood pressure to almost 100 and, in the process, has also identified three genes that have larger effects on blood pressure than previously found.”

̽��ֱ��study was also funded by the National Institute for Health Research (NIHR), National Institute of Health (NIH), Wellcome Trust and the Medical Research Council.

Reference:
Surendran et al. ‘Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension’. Nature Genetics 2016. DOI: 10.1038/ng.3654

Thirty-one new gene regions linked with blood pressure have been identified in one of the largest genetic studies of blood pressure to date, involving over 347,000 people, and jointly led by Queen Mary ̽��ֱ�� of London (QMUL) and the ̽��ֱ�� of Cambridge.

While we have known for a long time that blood pressure is a risk factor for coronary heart disease and stroke, our study has shown that there are common genetic risk factors underlying these conditions.

Joanna Howson

Yale Rosen

Pulmonary hypertension-associated vasculitis

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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