Impact of Genetics on Endocrine Manifestations of Cystic Fibrosis

Abstract

Cystic fibrosis (CF) is a monogenic multisystem disorder. Endocrine complications of CF are common and include diabetes, growth disorders, and bone disease among others. CF endocrinopathies may be influenced by two classes of genetic factors: 1) disease-causing CFTR variants that determine the level of CFTR dysfunction, and 2) variants in other genes throughout the genome known as genetic modifiers. This review highlights the impact of these genetic factors on selected endocrine manifestations of CF. CF-related diabetes (CFRD): CFRD is dependent on both variation at CFTR and genetic modifiers. Some genetic modifiers identified for CFRD influence non-CF forms of diabetes, e.g., type 2 diabetes, highlighting overlapping pathophysiology, while others appear to be unique to CFRD. Other CFRD modifiers influence multiple CF manifestations, suggesting influence of the CF disease process itself. Growth disorders: Genetic investigations of growth and nutritional status have likewise identified both CFTR and non-CFTR genetic influences, with the latter revealing overlapping as well as distinct pathophysiological mechanisms involved in weight regulation in the general population. CF-related bone disease (CFBD): Fewer CFBD studies have been conducted, but osteoporosis in the general population is a highly heritable trait with more than 1000 genetic modifiers already identified. Like studies of diabetes and growth, identifying genetic modifiers of osteoporosis-related traits in CF will likely reveal how pathophysiology of CF and non-CF bone disease are overlapping or distinct. Consideration of genetic influences on CF endocrinopathy can lead to better understanding for these endocrine manifestations in and outside of CF.

Graphical Abstract

Introduction

Cystic fibrosis (CF) is an autosomal recessive condition caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is expressed in epithelial tissues throughout the body causing both pulmonary and extrapulmonary complications, including diabetes and osteoporosis. Extrapulmonary manifestations affect morbidity and mortality in people with CF. As advances in CF treatments have extended survival of people with CF (pwCF) into the 6^th and 7^th decades¹, these extrapulmonary complications are expected to affect increasing numbers of pwCF.

Pathogenic CFTR variants cause CF and its complications, but varying amounts of residual CFTR function associated with different pathogenic CFTR variants can affect aspects of CF to different degrees.² Exocrine pancreatic insufficiency (PI) is highly correlated with CFTR genotype, such that having two minimal function (MF) CFTR variants is highly predictive of early-onset PI, and having at least one residual function (RF) variant is highly predictive of pancreatic sufficiency (PS). Tight correlation with CFTR function is not seen for all complications of CF. Obstructive azoospermia occurs with even mild CFTR dysfunction and thus affects >97% of males with CF.³ Likewise, CF lung disease is highly variable even within groups of people bearing the same CFTR genotypes.⁴ Thus, the severity of CF complications depends only in part on the CFTR genotype.

CF and its complications are also influenced by variants elsewhere in the genome known as genetic modifiers. An examination of non-CFTR genetic influences on phenotype may begin with twin studies to establish heritability of the phenotype.² Twin dyads raised in the same environment are somewhat controlled for non-genetic factors. If the phenotype concordance is greater in monozygotic twins than in dizygotic twins, this implies genetic factors are responsible, and heritability of the phenotype can be estimated. To identify heritable traits in CF, multisite consortia were established such as the European Twin and Sibling Study^5,6 and the North American CF Twin and Sibling Study.^7–9 Candidate gene studies then examined the relationship of a pre-selected variant in a gene of interest with the heritable trait. Hypothesis-agnostic genome-wide association studies (GWAS) explored the relationship between the phenotype and single nucleotide polymorphisms (SNPs) throughout the genotyped data of many patients. As millions of individual tests are performed within a GWAS, statistical significance is typically set at an alpha of 5x10⁻⁸ to account for the multiple testing and relatedness of these tests due to linkage disequilibrium. Like the twin studies, to attain sufficient power, large GWAS consortia were established such as the Canadian Consortium for CF Genetic Studies, International CF Genetic Modifier Consortium, and CF Genome Project. GWAS have identified genetic modifiers of CF severity (lung function and nutritional status)^10–13, diabetes^14–16, liver disease¹⁷, infection¹⁸, meconium ileus^19,20, and other CF manifestations.

Elucidating the sources of phenotypic variation in CF, both genetic and non-genetic factors^21,22, can help guide the development of CF treatments. Traits that are highly dependent on CFTR function (e.g., azoospermia or exocrine PI) may respond to CFTR-directed therapies depending on the developmental stage at which such CFTR-directed therapies are initiated.^23,24 CFTR-directed therapies include CFTR modulators, which improve endogenous CFTR function, but are highly dependent on CFTR genotype. Genetic modifier studies hold the promise of identifying therapeutic targets that, if successfully targeted, could improve outcomes in people with all CFTR genotypes. Precision medicine has already arrived to CF care with the use of CFTR modulator theratyping.²⁵ Beyond CFTR, similarly cataloging each person’s genetic modifiers could be used to stratify risk for CF complications, thereby enabling the development of personalized therapeutic plans.

This review will highlight the role of genetics in three endocrine complications of CF: diabetes, abnormal growth, and bone disease (Figure 1).

Figure 1. Schematic of genetic influences of endocrine manifestations of cystic fibrosis.

Endocrine manifestations of cystic fibrosis (e.g., diabetes, abnormal growth and bone disease) are influenced by genetic factors. Genetic factors include single nucleotide variants at the disease-causing cystic fibrosis transmembrane conductance regulator gene and throughout the genome (called genetic modifiers), as well as epigenetic modifications including methylation. Figure created with BioRender.com.

Diabetes

Cystic fibrosis-related diabetes (CFRD) is a distinct form of diabetes mellitus occurring in pwCF, characterized by a progressive loss of insulin secretion and a variable contribution from insulin resistance. The development of CFRD is multifactorial, involving CFTR dysfunction, genetic modifiers, inflammation, medications, and potentially epigenetic changes. With the advent of highly effective CFTR modulator therapies (HEMT), the landscape of CFRD risk and progression is evolving rapidly.

CFTR function and mechanisms of CFRD

CFTR encodes an ion channel involved in epithelial ion transport across various tissues, including the pancreas. Minimal function (MF) CFTR genotypes, e.g. homozygous F508del, are strongly associated with exocrine PI and increased risk of CFRD. In contrast, patients with residual function (RF) CFTR genotypes have a significantly lower risk of developing CFRD.^26,27 While the role of CFTR within pancreatic β-cells has been debated, most evidence suggests that intrinsic β-cell CFTR expression is minimal. The effects on insulin secretion are more likely driven by the exocrine environment and islet-associated inflammation rather than a direct CFTR-dependent mechanism.^27–30 Some studies, however, have reported CFTR expression in islets and propose a role in membrane potential regulation and vesicle exocytosis.³¹

CF-related exocrine pancreatic disease leads to ductal obstruction, inflammation, and fibrosis, disrupting islet microenvironment and architecture. This destruction along with oxidative stress, and alterations in α-cell function, contribute to β-cell dysfunction and impair insulin release. In animal models, early treatment with highly effective CFTR modulators, such as ivacaftor, can prevent pancreatic damage and glucose abnormalities, underscoring the developmental timing of CFTR-related pathophysiology.

Genetic modifiers of CFRD

Genetic factors outside of CFTR also influence the risk and severity of CFRD. GWAS have identified multiple CFRD-specific loci that modify risk, some of which overlap with those implicated in type 2 diabetes (T2D)^15,32,33 (see below). CFRD-specific genetic modifiers include variants at PTMA and SLC26A9, and more recently PRSS1 (Table 1).^15,16 SLC26A9 encodes an epithelial anion transporter that modulates pancreatic ductal secretion.^34,35 CFRD modifier variants at the SLC26A9 locus are also associated with early pancreatic insufficiency and exocrine pancreatic disease.³⁶ PRSS1 encodes cationic trypsinogen, and PRSS1 variants cause increased trypsin activation leading to acinar injury.³⁷ CFRD modifier variants at PRSS1 are also risk factors for chronic pancreatitis.^38,39 Thus, variants in SLC26A9 and PRSS1 may play a role in progressive exocrine damage and secondary impairment of islet cell function.

Table 1.

Summary of variants associated with cystic fibrosis-related diabetes

Variant / SNP*	Chromosome	Gene	Reason for Including	Association
				CFRD	T2D
rs4077468+	1	SLC26A9	CFRD locus identified by GWAS; involved in epithelial ion transport; also associated with meconium ileus in individuals with cystic fibrosis14–16,19,20	x
rs838455+	2	PTMA	CFRD locus identified by GWAS; CF-specific modifier15	x
rs6780171	3	IGF2BP2	T2D susceptibility locus associated with β-cell function; also modifies CFRD risk14,15,33	x	x
rs9873618	3	SLC2A2	Glucose transporter associated with T2D/fasting glucose; shared CFRD overlap15,32	x	x
rs11708067	3	ADCY8	Shared CFRD/T2D locus; adenyl cyclase signaling15,32	x	x
rs13085136	3	SHQ1	Shared CFRD/T2D locus; glycemic trait signal15	x	x
rs6819243	4	MAEA	Shared CFRD/T2D locus affecting β-cell pathways15,33	x	x
rs7756992	6	CDKAL1	T2D risk variant affecting insulin secretion; modifies CFRD14,15,33	x	x
rs17168486	7	DGKB	T2D locus affecting β-cell signaling; overlaps CFRD in shared genetic architecture analyses15,33	x	x
rs3757377+	7	PRSS1	Pancreatic exocrine gene; variants influence pancreatitis risk and endocrine dysfunction, plausibly modifying CFRD risk16,20	x
rs3802177	8	SLC30A8	T2D variant affecting zinc transporter and insulin secretion pathway15,33	x	x
rs13262861	8	ANK1	T2D locus; shared CFRD overlap15,33	x	x
rs10811660	9	CDKN2A/B	T2D risk locus influencing cell cycle/β-cell proliferation; also modifies CFRD14,15,33	x	x
rs10974438	9	GLIS3	T2D and fasting glucose trait locus; shared CFRD overlap15,33	x	x
rs7903146+	10	TCF7L2	T2D variant; modifies CFRD risk14,15,33,40	x	x
rs67232546	11	ETS1	Shared CFRD/T2D locus (FDR signal)15,32	x	x
rs11070332	15	LTK	Shared CFRD/T2D locus (FDR signal)15,32	x	x
rs72802342	16	BCAR1	T2D locus; shared CFRD overlap15,33	x	x
rs11699802	20	CEBPB	Shared CFRD/T2D/meconium ileus locus15,16,20,32	x	x

^*Due to linkage disequilibrium multiple variants at each locus may be associated with CFRD: a representative variant is shown

⁺Significant association with CFRD obtained via GWAS, all other listed variants were noted to have significant association with CFRD through targeted analysis.

Abbreviations: SNP: single nucleotide polymorphism, CFRD: cystic fibrosis-related diabetes, T2D: type 2 diabetes, FDR: false discovery rate.

Relevance of genetic modifiers of non-CF diabetes

Many of the loci harboring CFRD modifiers are also implicated in T2D occurring in people who do not have CF (Table 1). For example, TCF7L2 has been strongly implicated in T2D and is important for β-cell function. Variants at TCF7L2 were also identified via GWAS to be associated with CFRD which suggests shared genetic underpinnings with non-CF forms of diabetes.¹⁵ In the literature, 16 loci have been identified that are associated with both T2D and CFRD and are thought to be involved in insulin secretion/regulation and β-cell function.^15,32,33 This overlap supports the well-established association between family history of T2D and risk of CFRD development in individuals with CF. Consistent with this, a family history of T2D is associated with about a threefold risk of developing CFRD in pwCF compared to those without a family history of T2D.⁴⁰ In contrast, genetic loci associated with type 1 diabetes (T1D)—including autoimmune risk loci in the HLA region, INS, and PTPN22—have weak evidence of association with CFRD, underscoring fundamental differences in disease pathogenesis.¹⁵

Emerging hypotheses: Methylation and CFRD

Epigenetic regulation—especially DNA methylation—has emerged as a critical modifier of gene expression in T2D. Genome-wide methylation profiling of human islets has identified over 1,600 differentially methylated CpG sites in diabetic vs. non-diabetic individuals, many of which lie in non-CpG island regions and influence genes such as FTO, SREBF1, and TXNIP.⁴¹ Similar findings in adipose tissue and peripheral blood further support the role of methylation as a dynamic mediator of diabetes risk.⁴²

Although epigenetic contributions to CFRD remain underexplored, emerging studies suggest that CFTR dysfunction and the resulting inflammatory environment may induce epigenetic alterations in endocrine tissues. In CF airways, methylation differences in HMOX1, EDNRA, and GSTM3 have been linked to pulmonary disease severity.⁴³ Systemic inflammation could plausibly exert similar epigenetic pressure on islet cells. While direct methylation studies of islets in CFRD patients are lacking, extrapolation from T2D suggests that epigenetic silencing or activation of critical β-cell genes could contribute to CFRD susceptibility. These mechanisms may interact with genetic modifiers to explain some of the variability in CFRD onset, particularly in individuals with intermediate CFTR function.

Impact of CFTR correction on glucose metabolism

CFTR modulators have dramatically altered the course of CF, with growing evidence of their beneficial effects on glucose homeostasis. Ivacaftor monotherapy, particularly in patients with gating mutations (e.g., G551D), improves insulin secretion and glycemic control and in some cases, reverses impaired glucose tolerance.^44,45 However, earlier-generation corrector-potentiator combinations, such as lumacaftor/ivacaftor, have shown more modest or inconsistent metabolic benefits.

The advent of elexacaftor/tezacaftor/ivacaftor (ETI) has renewed optimism about the potential to prevent or reverse CFRD. Although recent studies report improvements in insulin secretion, reduced insulin requirements, and normalized oral glucose tolerance testing profiles in some patients following initiation of ETI, others do not show the same improvements.^45–47 Nevertheless, the magnitude of benefit varies by CFTR mutation class, age at therapy initiation, and duration of CFRD, and the link to clinical long-term outcomes is not known. Patients with longstanding diabetes and advanced islet loss may exhibit limited reversibility, whereas those with prediabetes or early CFRD show more robust responses.^28,29

Importantly, the improved nutritional status and weight gain associated with ETI may paradoxically increase insulin resistance, especially in older or overweight patients. Therefore, while modulators may preserve or restore β-cell function, close monitoring for evolving metabolic complications remains essential. Longitudinal studies, such as the PROMISE endocrine sub-study, aim to clarify the long-term effects of HEMT on glycemic trajectories in CF.^28,29,48

Abnormal Growth

Genetic and non-genetic factors contribute to growth and nutrition in people with and without CF. In the general population, heritability of anthropometric traits (e.g., height, weight, and body mass index (BMI)) is high, and genetic studies have provided evidence that each of these traits is highly polygenic. CF and its complications have adversely impacted growth in the past^49,50, but even recent cohorts of pwCF in the last two decades demonstrate shorter height⁵¹ and worse nutritional status⁵² than healthy controls.

Impact of CF on body mass index

Nutritional status in CF varies strongly according to age, PI status, other indicators of disease (e.g. inflammation) and its treatments (e.g. glucocorticoids and nutritional supplements).⁵² Having a RF CFTR genotype and having exocrine PS are associated with higher BMI.^52–56 When accounting for CFTR genotype severity and other potential confounders, BMI in CF remains widely variable, and heritability for BMI is high, suggesting influence of genetic modifiers.⁵⁷ A polygenic risk score for BMI and a high-effect variant in FTO, both associated with BMI in non-CF populations, were also correlated with BMI in CF with effect sizes that did not differ between PS and PI individuals.¹³ Thus, the FTO variant highlights an area of overlapping physiology of weight homeostasis between those with and without CF. In addition, a variant in ADAMTS5 was associated with BMI in CF and particularly in those with exocrine PI, highlighting pathophysiology that is not apparent in non-CF populations.

Impact of CF on height

Early growth in CF is correlated with final height⁵⁸ and clinical outcomes.^59,60 Linear growth may be impacted by disease severity and nutritional factors, producing stunting even if BMI is not reduced.⁶¹ This was especially true before advances in treatments and widespread CF newborn screening, but even in modern cohorts with tendency to lower disease burden, average stature is lower in children with CF than in healthy peers⁶²; this height difference is not explained by pubertal peak height velocity or by differences in genetic risk scores for height.⁵¹ Multiple factors may impact the growth hormone/IGF-1/growth plate axis, and alteration of IGF-1 and growth hormone levels have been reported in CF animal models and people with CF, but growth hormone deficiency is rare in most studies.⁶¹ Exocrine pancreatic sufficiency and ETI treatment have been associated with greater peak height velocity.⁶³ A polygenic risk score for height in the non-CF population was associated with height in CF individuals⁵¹, indicating that some of the same genetic factors influence height in both CF and non-CF populations. However, the non-CF height polygenic risk score appeared to have lower effect in PI than in PS populations, suggesting that CF-specific factors, either genetic modifiers specific to CF, or non-genetic contributors such as disease-related stunting, are of greater importance in the PI group.

Impact of CFTR correction on abnormal growth

It is anticipated that the indirect effects of CF on height, weight, and puberty (that is, mediated by severe chronic disease) will continue to reduce, if improved CF treatments reach increasing numbers of individuals. However, possible influences of CFTR on bone growth, central hormone function, and metabolism raise the possibility that body size and shape may still be altered in individuals with CF. Animal models of CF show varying effects on growth despite absence of CFTR.^64–67 In humans, the increasing rates of overweight and obesity are multifactorial^54,55 and started well before widespread availability of HEMT^55,68 so cannot be attributed solely to CFTR modulator treatment.

Bone Disease

CF-related bone disease (CFBD) is a distinct form of pediatric and young adult skeletal fragility characterized by low bone density and increased fracture risk.⁶⁹ Vertebral compression factures are 100-fold more common in pwCF than age-matched general population.⁷⁰ Children with CF have lower rates of bone accrual than age-matched peers, and young adults fail to maintain bone mass.^69,71 Multiple factors contribute to CFBD including chronic inflammation and undernutrition; however, the contribution of CFTR dysfunction cannot be ignored in this unique form of osteoporosis.

Genetic modifiers of non-CF osteoporosis

Osteoporosis and bone disease in people without CF are heritable traits, with 50-85% of phenotypic variance explained by genetics. Approximately 1000 genetic variants have been found to alter the risk for osteoporosis-related traits, e.g. any fracture, osteoporotic fracture and surrogates of fracture including bone density.⁷² Many osteoporosis genetic modifiers impact genes in known bone biology pathways including RANKL-RANK-OPG, ESR1 (estrogen receptor), and WNT.^72–75 Some modifiers alter genes that regulate these pathways, e.g. LRP4, LRP5, SOST, and DKK1 which regulate Wnt signaling.^73–75 Other osteoporosis genetic modifiers have been identified, but the candidate gene or its relation to the development of osteoporosis is not yet understood. Much like the CF Genome Project, large multinational consortia (e.g. GENOMOS and GEFOS)^75,76 have been created to identify genetic influences on osteoporosis.

As postmenopausal osteoporosis is the most common form of osteoporosis in the general population, much of these data relate to skeletal fragility in older populations. However, pwCF experience osteoporosis as young adults, an age at which osteoporosis is rare in the general population. Some modifiers for pediatric and young adult osteoporosis have been identified. The genetic speed of sound (gSOS) polygenic risk score⁷⁷ which predicts adult fracture⁷⁸ was later found to be associated with clinically significant fracture histories in children without osteogenesis imperfecta.⁷⁹

CFTR function contributes to CF-related bone disease

CFTR is expressed on osteoclasts, osteoblasts and osteocytes.⁸⁰ In vitro studies of cell lines derived from pwCF have found reduced differentiation of mesenchymal stem cells into osteoblasts and reduced osteoclast efficacy, which may in turn further reduce osteoblast differentiation.^81,82 Studies of human osteoblasts derived from pwCF who were F508del homozygous found a statistically significant decrease in RANKL production in basal and TNF-alpha stimulated conditions.⁸³

Clinical studies of pwCF have not consistently found an association of CFTR genotype severity with CFBD. In one cross-sectional study, having one or two copies of F508del was associated with significantly lower bone density than having no copies of F508del; in multivariable models combining variables that were significant in univariable analyses, no copies of F508del remained a significant predictor of higher bone density at the lumbar spine and femoral neck.⁸⁴ In contrast, other studies have not found a relationship between F508del and bone phenotype, although this may be because stratifying by F508del status will group people with MF and RF genotypes together. Further confounding the issue, exocrine pancreatic insufficiency is an expected CF complication in the MF genotype. Exocrine PI impairs the absorption of fat-soluble vitamins including Vitamin D; data are conflicting if exocrine pancreatic status itself contributes to CFBD separate from its sequalae: vitamin D and calcium deficiency, undernutrition and inflammation.^71,85,86 Thus, like lung disease in pwCF, reduced CFTR function, i.e. having CF, results in an osteoporosis phenotype at younger ages than healthy controls, but it is not clear if further reduction of CFTR function beyond RF variants increases CFBD risk.

Restoring CFTR function is anticipated to improve CFBD, either directly or indirectly through reduced inflammation, improved nutrition, and ameliorating other factors contributing to the development of CFBD. Studies of the HEMT ivacaftor which was initially FDA-approved in 2012 have been conflicting, with a small retrospective study finding an increase in bone density⁸³ not found in a prospective study which did find changes in microarchitecture.⁸⁷ National registrybased studies found that pwCF treated with ivacaftor had lower prevalence of bone complications.⁸⁸ On the other hand, studies of ETI which became widely available to pwCF in 2019 have found that bone density declined at a rate similar to prior to ETI initiation at the first follow-up (1.5 years after ETI initiation) but had plateaued at the second follow-up (4 years after ETI initiation).⁸⁹

Few studies of genetic modifiers of CF-related bone disease

There have been several small studies using the candidate gene approach. In two studies of known osteoporosis genetic modifiers (variants in the genes encoding the vitamin D receptor, estrogen receptor, calcitonin receptor and alpha-1 chain of type I collagen) which enrolled 82 and 101 participants, the L447P variant in CALCR was associated with lower bone density⁹⁰ and PvuII and XbaI variants in ESR1 were associated with differences in urinary calcium excretion.⁹¹ Slightly larger studies enrolling 180-198 participants examined variants relating to other aspects of CF morbidity (inflammation, oxidative stress and ion channels which were CFRD modifiers) and did not find an association with these pre-selected variants and CFBD.^92–94

Hypothesis-agnostic GWAS have not yet been performed to identify genetic modifiers of the skeletal phenotype in pwCF. Similarly, investigating epigenetic differences affecting CF bone disease is an interesting future direction, already being explored in non-CF osteoporosis.⁹⁵ In non-CF bone physiology, methylation is different in bone that has suffered a traumatic fracture compared to bone that has experienced an osteoporotic fracture. Similar to genetic epidemiology studies of other complications of CF, research is needed to explore how the genetic underpinnings of CFBD are overlapping with non-CF bone disease or unique from non-CF bone disease.

Discussion

Precision medicine for CF care has the potential to identify therapeutic targets, stratify risk for CF complications and ultimately facilitate the development of personalized therapeutic plans. To realize this potential, several research gaps must be addressed. To discover genetic modifiers of CF endocrinopathies, studies must match genetic data with accurate and thorough phenotyping of participants in longitudinal studies, e.g., national registries. Additional studies are needed to explore the role of methylation in CF endocrinopathies, to validate identified genetic modifiers through replication, and to elucidate the mechanism by which genetic modifiers impact endocrine complications of CF. These studies will require multicenter collaboration to achieve sufficient power, but studies of the CF population may benefit from lower heterogeneity in key clinical factors and environmental exposures (e.g. typical medication regimens for pwCF) and could require smaller cohorts than are typical for genetic studies in the general population.

Relating CF outcomes to genetics (both of CFTR and of genetic modifiers) has the potential to guide risk stratification (to identify those at greatest risk of CF complications).⁹⁶ For example, surveillance and early treatment for CFRD could be targeted to those most at risk (those with MF CFTR genotypes or with high load of CFRD genetic modifiers); studies of risk-based CFRD screening are under way. Genetics can also inform selection of treatments, both of CFTR modulators based on theratype and CFTR-agnostic treatments based on pharmacogenomics.⁹ Genetics, especially genetic modifiers, can also play a role in drug discovery, with the potential that new non-CFTR-based treatments might apply to all pwCF regardless of CFTR genotype. Drug discovery from CF modifiers is in its infancy, but multiple non-CF conditions have genetically informed treatments including hypercholesterolemia⁹⁷, osteoporosis⁷², and obesity.⁹⁸ Understanding of CF modifier loci and their mechanisms of action is needed to advance this aspect of CF therapeutics.

Conclusion

Genetic epidemiology studies have highlighted areas of distinct and overlapping pathophysiology for diabetes and nutritional status/obesity in CF so far, with studies of bone disease still yet to be done. CFRD genetic modifiers partially overlap with type 2 diabetes genetic risk factors and also highlight the importance of exocrine pancreatic pathophysiology and insulin secretion in CFRD pathogenesis. CFTR variants determining the severity of CFTR dysfunction are likely critically important for all CF endocrine complications with strong data for CFRD and growth so far. Genetics also has the potential for direct clinical application. Genetic risk scores may improve disease prediction and guide personalized screening. The pathophysiology revealed by genetic studies may contribute to developing treatments for CF endocrinopathies, whether through drug repurposing or identification of new drug targets. Future studies should examine the impact of genetics on endocrine manifestations as well as the role of epigenetic modifications on the development and progression of CF endocrinopathies.

Teaching Points.

• Endocrine complications of cystic fibrosis (CF) are influenced by genetic factors.

• Genetic modifiers of CF-related diabetes reveal the importance of abnormal beta cell function, insulin secretion, inflammation, and exocrine pancreatic function on developing CF-related diabetes.

• Growth and nutrition in CF are impacted not only by CF disease and CFTR genotype, but also by genetic modifiers.

• Osteoporosis is a heritable condition, and the genetic influences of CF-related bone disease should be examined further to reveal pathophysiology and targeted treatment options.

Clinical Relevance.

People with cystic fibrosis (CF) are at risk of diabetes, osteoporosis and altered growth. Genetic factors, including variants at the disease-causing CFTR gene, influence the risk of developing endocrine manifestations of CF. These genetic influences reveal unique and overlapping pathophysiology with non-CF endocrinopathies and may highlight potential therapeutic approaches.

Abbreviations:

BMI

body mass index

CF

cystic fibrosis

CFTR

cystic fibrosis transmembrane receptor

CFBD

cystic fibrosis-related bone disease

CFRD

cystic fibrosis-related diabetes

ETI

elexacaftor/tezacaftor/ivacaftor

GWAS

genome-wide association study

HEMT

highly effective modulator therapy

MF

minimal function

PI

pancreatic insufficiency

PS

pancreatic sufficiency

pwCF

people with cystic fibrosis

RF

residual function

SNP

single nucleotide polymorphism

T1D

type 1 diabetes

T2D

type 2 diabetes