Primary Care Corner with Geoffrey Modest MD: Nature vs nurture: studies on lipids and NAFLD

by Dr Geoffrey Modest

2 recent articles found significant genetic associations with 2 common clinical conditions: hyperlipidemia and non-alcoholic fatty liver disease (NAFLD). I bring these up to make the point that, though there is often a genetic association with disease, usually this is not determinant and there is an important role for a healthy lifestyle both in preventing the disease from happening and treating it if it does happen.

***Whole genome sequencing of two populations on the island Crete found some genetic variants which were either completely new, or rare in other populations, including one associated with increased HDL levels, and  another with decreased triglycerides and VLDL levels (see DOI: 10.1038/ncomms15606)



–945 patients from Crete, and specifically from Mylopotamos and Pomak villages, had genome-wide association studies done to look for common-frequency variants with small-to-modest effect sizes, evaluating 29 million single nucleotides variants in the Pomak and Mylopotamos cohorts. These results were imputed and validated for the larger populations in the areas

–there were 17 genome-wide significant independent signals found, including 2 novel cardiometabolic associations:

— chr16:70790626 for increased high-density lipoprotein levels (explaining 3.24% of the phenotypic variance in the Mylopotamos cohort)

— rs145556679, associated with decreased triglycerides and VLDL, so far only found in the Mylopotamos cohort and no other worldwide cohort.

— rs13382259, associated with decreased diastolic blood pressure in the Pomak population


–one advantage of looking at an isolated population is that low-frequency alleles will be amplified by the more limited gene pool

–though not commented on in the article, people from Crete are among the longest-livers in the world: Mylopotamos is called “Village of Long Life”. Of note, there is a similar genetic variant in isolated Amish populations in the United States. Interestingly, the people from Mylopotamos do eat a largely Mediterranean diet though their diet is high in animal fat, but with less atherosclerotic disease than would be predicted by their diet

***5-8% of lean people have evidence of NAFLD, despite the strong association with obesity. This study looked at 3 groups of patients stratified by BMI (see DOI: 10.1038/ajg.2016.318).  This is an Austrian study limited to Caucasian people; the prevalence of lean patients with NAFLD has been well-documented to be higher in Asian people but Caucasians had not been assessed previously. I am not sure about lean African Americans, though their overall prevalence of NAFLD is lower than either Latinos or white patients. This study was a subsample of the 2500 people in the Salzburg Colon Cancer Prevention Initiative study.


–187 nondiabetic patients were assessed by BMI groupings and had ultrasound evaluation:

–lean healthy: BMI <25, no steatosis, n=71

–age 56, 25male/46 female, bmi 22.7, whr 87 cm (waist-to-hip ratio), ALT 17, diabetes 0, impaired fasting glucose 13%, HDL 67/LDL 120/TG 86, A1c 5.4, adiponectin 13.8 [adiponectin has many functions but higher levels are associated with more insulin sensitivity], FIB4 score 1.2 [a noninvasive measure of hepatic fibrosis]

–lean NAFLD: BMI <25, steatosis, n=55

–age 61, 26male/29 female, bmi 23.6, whr 91 cm, ALT 21, diabetes 31%, impaired fasting glucose 20%, HDL 58/LDL 136/TG 117, A1c 5.5, adiponectin 10.4, FIB4 score 1.3

–obese NAFLD: BMI>30, steatosis, n=61

–age 63, 29male/32 female, bmi 32.7, whr 113 cm, ALT 28, diabetes 36%, impaired fasting glucose 32%, HDL 45/LDL 139/TG 169, A1c 5.8, adiponectin 8.9, FIB4 score 1.1

–all had oral glucose tolerance test,  serum metabolome, and genotyping for single-nucleotide polymorphisms (SNPs) associated with NAFLD


–lean NAFLD patients had fasting insulin levels similar to lean healthy ones, but did have markedly impaired glucose tolerance

–lean NAFLD patients  had a higher rate of the mutant PNPLA3 CG/GG variant vs lean healthy, 59% vs 35%.

–serum adiponectin levels were decreased in both NAFLD groups vs lean healthy (p<0.001 for both groups)

–metabolomics study showed variations in lysophosphatidylcholines, phosphatidylcholines, lysine, tyrosine and valine (several of these may have anti-inflammatory effects and increase insulin secretion, which could explain some of the differences in glucose tolerance between the groups)

–clinically no difference in lifestyle habits between the 2 lean groups, though the obese group did have more people consuming fast food at least once a week and had lower physical activity


–NAFLD is certainly much more prominent in those with obesity than in lean patients, though this does raise the question as to whether the prognosis is the same in these 2 BMI groups.  They did not do transient elastography (Fibroscans) or get liver histology in this study, though the lean NAFLD group did have the highest FIB4 score (suggesting more hepatic fibrosis, with a score of 1.3 being the cutpoint, suggesting that NAFLD is likely to be deleterious in this group)

–lean NAFLD patients were in between lean healthy and obese NAFLD in terms of metabolic derangements, though they did have much more impaired glucose tolerance than the lean healthy ones, and about 30% did have diabetes as defined by either fasting plasma glucose, impaired glucose tolerance, or A1c levels. The lower adiponectin levels in the two NAFLD groups further confirm their relative insulin resistance.

–the rate of the PNPLA3 allele were similarly high in both NAFLD groups, and much higher than in the lean healthy ones  (p=0.007). This does suggest that this genetic variant does seem to be associated with NAFLD independent of BMI (though not determinant, since 35% of the non-NAFLD people also had this allele). Unfortunately, there were no granular data presented to see if it were just this SNP which was responsible for the NAFLD, or if this subgroup happened to have a less healthy lifestyle. Would also be interesting to know if there were differences in their microbiomes as well, which is also affected by diet and exercise. See the multitude of prior blogs on NAFLD in the category, or just type NAFLD in the search window.

The reason I am evaluating these articles is to raise the general points that:

–clinically, we should still be suspicious of these underlying medical issues in patients who do not seem to fit the phenotype: a younger thin and athletic person who has a bad lipid profile, a thin person with an increase in their ALT levels on liver function testing, or evidence of fatty liver disease or glucose intolerance.  All of these people may have underlying medical problems (respectively, atherosclerotic disease, NAFLD) which might well affect their longer term morbidity/mortality

–and some anecdotes to fill this in, reinforcing the genetic components:

–one of my residents a few decades ago was curious about the strikingly high incidence of ASCVD/MIs in thin, athletic men in their 40’s in his Indian community near Boston. These men had surprisingly low HDL levels

–and lots of people who are morbidly obese with A1c in the mid 4 range, yet many who are much less obese (and some normal weight) who are either pre-diabetic or diabetic; I have found glucose intolerance in several thin patients with family history of diabetes

–as another example showing that risk factors may be discordant from the clinical picture: though obesity is the dominant risk factor for obstructive sleep apnea, it is found in about 11% of men with normal weight and about 3% of women (overall it is 2-3 times more common in men)

–so, we should think about risk factors when we see patients, but not be swayed too heavily and keep open mind to these diagnoses. Genes may be the dominant player in some patients.


On the other hand, there is usually some interplay between nature and nurture. Helping patients develop healthy lifestyles may well counteract the potentially deleterious effect of the genes, or potentially lead to more aggressive preventative approaches (eg, earlier uses of statins to prevent cardiac disease, etc)

–one interesting and I think poignant example of the nature/nurture interplay is that of the US Pima Indians in Arizona, who reportedly have the highest rates of diabetes and obesity in the US (see Schulz. Diabetes Care 2006; 29: 1866). In 1890 their water supply was taken over by white settlers, making it impossible to continue their agrarian lives. The US government subsidized  the food supply with sugar and white flour, and the previously lean population developed obesity and diabetes. It turns out that a group of Pimas, speaking the same language and from the same genetic stock, live in remote areas of rural Mexico and continue to practice their traditional agriculture. These Mexican Pimas have similar lower levels of obesity as other non-Pimas living in the same remote areas (around 7% in men and 20% in women), and have rates of diabetes close to the other non-Pima Mexicans (6.9% vs 2.6%). But the US Pimas have diabetes rate of 38% —  more than 5-fold higher!!! (and 68% in men older than 45, 70% of women older than 45 and 82%of women older than 55), which tracks with prevalent obesity (mean BMI=34), as well as their dramatically lower levels of physical activity there. A pretty clear example of a strong genetic predisposition to diabetes which manifests itself in the setting of a nonhealthy lifestyle/obesity….

so, I think all of this points to the fact that there are often important genetic factors leading to disease,and we as clinicians dealing with individual patients should still be attuned to patients who do not exhibit the typical profile (eg, those with high predisposition to heart disease or have abnormal LFTs from NAFLD but appear to be young and fit, or those who have OSA but are also of normal weight). And healthy lifestyles may not just help with these targeted diseases but are generally beneficial (collateral benefit… see blogs showing likely benefit from cancer, Alzheimers etc etc)

See here  for projected decreased cancer risk from exercise

See here for projected cardiovascular benefit from cardiovascular fitness

See here  for dietary influences on Alzheimers

Or, a slew of blogs on the benefits of Mediterranean diets