Is diabetes genetic? Using multi ancestry GWAS in about 2 million diabetic people, Vujikovic et al. found genetic variants associated with Type 2 Diabetes mellitus.
SUMMARY: Discovery of 568 novel genomic regions associated with type 2 diabetes in a multi-ethnic study.
OVERVIEW: Insulin is a hormone that promotes cells to intake sugar from the blood. People with type 2 diabetes no longer respond to insulin, meaning sugar has a hard time getting into cells and builds up in the blood. This study looked at the genetics of type 2 diabetes in 228,499 cases and 1,178.783 controls that included Europeans, African Americans, Hispanics, South Asians, and East Asians. The authors found 568 associations, 318 of which are novel. Using this information, they also discovered that a higher genetic risk of type 2 diabetes leads to a higher risk of chronic kidney disease, peripheral artery disease, and neuropathy, all of which can be caused by diabetes.
DID YOU KNOW? Nerve damage, called neuropathy, can be caused by high blood sugar. It’s important for diabetics to control their blood sugar to prevent damage to their nerves. [SOURCE]
SAMPLE RESULTS: Learn more about the Nebula Research Library.
DIABETES-ASSOCIATED VARIANTS: rs35011184, rs2237897, rs10440833, rs10811661, rs1421085, rs9859406, rs13266634, rs1111875, rs76895963, rs860262, rs2943650, rs13262861, rs10228796, rs10937721, rs11616380, rs28642213, rs11651755, rs10830963, rs464605, rs12910361, rs11257655, rs11602873, rs76675804, rs11708067, rs1260326, rs4929965, rs2796441, rs10184004, rs697239, rs17036160, rs757110, rs61779284, rs3751239, rs2257883, rs17866443, rs340874, rs13094957, rs8107527, rs72802365, rs243018, rs893617, rs34584161, rs75432112, rs6777684, rs2876354, rs730831, rs6567160, rs57286125, rs6946660, rs7732130, rs3130931, rs146886108, rs2290203, rs13434089, rs9379084, rs4237150, rs6813195, rs10938398, rs8071043, rs4865796, rs7163757, rs730497, rs79090772, rs12625671, rs2723065, rs56348580, rs9515905, rs12454712, rs8192675, rs7156625, rs3130283, rs529565, rs35895680, rs1127215, rs429358, rs3887925, rs56337234, rs6975279, rs34341, rs3918298, rs11759026, rs10188334, rs676387, rs3798519, rs2453051, rs58542926, rs9308614, rs9384, rs9316500, rs244415, rs6495182, rs2820446, rs9873519, rs12192275, rs4805881, rs8043085, rs66815886, rs1426371, rs4709746, rs55857387, rs10750397, rs10808671, rs3747207, rs1412234, rs12986742, rs2280141, rs79310463, rs67269808, rs917195, rs4923864, rs2115107, rs348330, rs56823429, rs12789028, rs13268508, rs72926932, rs80196932, rs12603589, rs3802219, rs11583755, rs1650505, rs73221116, rs11048457, rs11614914, rs6066138, rs10879261, rs3996350, rs55691245, rs149336329, rs838720, rs4809906, rs80234489, rs4930726, rs7147483, rs13040225, rs9472139, rs501470, rs7941510, rs6059662, rs177045, rs1801645, rs60384372, rs10773000, rs2282456, rs8054556, rs2409742, rs12883788, rs7674402, rs7758002, rs7633673, rs945187, rs56243018, rs4810145, rs4335, rs7224711, rs10998338, rs2169033, rs7178762, rs2591392, rs2040792, rs34247110, rs28819812, rs314879, rs73239895, rs12001437, rs539515, rs6741676, rs2277339, rs117316450, rs11078916, rs6792892, rs7659468, rs6538805, rs62492368, rs303760, rs2297508, rs8061528, rs10993072, rs1815591, rs56392746, rs2732469, rs9390022, rs9872347, rs7132908, rs75253922, rs7629, rs3816605, rs6956980, rs10408163, rs7895872, rs12419690, rs62618693, rs6716394, rs17035289, rs10916780, rs12380322, rs6710938, rs35251247, rs13237518, rs329118, rs4382480, rs2730827, rs113135335, rs12187734, rs75080135, rs2269247, rs7787720, rs144052331, rs9479, rs145904381, rs7227272, rs1561927, rs667920, rs6011155, rs6565922, rs1996617, rs36062478, rs583769, rs4776970, rs152839, rs10844519, rs11155073, rs112324411, rs117233795, rs7029718, rs7645613, rs8056890, rs28490139, rs13365225, rs149027146, rs7752666, rs12505942, rs7071036, rs60251368, rs187653072, rs6021276, rs2482506, rs11181613, rs3845843, rs10818763, rs8010382, rs2725370, rs2608953, rs11561066, rs993380, rs7246440, rs6073143, rs3887059, rs654629, rs34845373, rs111765639, rs13406280, rs2605281, rs1567353, rs57767539, rs3020781, rs5762925, rs6766859, rs41304257, rs3872707, rs2613499, rs4397977, rs924753, rs2188848, rs6549112, rs10737818, rs247975, rs7240767, rs6712905, rs2867570, rs17662402, rs174541, rs12185519, rs2872246, rs4479849, rs11646052, rs2032217, rs7970687, rs7554251, rs112515915, rs9814945, rs56799554, rs242105, rs61817176, rs2255703, rs2289739, rs12918782, rs3744347, rs379417, rs4777857, rs61736066, rs9587811, rs61579137, rs7742292, rs2056857, rs4906272, rs4671799, rs4343858, rs9913225, rs3755879, rs7483027, rs6835992, rs11201992, rs9568868, rs28712435, rs1408579, rs6714523, rs727734, rs12932337, rs12539264, rs13415288, rs76789970, rs4976033, rs9370243, rs11108094, rs3753693, rs11240351, rs34298980, rs13099581, rs62271373, rs34329895, rs9319943, rs506597, rs62262091, rs4655617, rs2956092, rs71495046, rs149447188, rs9257408, rs1431819, rs7546252, rs524903, rs200995462, rs9857204, rs12056338, rs2066827, rs9937296, rs35901985, rs7134150, rs1885234, rs72692804, rs1570247, rs12041243, rs12746673, rs11046164, rs2513505, rs4384608, rs10767659, rs2240716, rs10750840, rs1194592, rs2447198, rs2150999, rs16881572, rs3122231, rs3012060, rs12151653, rs9438610, rs1327123, rs9927842, rs6558173, rs73121277, rs9564268, rs261967, rs10096633, rs11913442, rs11998023, rs35753840, rs11199116, rs2408252, rs28408270, rs1470560, rs410150, rs6479591, rs10766076, rs858519, rs2252115, rs55812705, rs10404726, rs4902002, rs13059382, rs11173646, rs11159347, rs12128213, rs38221, rs4673712, rs28758542, rs62452060, rs13238568, rs10119430, rs723355, rs10159026, rs10889560, rs73642097, rs7274134, rs6597649, rs9991328, rs6972291, rs148106383, rs12856169, rs4833687, rs17810376, rs12669521, rs5010712, rs74677818, rs77424687, rs17265513, rs11096542, rs58090211, rs2633311, rs12422600, rs11258422, rs76263492, rs11114650, rs705145, rs7316626, rs59646751, rs33959228, rs884847, rs978444, rs1075855, rs2272163, rs2125799, rs7758115, rs17439448, rs138771, rs9869477, rs529623, rs4129858, rs4252505, rs6978327, rs9411425, rs79598313, rs11150745, rs116861182, rs1812707, rs72803684, rs1109442, 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rs9560114, rs17772814, rs111283203, rs2216063, rs1662185, rs4820323, rs12667919, rs12825669, rs10469860, rs712315, rs4832290, rs1929883, rs9449295, rs366577, rs28792187, rs13330163, rs62255926, rs11858759, rs372558, rs16907058, rs72846863, rs1877712, rs243513, rs6885157, rs538801, rs13288108, rs62490267, rs7130522, rs12140153
WEEKLY UPDATE: October 19, 2020
Further information: Is diabetes genetic?
|Image source: Glen Carries, Unsplash|
Introduction: Diabetes and its genetics
Diabetes mellitus is a chronic disease marked by increased blood sugar levels. It is a disorder of carbohydrate metabolism. Lack of insulin causes diabetes mellitus and leads to chronic hyperglycemia. The characteristics of this complex disorder include hyperglycemia, glucosuria, acidosis, and ketosis.
History of diabetes and its genetics
History of diabetes dates back to 250 BC when this term was coined by Apollonius of Memphis. The ancient Greeks and Persians have related diabetes with the sweet taste of urine. And this was due to the excessive excretion of sugars in the urine.
The idea of understanding the history of the genetic component of diabetes has always intrigued the scientists worldwide. In this context, it never goes without saying that studies from the 1970s have associated HLA genes with diabetes (type 1).
Published in 2000, results from genome wide screen for the susceptibility genes identified calpain-10 to be associated with diabetes (type 2) in a group of Mexican Americans. This work was among some of the first studies to map the susceptibility genes. In recent years, numerous other reports have identified the genetic architecture of diabetes (see below).
There are primarily three types of diabetes. They are Type1 Diabetes, Type 2 diabetes, Gestational Diabetes.
- Type 1 Diabetes mellitus: This type of diabetes is autoimmune in nature. In this diabetes insulin production does not occur. And this is because the β cells of the islets of Langerhans in the pancreas undergo destruction. For this reason, this diabetes is also known as insulin-dependent diabetes. Type 1 diabetes occurs most often during the teenage years and is therefore also called juvenile diabetes.
- Type 2 Diabetes mellitus: Type 2 Diabetes is the less severe form of diabetes. Although insulin is produced, the production is not sufficient. Also, it is likely that the body might not use insulin leading to insulin resistance. It is also known as non-insulin-dependent diabetes.
- Gestational Diabetes: Blood glucose level rises during pregnancy to cause gestational diabetes. This kind of diabetes most likely affects the baby and can cause severe complications if not treated in due time.
Physiology and genetics of diabetes
Insulin plays a crucial role in diabetes. It is a hormone made in the pancreas and promotes the absorption of glucose throughout the body.
Prior to diabetes, a pre-condition called prediabetes occurs. Prediabetes usually tends to precede Type 2 Diabetes and go unnoticed. During prediabetes, the blood glucose level goes up but does not cross the threshold of diabetes.
Mode of action of insulin
- The digestive system breaks down the complex carbohydrates (example: cereals, fruits, potatoes, etc.) into simple sugars namely glucose. These sugars are then absorbed into the blood through the intestinal wall and distributed throughout the body.
- The pancreas produces the hormone insulin in the β cells of the islets of Langerhans. Insulin causes glucose to be transported into the interior part of the cell. Once inside the cell, the glucose is then consumed to produce energy in a process known as glycolysis.
- In addition, insulin also causes glucose to be stored in the form of glycogen in the liver as well as in the muscle cells. Hence, this keeps the blood sugar level constant within narrow limits (approx. 80-120 mg/dL or 4.5-6.7 mmol/L).
- Even during long periods of fasting, the blood sugar level remains at a normal level. And this in turn is mainly ensured by the liver. This is due to the fact that glycogen that was previously formed is metabolized into glucose, then released back into the blood. And on the other hand, the liver constantly produces glucose by a process known as gluconeogenesis.
- In addition, insulin has another effect. It is one of those hormones in the human body that aids in the synthesis of fat. Simultaneously, it also ensures that this fat remains in the depots, an effect termed adipogenic effect.
What happens during insulin shortage?
- Sometimes it so happens that the β cells are unable to prepare sufficient amounts of insulin or no insulin at all. Due to this, both the uptake of glucose into the body’s cells and the inhibition of glucose regeneration in the liver (which can produce up to 500 grams of new glucose daily in humans) are no longer possible.
- This explains the rise in the blood sugar level in diabetics, for example, in the early morning. In diabetes mellitus, either glucose remains in the blood, or the glucose production in the liver continues unchecked. And a constant supply of glucose occurs.
- Resultantly the blood sugar level rises. Overall, it is a very complex and dynamic biochemical process in which synthesis, flux, and breakdown of glucose must be constantly balanced.
- Moreover, an increase in blood sugar compromises the body’s immune system. Hence, diabetic people are vulnerable to infections.
- A common manifestation of severe, persistent insulin deficiency is weight loss. This happens especially due to the utilization of the body fat and (muscle) protein for energy production.
- Mechanisms that lead to hyperglycemia are mainly based on insulin: absolute insulin deficiency, relative insulin deficiency due to insulin resistance, or both. Due to the long-term consequences of diabetes mellitus, the nervous and vascular systems undergo multiple changes.
- Over two decades, reports have identified diabetes-associated genetic variants in populations worldwide. However, capturing the diversity of the population is important to understand the genetic architecture of diabetes.
- Family history of type 1 diabetes is a potent risk factor in the development of diabetes in offspring. Much remains unclear when it comes to determining the extent to which family history plays a role in the development of type 2 diabetes.
|Figure: Sugar transport mechanism in normal (left) and diabetic (right) condition. Image source: Manu5, Wikimedia Commons, CC-BY-SA 4.0|
Epidemiology and prevalence of diabetes
GWAS reportedly disentangles the genetic epidemiology of diabetes.
Type 2 Diabetes is dominant in the majority of diabetics people. As of 2019 diabetes has been responsible for causing 4.2 million deaths worldwide. Besides, 232 million diabetic people remain undiagnosed. Around 79% of diabetic people reportedly live in low and middle-income countries.
According to the 2020 update by CDC, 34.2 million people are diabetic and account for 10.5% of the US population. And around 7.3 million people accounting for 21.4% of the diabetic population, remain undiagnosed.
A rough estimate in 2018 described 1.5 million new cases in the United States. Incidence rates of diabetes were higher in older adults than in young adults.
Further, prediabetes affects around 88 million of the adult US population of 18 years and above. Moreover, this condition affects around 24.2 million people of age 65 years and above.
Factors associated with diabetes
A combination of various risk factors determines a person’s chance of developing both type 1 and type 2 diabetes.
Genetic factors of type l diabetes
To date, more than 50 genes have been identified that tend to be associated with the development of type 1 diabetes. Most of the gene alterations described are polygenic. This means that several genetic alterations must be present for type 1 diabetes to develop.
In particular, genetic alterations of the short arm of chromosome 6, the so-called MHC region, could be held responsible for the development of diabetes mellitus type 1. The genes HLA-A and HLA-B of this region contain the genetic information for cell-surface proteins of the immune system. This being said, the HLA genotype is essential in type 1 diabetes.
Genes outside the HLA complex probably play a much smaller role in the genesis of type 1 diabetes. These include the gene for insulin (INS) and the gene CTLA4, which is responsible for T-lymphocyte regulation.
Genetic factors of type 2 diabetes
The genetic risk of type 2 diabetes is not solely restricted to a single gene. In fact, multiple genes across the genome underline this type of diabetes. Some of these genes associated with type 2 diabetes are TCF7L2, PPARG, IRS1, KCNJ11, WFS1, HNF1A, HNF1B, CAPN10.
Much about the interactions among these genes remain unclear. However, one of the few studies (in a population of Ashkenazi Jews) on genetic interplay has demonstrated that the TCF7L2-HNF4A and TCF7L2-WFS1 associations tend to increase the risk of type 2 diabetes.
Environmental factors (next to genetic factors of diabetes)
In addition to the genetic component of diabetes environment and socio-economic status reportedly impacts the onset of type 2 diabetes. Although not causal, the physical environment, air pollution, and noise are linked with the increased diabetes incidence. Moreover, socioeconomic status is also associated with diabetes. For example, low socio-economic status has attributed to about 40% – 60% of diabetes risk.
DNA viruses and RNA viruses have the potential to destroy the pancreatic cells thereby interfering with insulin metabolism. Studies in mice have proved that such auto-immune disruption causes type 1 diabetes. In another example, the Hepatitis C Virus that causes hepatic steatosis and insulin resistance may also lead to type 2 diabetes.
Diet and Lifestyle
Food intake is directly related to the development of type 2 diabetes. High amounts of saturated fats in some foods increase the risk of diabetes. On the other hand, micronutrients such as vitamins, magnesium as well as antioxidants like β-carotene might help reduce the risk of diabetes. Lifestyle factors such as eating habits, insomnia, stress, lack of physical activity correlate positively with diabetes.
The gut microbial composition is linked with diabetes and this is often accounted for by dysbiosis. In dysbiosis, the relative abundances of certain groups of microbes in diabetic people differ from those of non-diabetic people.
As an example, in a study cohort, Firmicutes decreased in relative abundance while Bacteroidetes and Betaproteobacteria increased in abundances in diabetic people. The researchers conducted this study to assess the bacterial communities via pyrosequencing.
In another study via a metagenome-wide association study, researchers observed a moderate extent of gut dysbiosis. However, infection-causing bacteria were higher in number while some butyrate producers showed a marked decrease.
A number of symptoms are common to both type 1 diabetes and type 2 diabetes. They are frequent hunger pangs, severe fatigue, frequent urination, dry skin and blurred vision, and slow healing of wounds.
Few specific symptoms:
Type 1 Diabetes- The most obvious symptom of type 1 diabetes is weight loss. Besides, diabetic ketoacidosis is also an apparent symptom. In this condition, a build-up of ketones occurs thereby causing nausea and vomiting. This type of diabetes mainly occurs in adolescence.
Type 2 Diabetes- Yeast infection generally accompanies this type of diabetes. Usually, adults of over 40 years of age are at risk of developing type 2 diabetes.
|Figure: Symptoms associated with diabetes, Image source: By Mikael Häggström, Wikimedia Commons|
Long term complications of diabetes
Diabetes plays a strong role in further developing a series of other health complications.
Diabetes specific skin problems include the following:
- Acanthosis nigricans: The folds of necks, armpits, genital areas develop pigmented patches. Overweight people are most likely to experience this condition.
- Diabetic dermopathy: Due to the changes in blood vessels, several pigmented circular, scaly patches form on the skin.
- Necrobiosis lipoidica diabeticorum: This is a rare condition similar to diabetic dermopathy, however, the spots are fewer and larger.
- Eruptive xanthomatosis: In this problem, the skin develops firm, yellow, pea-shaped blisters. And they are quite itchy. People with high levels of cholesterols in blood experience this condition.
- Calluses and ulcers: Due to poor circulation in diabetic people, callus formation escalates. Plus, the chances of developing foot ulcers follow.
Three specific diseases are common in diabetic patients. They are as follows:
- Glaucoma: In glaucoma, pressure in the eye blood vessels interfere with the blood transport to the retina and optic nerve.
- Cataracts: Although non-diabetic people do develop cataracts, diabetics are most likely to develop this condition. In this condition, clouding of the lens occurs that severely impacts vision.
- Retinopathy: In the non-proliferative retinopathy, blocked blood vessels lead to leaking of the fluid into the macula. Following this, the macula swells up and ultimately causes blurry or lost vision. In proliferative retinopathy, complete damage of blood vessels occurs. This damage induces new but weak blood vessel formation. Eventually, these new blood vessels start leaking blood and cause lost vision.
Nervous system damage
- Peripheral neuropathy: This causes numbness, pain, and weakening of hands and feet.
- Autonomic neuropathy: It damages the autonomic nerves regulating bladder and intestinal activities. This type of neuropathy is a common complication in diabetes.
In diabetes genetic factors, blood sugar, blood pressure determine the onset of kidney disease. In cases when this condition occurs, fluid build-up in the kidney is followed by poor appetite, upset stomach and severe weakness.
At present genetic testing for diabetes is not universally available to health-care providers.
The doctor makes the diagnosis mainly on the basis of the blood sugar level.
The A1C assay measures an average of the blood glucose level over the past three months. It is also known as glycohaemoglobin test. That is because it relies on the binding of the glucose to hemoglobin. A higher concentration of blood glucose indicates a higher binding pattern. And such results are usually provided in the form of percentages.
Fasting Plasma Glucose Test
In this test, the doctor measures the blood glucose levels after 8 hours of fasting. This is one of the most preferred tests in diabetes diagnosis.
Oral Glucose Tolerance Test
It measures the blood glucose level after fasting overnight. Next, the consumption of a sugary liquid follows. After this, the doctor measures the blood glucose level over the next 2 hours.
|Condition||A1C Test||Fasting Plasma Glucose Test||Oral Glucose Tolerance Test|
|In normal condition||Less than 5.7%||Less than 100mg/dL||Less than 140mg/dL|
|In diabetes||6.5% and higher||126mg/dL and higher||200mg/dL or higher|
Table: Result depicting the values of blood glucose levels for different diagnostic tests, Source: ADA(Diagnosis)
|Figure: Illustration of a typical kit for monitoring the blood sugar levels, Image source: Jessica Mertz, Wikimedia Commons, CC-BY 2.0|
Diabetic patients should pay attention to their blood sugar levels. Besides, treatments from a team of endocrinologists, ophthalmologists, nutritionists, etc. are important to treat this condition.
The prescribed drugs act via a number of mechanisms. For example, some drugs increase insulin production while others decrease intestinal glucose absorption. Besides, there are few other drugs that often improve the way in which the body uses insulin and improves insulin resistance. A number of drugs also inhibit glucose reabsorption into the kidney.
Diet and lifestyle management
In addition to the balanced diet, timing, and quantity of the food intake matters in order to allocate proper insulin dose. Other than these points, exercise is crucial for diabetic patients. It also provides relief from stress. Plus, the doctors often prescribe a glucose meter for measuring the blood glucose level.
Are you interested in delving deeper into the genetics of diabetes? Then do visit the website of Genetics Home Reference.